Autoimmunity Reviews 13 (2014) 873–879
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Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev
Review
Biologics-induced autoimmune renal disorders in chronic inflammatory rheumatic diseases: Systematic literature review and analysis of a monocentric cohort Matteo Piga ⁎, Elisabetta Chessa, Valentina Ibba, Valentina Mura, Alberto Floris, Alberto Cauli, Alessandro Mathieu Rheumatology and Rheumatology Unit, University and AOU of Cagliari, Cagliari, Italy
a r t i c l e
i n f o
Article history: Received 15 April 2014 Accepted 2 May 2014 Available online 16 May 2014 Keywords: Rheumatic diseases Biologic drugs Drug-induced glomerulonephritis Lupus nephritis Systemic vasculitis Anti-TNF-alpha
a b s t r a c t 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. © 2014 Elsevier B.V. All rights reserved.
Contents 1. 2.
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Introduction . . . . . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Systematic review . . . . . . . . . . . . . . . . . . 2.2. Longitudinal cohort analysis . . . . . . . . . . . . . 2.3. Case classification . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Literature search . . . . . . . . . . . . . . . . . . 3.2. Cohort study . . . . . . . . . . . . . . . . . . . . 3.3. Pooled cases from systematic review and cohort analysis 3.3.1. Demographic features . . . . . . . . . . . . 3.3.2. Clinical, serologic and histopathological features 3.3.3. Treatment and outcomes . . . . . . . . . . 3.3.4. Causality assessment . . . . . . . . . . . .
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⁎ Corresponding author at: Rheumatology Unit, University Clinic AOU of Cagliari, SS 554-09 042 Monserrato, Cagliari, Italy. Tel.: +39 070 5109 6381; fax: +39 070 5109 6382/513157. E-mail address: [email protected] (M. Piga).
http://dx.doi.org/10.1016/j.autrev.2014.05.005 1568-9972/© 2014 Elsevier B.V. All rights reserved.
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4. Discussion . . Take-home message Acknowledgment . References . . . .
M. Piga et al. / Autoimmunity Reviews 13 (2014) 873–879
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1. 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 CD20positive 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 [5–7]. 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.
2. Methods 2.1. 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, Ankylosing”[Mesh]) OR (“Arthritis, Psoriatic”[Mesh]) AND (“Interleukin 1 Receptor Antagonist Protein”[Mesh]) OR (“infliximab” [Supplementary Concept]) OR (“TNFR-Fc fusion protein” [Supplementary Concept]) OR (“adalimumab” [Supplementary Concept]) OR (“golimumab” [Supplementary Concept]) OR (“certolizumab pegol” [Supplementary Concept]) OR (“rituximab” [Supplementary Concept]) OR (“tocilizumab” [Supplementary Concept]) OR (“abatacept” [Supplementary Concept]) AND (“Glomerulonephritis”[Mesh]) OR (“Nephrotic Syndrome”[Mesh]) OR (“Nephrosis, Lipoid”[Mesh]). Additional papers were obtained by checking the references from the selected studies as well as from review articles and other sources
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878 878 879 879
known to the authors. All type of studies were allowed, but only full publications reporting on adult patients and written in English were included in the literature search. Once investigators have independently selected the articles, initially on the basis of titles and abstracts then if necessary on the full texts, eligibility assessment was performed independently in a blinded standardized manner. Disagreements between reviewers were solved by consensus. Whenever papers reported duplicate data, the most recent article was selected. To be included in the review, the retrieved papers had to provide the descriptive features of each reported case of biologics-induced AIRD. In particular, demographic, clinical, histopathologic (if performed), treatment and outcome data must be provided. In an attempt to clarify if AIRD are specific adverse reactions for biologic drugs, the WHO-UMC system for standardized case causality assessment (http://who-umc.org/Graphics/24734.pdf) was applied and the reported adverse drug reactions were classified in a six categories scale ranging from “certain” to “unassessable/unclassifiable”. Case reports classified in the last two categories of the scale, “conditional/unclassified” and “unassessable/unclassifiable”, were excluded from the analysis of results. Causality assessment was performed independently in a blinded standardized manner by the two reviewers. Disagreements between reviewers were solved by consensus. When retrieved studies did not report the characteristics required for case classification we tried to contact the authors asking them to notify us the lacking features. 2.2. Longitudinal cohort analysis The retrospective analysis of a prospectively followed-up population of adult with chronic IRD was performed. Data was retrieved using the database dedicated to patients treated with biological drugs at the Centre of Rheumatology of the University Hospital of Cagliari, Italy. For the purposes of the study, cases under investigation were defined as adult patients suffering from chronic IRD that had developed renal abnormalities following treatment with biotechnological drugs. The aim was to identify those patients that developed AIRD secondary to biologics treatment. Renal abnormalities were defined as: a) increased levels of blood urea nitrogen and serum creatinine; b) reduction of glomerular filtration rate; c) alterations of renal sediment (erythrocytes, leukocytes, casts); d) the appearance/worsening of proteinuria. To be included in the study a patient should have had blood tests and urine analysis at least three times per year and must have been followed-up for at least 12 months. Cases in which renal changes were explained by diseases (e.g. IRD by itself, infectious disease, diabetes, hypertension) or other drugs (e.g. gold salts, vaccination) were excluded. The diagnosis of AIRD was defined and reassessed according to kidney biopsy and clinical judgment. The WHO-UMC system for standardized case causality assessment was retrospectively applied to the identified cases. This study was performed according to the principles of Good Clinical Practice and the Declaration of Helsinki. 2.3. Case classification According to clinical manifestations and kidney histology the identified cases were classified as: a) glomerulonephritis associated with systemic vasculitis (GNSV), b) glomerulonephritis in lupus-like syndrome (GNLS), c) isolated autoimmune renal disorders (IARD). Clinical outcomes were defined as i) complete resolution (i.e. inactive urinary
M. Piga et al. / Autoimmunity Reviews 13 (2014) 873–879
sediment, absent proteinuria and normal or stable renal function), ii) partial resolution (i.e. significant improvement of proteinuria, urinary sediment and renal function but they did not return to normal values) and iii) worsening of clinical conditions (i.e. worsening of proteinuria and/or urinary sediment, deterioration of renal function even until end stage renal disease or death). Results from systematic review and cohort analysis have been pooled and will be presented together.
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RA during follow-up was: Adalimumab (ADA) 46.5%, Etanercept (ETN) 35.8%, Tocilizumab (TCZ) 7.9%, Abatacept (ABA) 4.4%, Rituximab (RTX) 3.8%, Golimumab (GOL) b 1.0%, Infliximab (IFX) b1.0%, Certolizumab (CTZ) b1.0%. Among AS patients (56 F, 112 M; follow-up 4.8 ± 2.4 years; 722.7 patient-years) the 48.1% were on ADA, 36.1% on ETN, 15.0% on IFX and b 1.0% on GOL. During a mean follow-up of 5.4 ± 2.3 years (488.3 patient-years) patients with PsA (48 F, 64 M) received: ETN 59.3%, ADA 37.2% and IFX 3.5%.
