Keywords: anti-TNFα inhibitor, crescentic GN, lupus or lupus-like nephritis, thrombotic microangiopathy
Abstract
Key Points
This renal biopsy study documents clinical renal dysfunction and pathologic lesions encountered in patients after anti-TNFα therapy and compares them with similar patients without treatment.
This study highlights the spectrum of autoimmune, serologic, and other kidney adverse effects of anti-TNFα therapy.
Unrelated active or chronic renal lesions including amyloidosis secondary to the underlying systemic inflammatory states may be observed.
Background
Anti-TNFα inhibitors, as biological agents, are used in autoimmune inflammatory states, rheumatoid arthritis (RA), psoriatic arthritis (PA), and Crohn disease. They can induce autoimmune serologic responses and clinical disorders, including systemic vasculitis and lupus-like diseases, affecting the kidney.
Methods
Retrospective analysis of clinicopathologic features of kidney disease after anti-TNFα therapy (treatment group) from our renal biopsy files from 2000 to 2018 is conducted and compared with 106 patients without therapy (control group).
Results
Forty-eight patients using anti-TNFα agents had renal biopsies: RA in 30, PA six, Crohn disease six, RA and PA one, RA and Crohn disease one, and others four. Twenty received etanercept, 15 adalimumab, eight infliximab, and five two forms of agents manifesting new-onset nephritic syndrome or CKD, 17 with AKI and 16 nephrotic syndrome, with recent ANCA and/or lupus serology. The renal lesions were crescentic GN in eight, pauci-immune–type in five, and ANCA+ in five. Lupus or lupus-like nephritis was seen in six: International Society of Nephrology/Renal Pathology Society 2018 class II—2, class V—2, class III+V—1, and class IV+V—1, and concurrent fibrillary GN, scleroderma/thrombotic microangiopathy (TMA), and amyloidosis in three. Renal lesions unrelated to anti-TNFα therapy or underlying autoimmune disease were noted in 23 patients (e.g., diabetic nephropathy, interstitial nephritis, acute tubular injury, infection-related GN); immunoglobulin A nephropathy, renal sarcoidosis, and amyloid A amyloidosis were noted in five patients. TMA was recognized in five patients, one associated with scleroderma and one anti-phospholipid antibodies, and two had nephrotic syndrome secondary to podocytopathy. The control group was similar with higher number of immune-mediated GN, interstitial nephritis, and amyloidosis.
Conclusion:
The renal lesions during anti-TNFα therapy have an autoimmune basis such as ANCA and lupus or lupus-like disease, correlated with new-onset serology, while others were similar to those observed in the control group. Renal biopsy findings integrated with clinical features and therapy can identify the underlying pathophysiologic process for appropriate management.
Introduction
Anti-TNFα inhibitors (anti-TNF) are used worldwide as biological therapy for chronic inflammatory diseases such as rheumatoid arthritis (RA), juvenile RA, psoriatic arthritis (PA), ankylosing spondylitis, and Crohn disease.1 The five agents currently used as anti-TNFα therapy are listed in Table 1. They are generally well tolerated with mild constitutional and unrelated adverse effects, but serious side effects such as infections and hematological disorders are rarely seen.2 In addition, anti-TNFα therapy is known to evoke autoimmune phenomena with serologic responses leading to several autoimmune disorders including systemic vasculitis and lupus-like disease.3 As an adverse effect, the use of anti-TNFα inhibitors often induce a range of autoantibodies, such as anti-nuclear antibody (ANA), anti-double strand DNA (dsDNA) antibody, anti-cardiolipin antibody, ANCA, and other nonspecific autoantibodies,4 which are mostly linked with cumulative dosage of the agents administered. The factors that may trigger an immunological response with the production of autoantibodies, initiating development of de novo systemic autoimmune disorders, are unclear. Renal involvement, such as lupus-like nephritis and pauci-immune–type necrotizing or crescentic GN (CrGN), was previously reported.5 In addition, the original autoimmune disease itself, especially RA, may be complicated by secondary systemic amyloidosis, immunoglobulin A (IgA)-dominant GN, membranous GN, rheumatoid factor-mediated various forms of mesangial and proliferative GN, often with immune complex deposits.6 However, resolving a differential diagnosis of concurrent autoimmune phenomena is sometimes difficult in a clinical setting, whether they are de novo biologics-induced autoimmune disease or coincidental host-autoimmune disease itself or an unrelated kidney disease. In this study, we have collected and discussed trends in the clinicopathologic findings of the identified kidney diseases (KDs) during or after anti-TNFα therapy and those without such therapy from a single institution.
Table 1.
Anti-TNFα agents currently used
| Agent Name | Product Name | Source | Mechanism of Action |
|---|---|---|---|
| Etanercept | Enbrel | Immunex, Seattle, WA | A soluble TNFα receptor |
| Infliximab | Remicade | Centocor Inc., Malvern, PA | A chimeric monoclonal IgG1 anti-TNFα antibody |
| Adalimumab | Humira | Abbott, Chicago, IL | A humanized monoclonal anti-TNFα antibody |
| Golimumab | Simponi | Janssen Biotech, Inc., Horsham, PA | A humanized monoclonal anti-TNFα antibody |
| Certrolizumab pegol | Cimzia | UCB, Brussels, Belgium | A humanized monoclonal anti-TNFα antibody PEGylated Fab' fragment |
IgG; immunoglobulin G.
Materials and Methods
Forty-nine patients treated with one or more anti-TNFα agents (Table 1) manifesting KD (treatment group) (Table 2) and 106 patients with similar autoimmune diseases treated with other therapeutic agents (nonsteroidal anti-inflammatory drugs [NSAIDs], steroids, methotrexate) (control group) (Table 3) were identified from our renal biopsy files from 2000 to 2018. Clinical, laboratory, and pathological findings available from retrospective chart review or those provided by the clinician for the treatment group are tabulated in several tables (Table 4, Supplemental Tables 1–4). The kidney biopsies were processed in the renal pathology laboratory at Weill Cornell Medicine, New York, using standard techniques for light microscopy, immunofluorescence, and electron microscopy. One of them from the treatment group was excluded due to insufficient biopsy material. A brief comparison is made with the data from the treated and control groups.
Table 2.
The spectrum of dominant kidney biopsy lesions in patients using anti-TNFα therapy
| Histological Diagnosis | No. of Patients | Cases in Table |
|---|---|---|
| Single diagnosis | ||
| CrGN (including ANCA-associated GN) | 6 | Supplemental Table 1, case 3–8 |
| Lupus or lupus-like nephritis ISN/RPS class III+V-1, class IV+V-1, class V-1 |
3 | Supplemental Table 2, case 2, 5, 6 |
| TMA | 3 | Supplemental Table 3, case 1, 3, 5 |
| IgA-dominant GN | 2 | Supplemental Table 4, case 17, 18 |
| Mesangial proliferative GN | 1 | Supplemental Table 4, case 24 |
| Minimal change nephrotic syndrome | 1 | Supplemental Table 4, case 25 |
| Focal segmental GN | 1 | Supplemental Table 4, case 26 |
| Postinfectious GN | 1 | Supplemental Table 4, case 28 |
| Renal amyloidosis, AA-type | 3 | Supplemental Table 4, case 11–13 |
| Diabetic KD | 4 | Supplemental Table 4, case 7–10 |
| Interstitial nephritis | 2 | Supplemental Table 4, case 19, 20 |
| Acute tubular injury alone | 2 | Supplemental Table 4, case 21, 22 |
| Neoplasm (atypical plasma cell infiltration) | 1 | Supplemental Table 4, case 29 |
| Renal sarcoidosis | 1 | Supplemental Table 4, case 23 |
| Compensatory glomerular hypertrophy due to solitary kidney | 1 | Supplemental Table 4, case 27 |
| No pathologic alterations and minimal glomerular change | 3 | Supplemental Table 4, case 14–16 |
| Vascular sclerosis alone | 6 | Supplemental Table 4, case 1–6 |
| Concurrent diagnoses | ||
| CrGN (ANCA-negative)+renal amyloidosis, AA-type | 1 | Supplemental Table 1, case 1 |
| CrGN (P-ANCA–positive)+rheumatoid factor–associated proliferative GN | 1 | Supplemental Table 1, case 2 |
| Lupus or lupus-like nephritis (class V)+fibrillary GN | 1 | Supplemental Table 2, case 1 |
| Lupus or lupus-like nephritis (class II)+TMA (secondary to scleroderma renal crisis) | 1 | Supplemental Table 2, case 3, Supplemental Table 3, case 4 |
| Lupus or lupus-like nephritis (class II)+interstitial nephritis | 1 | Supplemental Table 2, case 4 |
| TMA+interstitial nephritis | 1 | Supplemental Table 3, case 2 |
| Interstitial nephritis+diabetic glomerulosclerosis | 1 | Supplemental Table 4, case 30 |
| Total | 48 |
ISN/RPS, International Society of Nephrology/Renal Pathology Society; TMA, thrombotic microangiopathy; IgA, immunoglobulin A; AA, amyloid A; KD, kidney disease; CrGN; crescentic GN; P-ANCA, perinuclear ANCA.
Table 3.
Spectrum of dominant kidney biopsy lesions with renal dysfunction in patients with rheumatoid arthritis without anti-TNFα therapy (106 patients)
| Histological Diagnosis | No. of Patients |
|---|---|
| Pauci-immune CrGN (including ANCA-associated—6) Active—1, active and chronic—6, chronic—4 |
11 |
| Lupus or lupus-like GN ISN/RPS class III—4, class IV—2, class V—2 |
8 |
| Membranous GN (polyclonal IgG+C3) | 8 |
| Mesangial proliferative GN (with IgG immune complexes—5) | 10 |
| IgA nephropathy | 7 |
| Cryoglobulinemic GN | 1 |
| Fibrillary GN | 2 |
| Diffuse podocytopathy Minimal change disease—3, focal segmental glomerulosclerosis—3 |
6 |
| Amyloidosis, AA-type | 11 |
| Diabetic KD | 15 |
| Tubulointerstitial nephritis Active—6, active and chronic—4, chronic—1 |
11 |
| Acute tubular injury | 3 |
| Plasma cell-rich interstitial nephritis (Sjogren type) | 1 |
| Nonspecific tubulointerstitial scarring | 3 |
| TMA (one secondary to malignant hypertension) | 3 |
| Progressive arteriosclerosis (clinical hypertension) | 3 |
| Urate nephropathy | 1 |
| Myeloma cast nephropathy | 1 |
| Thin glomerular basement membrane disease | 1 |
| Total | 106 |
CrGN, crescentic GN; ISN/RPS, International Society of Nephrology/Renal Pathology Society; IgG, immunoglobulin G; IgA, immunoglobulin A; AA, amyloid A; KD, kidney disease; TMA, thrombotic microangiopathy.