3. Results 3.3. Pooled cases from systematic review and cohort analysis 3.1. 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 AIRD, leading to a “unclassified” or “unclassifiable” evaluation according to the WHO-UMC criteria 3.2. Cohort study Three out of 707 adult patients with IRD identified through the monocentric retrospective analysis was classified as suffering with biologics induced AIRD (Table 1). The cohort study included 427 Rheumatoid Arthritis (RA), 168 Ankylosing Spondylitis (AS) and 112 Psoriatic Arthritis (PsA), treated with biologics between January 2004 and January 2014. All patients were treated with biologics because of inadequate response to first line drugs and after screening for detection of latent chronic infectious diseases (i.e. tuberculosis) and exclusion of connective tissue diseases (i.e. SLE) according to local and international guidelines. Patients affected with RA, 326 Female (F) and 111 Male (M), showed a mean follow-up on biologics treatment of 5.6 ± 6.2 years for a total of 2116.8 patient-years. The distribution of biologic drugs in patients with
3.3.1. Demographic features 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 ETN (15 cases, 51.7%) followed by ADA (9 cases, 31.0%) and IFX (3 cases, 10.3%) while TCZ and ABA were reported in 1 case (3.4%) for each. AIRD usually appeared within 18 months since the beginning of treatment, but in 8 cases (27.5%) it was diagnosed later. Thirteen out of 29 cases were classified as affected by IARD (Table 1) [10–18], 12 with GNSV (Table 2) [10,13,19–28] and 4 with GNLS (Table 3) [13,29,30]. Patients reported as developing GNLS showed younger age at onset (mean age 37.0 years; range 22–52) than patients with GNSV (mean age 49.7 years; range 28–69) and IARD (mean age 55.0 years; range 29–64). No major differences were identified on disease duration at the time of AIRD development between GNLS (mean 15.0 years; range 7–23) and GNSV (mean 13.4 years; range 1–30) while patients with IARD showed longer disease duration (mean 17.9 years; range 5–30). 3.3.2. Clinical, serologic and histopathological features Clinical presentation was represented by cutaneous lesions, mostly purpura, or other organ manifestations in patients with GNSV (66.6% and 41.6% respectively) and GNLS (50% and 75% respectively), while patients with IARD mainly presented with lower limbs edema (38.5%) and no or few systemic involvement. Impaired renal function with increased serum creatinine was more frequent in GNSV (83.3%) and GNLS (75%) than in IARD (37.5%). Urinary sediment changes were reported in
Fig. 1. Flow diagram illustrating the results of the literature search.
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Table 1 Demographic and clinical features of biologics-induced isolated autoimmune renal disorders. Age/sex
IRD (duration)
Drug
Latency
Associated features
Renal abnormalities
Kidney biopsy
Treatment
Outcome
WHO-UMC assessment
[10]
64/F
RA (20 years)
ETN
18 months
Bucillamine induced MN.
NCGN
Possible
60/F
AS (40 years)
ETN
2 months
Anasarca
Complete resolution
Certain
[12] [13]
61/F 53/F
RA (12 years) RA, sSS (30 years)
ADA ETN
48 months 6 months
Complete resolution Partial resolution
Possible Probable
[13]
64/F
RA (30 years)
IFX
10 months
RF Peripheral neuropathy, lower limbs edema. RF, ANA 1:160, anti-SSA anti-SSB RF, type II diabetes mellitus
Worsened
Possible
[14]
64/M
RA (21 years)
ADA
12 months
Gold's salt nephropathy. RF
Complete resolution
Certain
[15]
37/M
AS (16 years)
IFX
36 months
ANA 1:80
ETN withdrawal. Iv MPRE, PRE. ETN withdrawal. Switch to ADA. Iv MPRE, PRE. ETN withdrawal. PRE, CyA. IFX withdrawal. CY, PRE ADA withdrawal. CY, PRE. IFX withdrawal.