Table 4.
Summary of clinicopathological findings of main kidney disease groups in patients using anti-TNFα therapy
| Kidney Disease | CrGN | Lupus or Lupus-Like Nephritis | TMA | Total |
|---|---|---|---|---|
| No. of cases | 8 | 6 | 5 | 48 |
| Anti-TNFα agent | Etanercept 3, infliximab 2, and adalimumab 3 | Etanercept 2, adalimumab 1, and two agents 3 | Etanercept 3, infliximab 1, and adalimumab 1 | Etanercept 21, infliximab 8, adalimumab 15, and two agents 4 |
| Average duration of therapy (mo) | 12.8 (3–24) | 30.8 (3–84) | 44.5 (1.5–120) | |
| Clinical information | ||||
| Average age (yr) | 57.6 (33–80) | 37.8 (22–50) | 45.6 (37–62) | 53.3 (22–84) |
| Sex (male, female) | All female | 2, 4 | All female | 15, 33 |
| Autoimmune disease | RA 7 and RA+Crohn 1 | RA 2, juvenile inflammatory arthritis 1, PA 1, MCTD 1, and RA+PA 1 | RA 4 and MCTD 1 | RA 30, PA 6, Crohn 6, and RA+Crohn 1 |
| Clinical Feature of KD | All nephritic syndrome | Nephrotic syndrome+renal failure 2, renal failure 3, and nephritic 1 | Nephritic 2 and renal failure/AKI 3 | |
| Average SCr at biopsy (mg/dl) | 3.5 (0.8–10.6) | 2.0 (0.8–3.7) | 3.4 (1.5–5.1) | |
| Serology | pANCA/MPO 3, cANCA/PR3 1, both ANCAs 1, ANA 4, and dsDNA 3 | ANA 6, dsDNA 4, anti-Scl70 1, and anti-RNP 1 | ANA 2, dsDNA 2, anti-Scl70 1, anti-RNP 1, and anti-phospholipid 1 | |
| Pathological diagnosis | All pauci-immune type CrGN, EUVAS class: Focal 2, Cres 2, Mixed 3, and undetermined 1 | ISN/RPS 2018 class: II 2, III+V 1, IV+V 1, and V 2 | Active and chronic TMA 1, diffuse chronic TMA 3, and focal TMA with AIN 1 |
CrGN, crescentic GN; TMA, thrombotic microangiopathy; RA, rheumatoid arthritis; PA, psoriatic arthritis; MCTD, mixed connective tissue disease; SCr, serum creatinine; pANCA, perinuclear antinuclear cytoplasm antibody; cANCA, cytoplasmic antinuclear cytoplasm antibody; MPO, myeloperoxidase; PR3, proteinase 3; ANA, antinuclear antibody; EUVAS, European Vasculitis Study Group; ISN/RPS, International Society of Nephrology/Renal Pathology Society; KD, kidney disease; dsDNA, double strand DNA; RNP, ribonuclear protein; AIN, acute interstitial nephritis.
Research Ethics
This study was approved by the Institutional Review Board of Weill Cornell Medicine, New York. Informed consent of patients was not required because the study was a retrospective review of clinical records and pathological results only. This study was conducted according to the Declaration of Helsinki. Records of patients were anonymized for personal information, so they could not be identified.
Results
Clinical Findings of the Treatment Group
Forty-eight patients using anti-TNFα inhibitors with renal biopsies were studied. The average patient’s age was 53.3±14.3 years (range 22–84 years), and the number of female patients was 27 (56.3%). The original autoimmune diseases being treated were RA in 30 patients (62.5%), PA six, Crohn disease six, RA and PA one, RA and Crohn disease one, and four others (RA and ankylosing spondylitis, juvenile inflammatory arthritis, mixed connective tissue disease [MCTD], sarcoidosis). Among them, 20 patients received etanercept, 15 adalimumab, eight infliximab, and five two forms of anti-TNF agents. The patients presented mostly with a nephritic syndrome or CKD, 17 patients (35.4%) with AKI or progressive renal failure, and 16 patients (33.3%) nephrotic syndrome.
KD Lesions in the Treatment Group
The main renal lesions on biopsy of the 48 patients are presented in Table 2. They are listed as immune-mediated, those secondary to chronic inflammatory processes, and other nonrelated kidney lesions. Six patients concurrently had two KD lesions. Among anti-TNFα therapy–related KDs, eight patients (16.7%) with CrGN, five of which are ANCA-associated GN, and six (12.5%) with lupus or lupus-like nephritis were included. In addition, five patients (10.4%) with thrombotic microangiopathy (TMA) were diagnosed by renal biopsy. Other immune-mediated diseases were IgA-dominant nephropathy, mesangial GN, renal sarcoidosis, and interstitial nephritis. Approximately half of the patients were unrelated to the underlying autoimmune disease or anti-TNF therapy.
Summary of Previously Reported Cases
Table 5 summarizes a review of existing literature of case series and anecdotal patients (16) in the past 15 years, citing renal lesions associated with anti-TNFα therapy. This disclosed 12 patients with CrGN (nine ANCA+, three ANCA–, six ANA+) in RA (10) and juvenile RA (2), who received etanercept (7), infliximab (3), and adalimumab (2). Four patients with proliferative lupus nephritis (one class III and three class IV lupus nephritis [LN]) in RA (2) and juvenile RA (2) were treated with etanercept (3) and adalimumab (1) showing positive serology for ANA and anti-dsDNA and low complement levels. Almost all had a good response to discontinuation of anti-TNF therapy and additional immunosuppression, except one reached end stage requiring dialysis and one died without renal failure. Concomitant other glomerular lesions (amyloid A [AA] amyloidosis, mesangial immunoglobulin G (IgG) GN, membranous GN, and IgA nephropathy) were found in four patients with CrGN. Extrarenal involvement in these patients included skin lesion in three patients, pulmonary lesion in two patients, and peripheral neuropathy in one patient.
Table 5.
Literature review of renal lesions in patients taking anti-TNFα therapy
| Author, year | Patients | Autoimmune Disease | Anti-TNF-α Inhibitor | Serology Positivity | Clinical Feature | Renal Histology | Extrarenal Lesion | Discontinuance of Anti-TNFα Inhibitor | Treatment | Prognosis |
|---|---|---|---|---|---|---|---|---|---|---|
| CrGN | ||||||||||
| Doulton et al.,15 2004 | 32 yo, female | RA | Etanercept | MPO-ANCA, ANA | Proteinuria, hematuria, and renal failure | CrGN, pauci-immune–type | No | Yes | mPSL pulse, POCY | Good response |
| Stokes et al.,5 2005 | 55 yo, male | RA | Etanercept | pANCA, ANA | Proteinuria, hematuria, and renal failure | CrGN, pauci-immune–type | Skin rash, mononeuritis, and pulmonary vasculitis | No | IVCY | Death without ESKD |
| Stokes et al.,5 2005 | 64 yo, female | RA | Infliximab | Negative tests | Proteinuria and hematuria | CrGN, pauci-immune type, mild AA amyloidosis | No | No | PSL, IVCY | Poor response without ESKD |
| Ashok et al.,16 2008 | 31 yo, male | RA | Infliximab | PR3-ANCA, ANA | Hematuria and acute renal failure | CrGN, pauci-immune–type | Skin rash | Yes | mPSL pulse, POCY, and Aza | Good response |
| Simms et al.,17 2008 | 62 yo, female | RA | Adalimumab | PR3-ANCA, ANA | Proteinuria, hematuria, and renal failure | CrGN, pauci-immune type | Cutaneous vasculitis | NA | mPSL pulse, PLEX, and POCY | Good response |
| Fournier et al.,18 2009 | 58 yo, female | RA | Adalimumab | MPO-ANCA, ANA | Proteinuria, hematuria, and renal failure | CrGN | No | NA | mPSL pulse, PLEX, IVCY, and Aza | ESKD |
| Mene et al.,19 2010 | 15 yo, female | Juvenile PA | Etanercept | Negative tests | Proteinuria, hematuria, and acute renal failure | CrGN, pauci-immune–type | No | Yes | mPSL pulse | Good response |
| Kaneko et al.,20 2010 | 36 yo, female | RA | Etanercept | MPO-ANCA, ANA | Proteinuria and hematuria | CrGN with focal mesangial IgG | Organizing pneumonia | Yes | PSL | Good response |
| Kaneko et al.,20 2010 | 64 yo, female | RA | Etanercept | Negative tests | Rapidly progressive GN | CrGN with MGN (IgG, IgM, C3, and C1q deposits) | No | Yes | mPSL pulse | Good response |
| Hirohama et al.,21 2010 | 33 yo, female | RA | Infliximab | MPO-ANCA | Proteinuria and hematuria | CrGN, pauci-immune–type | No | Yes | mPSL pulse | Good response |
| Reitblat and Reitblat,22 2013 | 58 yo, male | Juvenile RA | Etanercept | cANCA | Acute renal failure | CrGN | No | Yes | PSL | ESKD |
| Alkhunaizi and Dawamneh,23 2017 | 30 yo, female | RA | Etanercept | MPO-ANCA | Nephrotic range proteinuria, hematuria, and acute renal failure | CrGN with mesangial IgA, and C3 deposits | No | Yes | PSL and POCY | Good response |
| Lupus-like nephritis | ||||||||||
| Mor et al.,24 2005 | 22 yo, female | Juvenile RA | Etanercept | ANA, anti-dsDNA, anti-SSA, anti-Sm, anti-histone, and hypocomplements | Proteinuria and hematuria | Diffuse proliferative lupus nephritis, WHO class IV | Cutaneous vasculitis | Yes | mPSL pulse | Good response |
| Stokes et al.,5 2005 | 30 yo, female | Juvenile RA | Etanercept | ANA, anti-dsDNA, anti-CL, and hypocomplements | Nephrotic range proteinuria, and progressive renal failure | Diffuse proliferative lupus nephritis, ISN/RPS 2003 class IV | No | Yes | PSL and MMF | Good response |
| Stokes et al.,5 2005 | 52 yo, female | RA | Adalimumab | ANA, anti-dsDNA, and hypocomplements | Nephrotic range proteinuria, hematuria, and acute renal failure | Focal proliferative lupus nephritis, ISN/RPS 2003 class III | No | Yes | mPSL pulse | Good response |
| Piccolo et al.,25 2008 | 44 yo, female | RA | Etanercept | ANA, anti-dsDNA, pANCA, and hypocomplements | Proteinuria and hematuria | Diffuse proliferative lupus nephritis, ISN/RPS 2003 class IV | No | Yes | PSL, IVCY, MMF, PLEX, HD, and Aza | Good response |
RA, rheumatoid arthritis, PA, psoriatic arthritis, MPO, myeloperoxidase; PR3, proteinase 3; ANA; anti-nuclear antibody, CrGN, crescentic GN; AA, amyloid A; NA, not available; mPSL, methylprednisolone; POCY, per os cyclophosphamide; IVCY, intravenous cyclophosphamide; cANCA, cytoplasmic antinuclear cytoplasm antibody; PSL, prednisolone; IgG, immunoglobulin G; IgM, immunoglobulin M; Aza, azathioprine; ISN/RPS, International Society of Nephrology/Renal Pathology Society; MMF, mycophenolate mofetil; PLEX, plasmapheresis; HD, hemodialysis; dsDNA, double strand DNA; CL, cardiolipin; pANCA, perinuclear antinuclear cytoplasm antibody.