Partial resolution
[11]
RBC, WBC, ↑ s-Cr, ↑ u-Prt (10 g/day) RBC, WBC, casts, ↑ u-Prt (10 g/day) RBC, ↑ u-Prt (6 g/day) RBC, WBC, ↑ s-Cr, ↑ u-Prt (7.9 g/day) RBC, casts, ↑ u-Prt (1.8 g/day) ↑ u-Prt (16.7 g/day)
Partial resolution
Possible
[15]
61/F
RA (13 years)
TCZ
16 months
Lower limbs edema RF, ANA 1:40
Complete resolution
Probable
[17]
47/F
RA (5 years)
ABA
4 months
Partial resolution
Possible
[18]
42/M
AS (6 years)
ADA
18 months
Partial resolution
Certain
Present study
29/M
PsA (7 years)
ADA
11 months
Partial resolution
Certain
Present study
58/M
RA (7 years)
ADA
60 months
Complete resolution
Possible
Present study
75/F
RA, sSS (26 years)
ETN
8 months
Complete resolution
Certain
MGN MGN MGN and IC mediated renal vasculitis NCGN and amyloidosis MGN
RBC, ↑ s-Cr, ↑ u-Prt (1.7 g/day) RBC, ↑ u-Prt (2.0 g/day)
mGN
RF, aCCP, pre-existing hematuria and proteinuria Hilar adenopathy, bilateral uveitis, ANA 1:320 ANA 1:40
RBC, ↑ u-Prt (2.9 g/day)
IgA mGN
↑ s-Cr
Granulomatous interstitial nephritis mGN
Lower limbs edema, type II diabetes mellitus Lower limbs edema RF
RBC, casts, ↑ s-Cr, ↑ u-Prt (3.7 g/day) Casts, ↑ s-Cr, ↑ u-Prt (5.7 g/day)
↑ u-Prt
IgA mGN
NA
TCZ withdrawal. PRE ABA withdrawal. PRE ADA withdrawal. PRE. ADA withdrawal. PRE. ADA withdrawal.
Minimal change disease
ETN withdrawal. Iv MPRE, PRE.
F: female. M: male. IRD: inflammatory rheumatic disease. AS: Ankylosing Spondylitis. RA: Rheumatoid Arthritis. PsA: Psoriatic Arthritis. sSS: secondary Sjogren Syndrome. ETN: Etanercept. ADA: Adalimumab. IFX: Infliximab. TCZ: Tocilizumab. ABA: Abatacept. RF: Rheumatoid Factor. ANA: antinuclear antibodies. aCCP: anti cyclic citrullinated peptides. RBC: red blood cells. WBC: white blood cells. ↑ S-Cr: increased serum creatinine. ↑ U-Prt: increased proteinuria. MGN: membranous glomerulonephritis. NCGN: necrotizing crescentic glomerulonephritis. mGN: mesangial glomerulonephritis. NA: not available. Iv: intravenous. MPRE: metil-prednisolone. PRE: prednisone.
M. Piga et al. / Autoimmunity Reviews 13 (2014) 873–879
Ref.
7 months 3 months 5 months 11 months 84 months 6 months ETN ETN ETN ETN ETN ETN 32/F 60/F 28/F 57/M 58/F 61/M [23] [24] [25] [26] [27] [28]
RA (3 years) RA (20 years) RA (16 years) PsA (20 years) RA (13 years) AS (30 years)
6 months 8 months 48 months ADA IFX ADA 47/M 31/M 62/F [20] [21] [22]
AS (14 years) RA (8 years) RA (15 years)
4 months ADA 69/F [19]
RA (1 years)
4 months ETN RA (10 years) 55/M [13]
F: female. M: male. IRD: inflammatory rheumatic disease. AS: Ankylosing Spondylitis. RA: Rheumatoid Arthritis. PsA: Psoriatic Arthritis. ETN Etanercept. ADA: Adalimumab. IFX: Infliximab. RF: Rheumatoid Factor. ANA: antinuclear antibodies. ANCA: Anti-neutrophil cytoplasmic antibody. RBC: red blood cells. WBC: white blood cells. ↑ S-Cr: increased serum creatinine. ↑ U-Prt: increased proteinuria. NCGN: necrotizing crescentic glomerulonephritis. mGN: mesangial glomerulonephritis. HSP: Henoch–Shonlein Purpura. NA: not available. Iv: intravenous. MPRE: metil-prednisolone. PRE: prednisone. CY: cyclophosphamide. PEX: plasma exchange. AZA: Azathioprine. MMF: mycophenolate mofetil.