Control (Untreated) Group
Clinical Findings of the Control Group
Most of these patients had a clinically dominant autoimmune disease, RA or a forme fruste of RA, a proportion of which were in the setting of MCTD and a few with ulcerative colitis and ankylosing spondylitis. The duration of the autoimmune disease ranged from 1 to 20 years in nearly 70% (history obtained in 78/106) of patients. The age at renal biopsy ranged from 10 to 89 years among 106 patients, with a male-to-female ratio of 1:2. In addition, 70% of 106 patients presented between 50 and 80 years with renal dysfunction (hematuria, proteinuria and/or elevated creatinine), 20% between 10 and 50 years, and the rest were older than 80 years. While <1/3 of them presented with hematuria and 25% had normal renal function, a wide range of proteinuric states (0 to >4 g/24 h) and varying levels of elevated creatinine (1 to >4 mg/dl) were observed, mostly reflecting the appropriate renal pathology findings of glomerular, tubulointerstitial, vascular, or other lesions.
KD in the Control Group
The main renal lesions in this group (Table 3) comprise glomerular, tubulointerstitial, and vascular lesions (potentially related to the underlying autoimmune diseases or those secondary to therapy), along with other unrelated/nonspecific lesions. Eight patients had concurrently two KD lesions. Within this group, we identified 11 patients (10.3%) with pauci-immune CrGN, six ANCA+, eight (7.4%) lupus or lupus-like nephritis, three TMA (one with malignant range hypertension), ten membranous GN, ten mesangial proliferative GN (five with polyclonal IgG immune complex deposits), seven IgA-dominant nephropathy, one cryoglobulinemic GN, and two fibrillary GN. In addition, podocytopathy in six patients (three minimal change disease, three focal segmental glomerulosclerosis), AA amyloidosis in 11 patients, interstitial nephritis (active and/or chronic) in 11 patients, acute tubular injury in three patients, and plasma cell-rich interstitial nephritis in one patient were also noted. The rest showed unrelated KDs to the autoimmune disease.
Brief Comparison of Kidney Biopsy Lesions From Patients with and without Anti-TNFα Therapy (Treatment and Control Group)
The demographic findings such as age range, male-to-female ratio, and duration of the original autoimmune disease appear similar, as well as the rate of the various clinical renal presentations, except 25% of the control group with normal renal function. The occurrence of pauci-immune CrGN was 16.6% (5/8 ANCA+) in the treatment group compared with 10.3% (6/11 ANCA+) in the control group while lupus or lupus-like GN with positive serologic evidence was 12.5% (LN class III, IV, V) versus 7.4% (LN class III, IV, V) in the treatment and control group, respectively, both lesions being higher in the treatment group. Patients with recent or chronic endothelial injury or evidence of active TMA are observed in both categories (5/48 in the anti-TNF treatment group and 3/106 in the control group) showing different potential underlying etio-pathogenetic mechanisms such as scleroderma renal crises, anti-phospholipid antibodies, and positive lupus serologies. However, a significantly higher number of autoimmune-mediated glomerular lesions (with or without immune deposits), AA (secondary) type of amyloidosis, and tubulointerstitial nephritis are observed in the control group, which comprise nearly 75% of the 106 patients, reflecting the underlying diseases.
Clinicopathological Analysis of the Main KD Lesions in the Treated Group
First Group
CrGN was seen in eight patients (Table 4 and Supplemental Table 1, representative histology in Figure 1, A and B). The average patient age was 57.6±16.9 years (range 33–80 years). All patients were female, and CrGN occurred in seven patients with RA and one with RA and Crohn disease. Among these, three patients received etanercept, three adalimumab, and two infliximab. The average duration of treatment was 12.8 months (range 3–24 months). Most patients clinically manifested nephritic syndrome, six had AKI or progressive renal failure, and one had nephrotic syndrome. The average serum creatinine level was 3.5±3.0 mg/dl (range 0.8–10.6 mg/dl). While three patients had positive myeloperoxidase-ANCA (MPO-ANCA)/perinuclear ANCA, one patient with positive proteinase 3 ANCA (PR3-ANCA)/cytoplasmic ANCA, and one patient with both forms of ANCAs positive, three patients had both ANCAs negative. A combination of ANA and anti-dsDNA antibody with ANCA-positive serology was recognized in four patients. Five patients were given concomitant immunosuppressive agents including prednisolone, methotrexate, and cyclophosphamide. Six patients presented with hypertension, and three patients had extrarenal vasculitic lesions. By renal histology, five patients were pauci-immune–type. Glomerular lesions were categorized based on the European Vasculitis Study Group–proposed classification7: two Focal class, two Crescentic class, and three Mixed class and one undetermined because of insufficient glomeruli. All samples showed varying degrees of interstitial inflammation, five of which were active with no evidence of renal arteritis or arteriolitis. One also showed concurrent renal amyloidosis, AA-type, and another with rheumatoid factor serology and mild mesangial proliferative GN (mesangial immunoglobulin M and C3-positive). To present a typical clinical course after renal biopsy as in case 6, adalimumab was discontinued and pulse steroids and rituximab were started. At 6 months, blood pressure had normalized and the double-stranded DNA was negative, with ANA still at 1:160. The PR3-ANCA was negative, and the MPO-ANCA dropped from 38 to 28. Rheumatoid factor remained positive. The creatinine level had decreased from 2.4 to 1.48 mg/dl. The patient was last seen in clinic 3 years after the initial presentation with a creatinine level of 1.24 mg/dl. The urinalysis was bland, and ANA, dsDNA, and ANCAs were all negative.
Figure 1.
Histological findings of anti-TNFα therapy or autoimmune disease-related lesions. CrGN: Segmental cellular crescent (A) and circumferential fibrocellular crescent (B) were seen. PAS stain, magnification ×400. Lupus or lupus-like nephritis: Global thickening of peripheral capillary walls and mesangial proliferation are found (C). PAS stain, magnification ×400. Immunofluorescence showed anti-C1q positivity in periphery and mesangium (D). On electron microscopy, subendothelial, intramembranous, and mesangial electron dense deposits were frequently found (E). Magnification ×5000. TMA: Diffuse glomerular collapse with widening of capillary walls and tubulointerstitial damage on the basis of vascular lesions were noted (F). PAS stain, ×100. Electron microscopy showed subendothelial widening with endothelial degeneration and mesangial interposition (G). Magnification ×2000. PAS, periodic acid–Schiff.
Second Group
Lupus or lupus-like nephritis was diagnosed in six patients (Table 4 and Supplemental Table 2, representative histology Figure 1, C–E). The average age was 37.8±9.1 years (range 22–50 years), and four were female. Two patients had RA, one PA, and one RA and PA. Among them, two patients received etanercept, one adalimumab, two adalimumab and etanercept, and one adalimumab and infliximab. The average duration of treatment was 30.8 months (range 3–84 months). Two patients presented with CKD, two had AKI or progressive renal failure, and two had nephrotic syndrome. The average serum creatinine level was 2.0±1.0 mg/dl (range 0.8–3.7 mg/dl), lower than that of patients with CrGN. All patients showed positivity for ANA and/or anti-DNA antibody and none with ANCA, and three patients had a low serum complement level. Biopsy findings based on the International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2018 classification8 showed two class II, two class V, one class III+V, and one class IV+V. All samples displayed IgG, immunoglobulin M, C3, and C1q-positive immune deposits, and four revealed a “full-house” pattern by immunofluorescence staining. On electron microscopy, immune deposits were found in various glomerular locations in all samples, with focal fingerprint-like substructure in one and endothelial tubuloreticular inclusions in three. Three concurrent kidney diseases were also noted, including fibrillary GN, scleroderma renal crisis, and interstitial nephritis.
Third Group
Active or chronic TMA was noted in five patients (Table 4 and Supplemental Table 3, representative histology Figure 1, F and G). The average patient age was 45.6±11.3 years (range 37–62 years), all being female. Four patients with RA and one patient with MCTD treated with anti-TNFα were included. Among them, three patients received etanercept, one adalimumab, and one infliximab. All patients presented with renal failure including three patients with AKI or progressive renal failure, and none had nephrotic syndrome. The average serum creatinine level was 3.4±1.8 mg/dl (range 1.5–5.1 mg/dl). On serologic workup, two patients with anti-dsDNA antibody positivity, one patient with anti-phospholipid antibody, and one patient with both anti-Scl70 and anti-ribonuclear protein antibodies were noted. None had ANCA-positive serology. Nearly all patients had hypertension and anemia, three had thrombocytopenia, and one had schistocytes on peripheral smear. On biopsy, three patients had mostly chronic change, one active and chronic disease, and one focal TMA. Two patients revealed intraglomerular thrombi. All patients showed acute tubular injury, varied interstitial inflammation, and endothelial injury in arterioles or small-sized arteries. One patient seemed to be secondary to scleroderma renal crisis. Two concurrent kidney diseases were interstitial nephritis and mesangial lupus nephritis, ISN/RPS 2018 class II. To present a characteristic clinical course after biopsy, as case 5, etanercept was discontinued and the complement inhibitor, eculizumab, was administered with a good response. The renal dysfunction and hematological findings normalized.
In addition, other immune-mediated KD lesions or as a consequence of a long-standing inflammatory state showed typical histological features in five patients (Table 2, Supplemental Table 4). Of them, three RA patients had AA-type renal amyloidosis (Figure 2, A and B), and two patients (one PA and one Crohn disease) had IgA-dominant GN (Figure 2, C and D). Two patients with nephrotic syndrome secondary to a podocytopathy were present in the treatment group, one RA patient taking etanercept had minimal change disease and the other PA patient taking adalimumab had focal segmental glomerulosclerosis of not otherwise specified type (Figure 2, E–G). All other unrelated KDs were in greater proportion in the treatment group (Table 2, Supplemental Table 4). Moreover, diabetic KD and/or hypertension-associated vascular sclerosis were identified in four and six patients, respectively.
Figure 2.