Possible Certain Certain Certain Unlikely Certain NCGN IgA and C3 mGN (HSP) NCGN NA (HSP) NGN IgA and C3 mGN (HSP) RBC, ↑ s-Cr, ↑ u-Prt (3.5 g/day) RBC ↑ s-Cr, ↑ u-Prt (4.5 g/day) RBC, casts, ↑ s-Cr, ↑ u-Prt ↑ s-Cr RBC, ↑ s-Cr, ↑ u-Prt
Complete resolution Complete resolution Dialysis Complete resolution Dialysis Complete resolution
Probable Certain Probable NCGN CGN NCGN RBC, ↑ s-Cr, ↑ u-Prt (2.6 g/day) RBC, ↑ s-Cr, ↑ u-Prt (1.5 g/day) RBC, ↑ s-Cr, ↑ u-Prt (N6 g/day)
Partial resolution Partial resolution Partial resolution
Probable
ADA withdrawal. Iv MPRE, 6 PEX, PRE, CY. ADA withdrawal. Iv MPRE, PRE, CY. IFX withdrawal. Iv MPRE, CY. ADA withdrawal. Iv MPRE, 8 PEX, hemodialysis PRE, CY. ETN withdrawal. Iv MPRE, CY ETN withdrawal. Iv MPRE, CY ETN withdrawal. PRE, AZA (later MMF) ETN withdrawal. Iv MPRE, PRE ETN withdrawal. PRE ETN withdrawal. Iv MPRE, PRE NA RBC, casts, ↑ s-Cr
Dialysis
Certain Continued ETN. CY NCGN RBC, WBC. ↑ s-Cr, ↑ u-Prt (1 g/day)
Death
Probable Complete resolution ETN withdrawal. PRE. NCGN RBC, casts, ↑ u-Prt (2.1 g/day)
Organizing pneumonia. RF, ANA 1:80, p-ANCA Alopecia, rash, neuropathy. RF, ANA 1:320, p-ANCA Lower limbs edema, purpura. p-ANCA, aCCP, antiGBM IgG4 + ve mediastinic mass. c-ANCA Purpura. RF, ANA 1:320, c-ANCA Lower limbs edema, purpura, oral ulcer, anemia. RF, ANA 1:640, c-ANCA RF, p-ANCA Purpura, sinusitis. RF, ANA 1:640 Rash. RF, ANA 1:3200 Purpura, abdominal pain c-ANCA Lower limbs edema, purpura, fatigue. ANA 1:80, anti-histone 24 months 36/F [10]
RA (11 years)
ETN
Associated features Latency Drug IRD (duration) Age/Sex Ref.
Table 2 Demographic and clinical features of biologics-induced glomerulonephritis associated with systemic vasculitis.
Treatment Kidney biopsy Renal abnormalities
Outcome
WHO-UMC assessment
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almost all patients; hematuria was the most frequent sediment abnormality being present in 100% GNLS, 83.3% GNSV and 69.2% IARD. Proteinuria in nephrotic range (N3 g in 24 h) was prevalent in GNLS (75%) and IARD (53.8%) than in GNSV (25%), while 50% of patients with GNSV showed a 24-hour urinary protein excretion less than 3 g (IARD 38.5%, GNLS 25%). As regards to histopathologic findings, patients affected with GNLS showed class IV lupus nephritis in 3 cases and class III in 1 case; all of them had high titer of ANA (≥ 1:640) and anti-dsDNA while antihistone antibodies were reported in only 1 case. In patients with GNSV the most frequent histopathological finding was necrotizing GN with crescents (70%) followed by mesangial GN (20%). Necrotizing crescentic GN (NCGN) was associated with clinical and serological picture of ANCA-associated vasculitis, with detection of p-ANCA in 3 and c-ANCA in 4 cases of biopsy proven NCGN. Mesangial GN was associated with the typical clinical features of Henoch–Shönlein Purpura (HSP). In the group with IARD, 4 cases were defined as affected by membranous GN, 4 by mesangial GN (with IgA deposits in 2 cases), 2 by NCGN, 1 by minimal change disease and 1 by granulomatous interstitial nephritis in the picture of TNF-alpha induced sarcoidosis. The search for possible predisposing or precipitating factors has revealed the presence of infection immediately prior to the onset of AIRD in 6 cases [13,17,21,22,24,29]. Previous autoantibodies positivity was reported in 3 cases with GNSV, 2 p-ANCA and 1 ANA, but the systematic search of autoantibodies before the start of biological therapy was performed only in a few cases among those identified in the literature. Moreover, in at least five IARD cases retrieved from literature [10, 15,26,29] and in 1 case identified in the monocentric cohort, other possible pre-existing causes of nephropathy were identified namely pre-existing urinary sediment abnormalities, past drug-induced nephropathy and long-standing diabetes mellitus.