Histological finding of autoimmune disease-related lesions. Renal AA amyloidosis: Anti-AA stain was positive in global mesangium (A). Magnification ×400. On electron microscopy, amyloid fibrils were abundantly seen (B). Magnification ×25,000. IgA-related GN: Segmental and mild mesangial widening was found, and segmental sclerosis with small extraglomerular lesion was also seen (C). PAS stain, magnification ×400. Immunofluorescence of anti-IgA was positive in mainly mesangium (D). Magnification ×400. Diabetic nephropathy: Global mesangial widening and vascular pole hyalinosis were apparent (E). PAS stain, magnification ×400. Active interstitial nephritis: Monocytic inflammatory cells infiltrated in diffuse interstitial tissue (F). HE stain, magnification ×100. Tubulitis were marked with severe interstitial infiltration (G). HE stain, magnification ×400. PAS, periodic acid–Schiff.
Discussion
This is a clinicopathologic study of 48 patients with RA and other related autoimmune diseases found to have clinical KDs after anti-TNFα therapy. Nearly one half of these patients included several forms of glomerular lesions such as ANCA+ or − CrGN, lupus-like and lupus nephritis, occasional cases of IgA nephropathy or mesangial GN, podocytopathies, and amyloidosis. The rest showed findings secondary to a chronic inflammatory state or other nonspecific/unrelated KD category. In addition, TMA was also a notable cause of KD in these patients. A review of existing literature with anecdotal case reports of 16 patients has shown mainly pauci-immune CrGN and lupus nephritis, most of whom had a good response to discontinuation of anti-TNF therapy and additional immunosuppressive treatment. The renal lesions in the treatment group were compared with a larger, control group of 106 patients from the same period, with similar autoimmune diseases, but without treatment using any biologic agents.
Anti-TNF therapy has emerged as a proven effective therapy for chronic immune-mediated inflammatory states and rheumatic diseases. Five anti-TNFα inhibitors were approved for use by the US Food and Drug Administration for RA therapy in these patients.9,10 This rapid and widely developing usage of anti-TNFα inhibitors for more than 20 years displayed a broad spectrum of systemic adverse effects, including infectious complications and cardiovascular and cancer risks. Anti-TNFα therapy–induced autoimmune phenomena range in severity from mere asymptomatic autoimmune serological abnormalities to severe symptomatic systemic autoimmune diseases, involving one or more organs. Several clinical trials and studies using anti-TNF therapy have highlighted a significant frequency of autoantibody formation and/or corresponding clinical manifestations of lupus erythematosus in some patients.11 As an example, in a 1-year clinical trial for infliximab plus methotrexate comparing methotrexate alone in 428 RA patients, positive ANA developed in 53%–68% of the infliximab group and only 26% of the patients control group and anti-dsDNA in 7%–10% of the infliximab group but in none of the control group.12 Of these, only one patient on infliximab developed a cutaneous rash. New-onset autoimmune phenomena and serologic responses induced by biological agents including anti-TNF were reported in over 1500 patients in 2013.3 These biologic agent-linked autoimmune diseases include both systemic processes such as lupus, vasculitis, sarcoidosis, anti-phospholipid syndrome, and organ-specific processes such as interstitial lung disease, uveitis, optic neuritis, peripheral neuropathies, multiple sclerosis, psoriasis, and inflammatory bowel syndrome.
Anti-TNF therapy–associated small vessel vasculitis (SVV) involving the kidney showing necrotizing and Cr GN has been well documented. Ramos-Casals et al. reviewed 132 patients with anti-TNF–associated vasculitis in previously reported literature until 2008.13 Although clinical manifestations were varied and multisystemic, ANCA serology was positive in 13 of 22 patients tested (59%); cutaneous vasculitis was most common in 96 patients (72.7%), followed by 18 patients with peripheral neuropathy and 17 patients with glomerular lesions. Of these, 7 of 17 patients had pauci-immune–type CrGN, two IgA-related GN, and seven membranous GN. Sokumbi et al. reported eight patients with anti-TNFα therapy–associated vasculitis from a single US center14 with predominant cutaneous involvement in five patients (63%) and one patient with IgA vasculitis by renal biopsy. The previously reported literature of biopsy-proven CrGN (Table 5)5,15-23 and analyzed in the results section, glomerular immune deposits were observed in three. These latter findings could represent primary autoimmune disease, but may not be readily distinguishable with new-onset lesions. In most cases, anti-TNFα therapy was discontinued and immunosuppressive treatment was instituted in all patients with a good response to treatment. The clinicopathological characteristics of eight patients in this study including five of the pauci-immune type of CrGN and five with serum ANCA positivity were similar to previously reported cases, thus representing the most common type of renal adverse effect with anti-TNF therapy. However, SVV may also occur in RA patients in the form of CrGN (ANCA+ and ANCA−) as seen in 10.37% of the control group.
Anti-TNF–induced lupus-like illness is often clinically manifested but may show renal involvement of immune complex-mediated GN as lupus or lupus-like nephritis.3 While lupus-like mucocutaneous features are common namely malar rash, oral ulcers, discoid lupus and photosensitivity, visceral involvement such as the kidney and central nervous system is relatively rare, <10% of patients.3 In our summary of previous reports of biopsy-proven lupus and lupus-like nephritis in Table 4,5,24,25 the renal pathological diagnosis was ISN/RPS lupus nephritis class IV in three patients and class III in one. Extrarenal involvement was infrequent, but there was cutaneous vasculitis in one class IV patient. In all patients, anti-TNF therapy was discontinued with additional immunosuppression with good response. The spectrum of our present treated patients (6) was varied, including mesangial (2) and membranous lupus nephritis (2) (class II and class V) as well as one class III+V and one class IV+V, while the RA patients in the control group manifested class III (4), class IV (2), and class V (2) with appropriate serology, accounting for 12.5% and 7.5% of the patients studied, respectively.
Some kidney lesions can develop secondary to the underlying autoimmune disease or chronic inflammatory states (RA, PA, and ankylosing spondylitis), such as AA amyloidosis and mesangial or endocapillary proliferative GN and IgA-GN, some of which may be found with a more recent/active CrGN in anti-TNF–treated patients. A higher number of secondary AA amyloidosis to chronic inflammation, mesangial proliferative GN, IgA-dominant deposits, or other forms of GN are observed in those without anti-TNFα therapy (6). Patients with a known autoimmune disease such as RA are also at risk of developing other autoimmune KDs, such as lupus-like nephritis or ANCA-associated CrGN, even in the absence of a drug-induced trigger, as demonstrated in our control group (Table 3).
Furthermore, we observed five patients with TMA in this treatment group (two possibly associated with scleroderma and anti-phospholipid antibodies) and three patients in the control group. Thrombotic events related to anti-TNFα therapy are known,3 but no previous reports directly linking anti-TNFα therapy and TMA are found. Two patients with podocytopathy were in the treatment group and six patients in the control group. Autoimmune state (6) or drug-induced podocytopathy has been documented after usage of interferon, pamidronate, lithium, NSAIDs, sirolimus, and androgenic anabolic steroids.26 However, we found only one previously reported patient with RA while on treatment with etanercept showing minimal change disease with proteinuria.27 Although the exact pathogenesis is unknown, correlation with the clinical context and future observations could elicit more insight into this association.
The limitations of this study include its small sample size and it being on the basis of retrospective analysis of patients. Next, significant follow-up clinical data could not be obtained because of the 18-year duration and multiple sources of data collection. Short- and long-term follow-up may reveal greater differences in the prognostic significance of the renal lesions, both in the treatment and control groups. Follow-up data and management from the previously reported anecdotal patients with CrGN and lupus-like nephritis may supplement our findings.
In conclusion, certain autoimmune disease-mediated renal lesions may be similar in patients with RA and related entities, both in those treated or untreated with anti-TNFα agents. Sometimes, an etiological categorization of the immune-mediated kidney disease directly linking anti-TNFα therapy may not be entirely possible on the basis of the morphological pattern alone or the pathogenetic mechanisms. However, the temporal nature of the development of autoimmune phenomena, active serologies, and subsequent related renal lesions after a variable duration of anti-TNFα therapy in a proportion of our treatment group (Table 2) and in those anecdotally reported patients (Table 4) can support such an association. Renal biopsy examination may aid in resolving the pathologic and pathogenetic processes in selected patients for discontinuation of therapy and appropriate management in these patients.
Supplementary Material
Acknowledgments
The authors thank the following nephrologists: Drs. Nazifa Banu, Alvin Bell, Nathaniel Berman, Miriam H Chung, Sanford Cooper, Marilyn Galler, Frank Liu, Alicia R Notkin, and James M Chevalier for providing the clinical information.
This study was presented as part of the American Society of Nephrology Kidney Week, November 5–10, 2019, Washington, DC.
Disclosures
S.P. Salvatore reports the following: Ownership Interest: AAPL, CCNE, COIN, DIS, DKNG, Fundrise, IBM, KD, LCID, MJ, RIVN, and VZ. K. Yamagata reports the following: Consultancy: Boehringer Ingelheim and Medtronic Co. Ltd; Research Funding: Kyowa-Kirin and Tanabe-Mitsubishi; and Honoraria: Asteras, AstraZeneca, Kyowa-Kirin, Mochida, Otsuka, and Tanabe-Mitsubushi. The remaining authors have nothing to disclose.
Funding
Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Numbers JP17K09684, JP19KK0216, JP21H02822 (J.U.) were used for J. Usui's research activities to work at the Department of Pathology, Weill Cornell Medicine, Cornell University, New York, NY.
Author Contributions
Conceptualization: Surya V. Seshan, Joichi Usui.
Data curation: Steven P. Salvatore, Surya V. Seshan, Joichi Usui, Kunihiro Yamagata.
Formal analysis: Surya V. Seshan, Joichi Usui, Kunihiro Yamagata.
Funding acquisition: Joichi Usui.
Investigation: Surya V. Seshan, Joichi Usui.
Methodology: Surya V. Seshan, Joichi Usui.
Resources: Surya V. Seshan.
Supervision: Surya V. Seshan.
Writing – original draft: Surya V. Seshan, Joichi Usui.
Writing – review & editing: Steven P. Salvatore, Surya V. Seshan, Joichi Usui, Kunihiro Yamagata.
Data Sharing Statement
All of the data are included in the manuscript and supplemental material.
Supplemental Material
This article contains the following supplemental material online at http://links.lww.com/KN9/A310.
Supplemental Table 1. Clinicopathological findings of eight patients with pauci-immune–type crescentic glomerulonephritis in the treatment group.
Supplemental Table 2. Clinicopathological findings of six patients with lupus or lupus-like nephritis in the treatment group.
Supplemental Table 3. Clinicopathological findings of five patients with thrombotic microangiopathy in the treatment group.
Supplemental Table 4. Clinicopathological findings of 30 patients excluding pauci-immune–type crescentic glomerulonephritis, lupus or lupus-like nephritis, and thrombotic microangiopathy in the treatment group.
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