3.3.3. Treatment and outcomes In almost all described cases, biologics were discontinued at the time of AIRD clinical presentation and only in 2 cases [12,13] were continued during treatment for the acquired autoimmune kidney disorder. All GNSV and GNLS patients were treated with corticosteroids and/or immunosuppressant, more frequently cyclophosphamide, while only in most severe cases plasma-exchange and/or hemodialysis were required. Corticosteroids were frequently administered in IARD but immunosuppressive drugs were less used and in few cases the withdrawal of biologic drug alone lead to resolution of clinical manifestations. A complete resolution of AIRD was reported in 46.1% IARD, 41.7% GNSV and 25% GNLS, while partial resolution account for 75% in GNLS, 46.1% in IARD and 25% in GNSV. Worsening of clinical conditions was reported in 4 cases with GNSV (33.3%) and 1 with IARD (7.7%); end stage renal failure was reported in 3 cases with GNSV and 1 with IARD, 1 death was reported in GNSV.
3.3.4. Causality assessment The case causality assessment for GNSV and GNLS identified a high rate of cases classified in the categories “certain” (GNSV 50%, GNLS 50%, IARD 38.5%) and “probable” (GNSV 33.3%, GNLS 50.0%, IARD 15.4%), with stronger evidence for an etiologic role for biologic drugs in inducing AIRD. By contrast 46.2% IARD cases were defined as “possible” (GNSV 8.3%, GNLS 0%), therefore with a weaker evidence of causality between biologics treatment and AIRD development. Major reason for classifying cases in this category was the presence of other equally likely explanation for AIRD development, namely pre-existing or co-occurring causes of nephropathy. Among 29 identified cases only 1 (8.3%) GNSV was defined as “unlikely” due to the very long latency (84 months) between biologic intake and AIRD development.
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M. Piga et al. / Autoimmunity Reviews 13 (2014) 873–879
Table 3 Demographic and clinical features of glomerulonephritis in lupus-like syndrome. Ref.
Age/ IRD Drug Latency Sex (duration)
[13] 30/F [13] 52/F [29] 22/F
[30] 44/F
RA ETN (23 years) RA ADA (22 years) JRA ETN (8 years) RA (7 years)
ETN
Associated Features
30 months Recurrent pleurisy and cutaneous vasculitis. RF, ANA 1:640, anti dsDNA, IgG ACL. 3 months RF, ANA 1:640, anti dsDNA, atypical ANCA 48 months Family history of SLE, lower limbs edema, purpura. ANA 1:320, anti dsDNA, anti-histone, anti-SSA 9 months Oral ulcers, rash, headache, fatigue, lower limbs edema. RF, ANA 1:2560, anti dsDNA, p-ANCA
Renal abnormalities
Kidney Treatment biopsy
Outcome
WHO-UMC assessment
RBC, casts, ↑ s-Cr, ↑ u-Prt (7 g/day) RBC, casts, ↑ s-Cr, ↑ u-Prt (3.8 g/day) RBC, WBC, casts, ↑ s-Crs, ↑ u-Prt (3.6 g/day) RBC, ↑ u-Prt (3 g/day)
Class IV Class III Class IV
ETN withdrawal. PRE, MMF ADA withdrawal. Iv MPRE, PRE ETN withdrawal. Iv MPRE
Partial resolution Partial resolution Complete resolution
Probable
Class IV
ETN withdrawal. CY (later Partial MMF), PRE. PEX, dialysis. resolution
Certain Probable
Certain
F: female. IRD: inflammatory rheumatic disease. RA: Rheumatoid Arthritis. ETN: Etanercept. ADA: Adalimumab. RF: Rheumatoid Factor. ANA: antinuclear antibodies. ANCA: Antineutrophil cytoplasmic antibody. ACL: anticardiolipin. RBC: red blood cells. WBC: white blood cells. ↑ S-Cr: increased serum creatinine. ↑ U-Prt: increased proteinuria. NA: not available. Iv: intravenous. MPRE: metil-prednisolone. PRE: prednisone. CY: cyclophosphamide. PEX: plasma exchange. MMF: mycophenolate mofetil.
4. 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 related to the use of NSAIDs, synthetic DMARDs, such as gold salts, D-penicillamine and bucillamine, and more recently has been linked to anti-TNF-alpha therapy. Since the first report by Kemp and colleagues [34], describing the development of GN in 2 patients suffering with RA after being treated with ETN, several cases have been reported in literature, both in IRD [6–26] and in other conditions such as psoriasis and inflammatory bowel diseases [35–39]. This study shows that the paradoxical development of biologicsinduced AIRD in patients affected by IRD is rare, but not exceptional, and apparently unpredictable. It is worthy of mention that AIRD could be life-threatening and may lead to renal failure and death. They may occur as part of induced autoimmune systemic disease, such as systemic vasculitis and rarely SLE, or as an induced autoimmune process limited to the kidney. Cases of AIRD and especially GNSV and GNLS have been overwhelmingly related to the administration of the most frequently used anti-TNF-alpha agents (ETN, ADA and IFX). This could be due to TNF-alpha blocking or to the longer availability of these agents as compared with the newer ones. In support to the latter explanation, two cases of isolated GN has been recently associated to the use of Tocilizumab [16], a humanized monoclonal antibody directed against the IL6R, and Abatacept [17], a fusion protein capable of binding to CD80 and CD86. The real incidence of biologics-induced AIRD is unknown, but they are supposed to be very rare. A French nationwide survey on more than 10.000 patients treated with biologics identified 22 patients with induced SLE, of whom none developed GNLS, and 39 with induced vasculitis complicated by GNSV in 7 cases [40,41]. Systematic reviews reported the incidence of biologics-induced SLE to be less than 1% and that of GNLS in these patients to be 7–9% [42,43] while GNSV was present in 13% of patients with biologics-induced systemic vasculitis [44]. The cohort analysis performed in this study did not identify cases with GNLS or GNSV, but estimated the prevalence of IARD at 0.5% and the incidence rate at 0.9 cases per 1000 patient-years. To our knowledge, these are the first data available in the literature on the epidemiology of IARD, which has never been specifically addressed in previous studies. When AIRD occur as GNSV and GNLS their clinical, serological and histopathological findings are similar to those of the primitive disorders, suggesting that they mostly represent a true drug-induced vasculitis or drug-induced SLE rather than a systemic reaction against the biologic
drug, as hypothesized in isolated hypersensitivity cutaneous vasculitis and lupus-like syndrome. By contrast, the variety of renal disorders classified as IARD may mirror different underlying pathogenetic mechanisms. Such an observation is partly confirmed by the different time of induction, response to treatment and outcomes observed between the various AIRD subgroups. Despite still debated, the pathogenetic mechanisms suggested for AIRD development range from self-limited reaction against the drug, resulting in immuno-complex deposition and kidney damage, to the direct effect of biologic agents on cytokine production and lymphocyte functions. As an example, it has been suggested that anti-TNF-alpha drugs may favor the drifting of the immune system to a Th-2 profile, thus up-regulating production of antibodies such as ANA, anti-dsDNA and ANCA in susceptible subjects [45]. Alternatively, an increase in viral or bacterial infections in the setting of biologic treatment, mainly anti-TNF-alpha, might promote autoimmune reactions by different mechanisms such as molecular mimicry, bystander activation or epitope spreading [46]. In agreement with this hypothesis is the finding of infection prior to the onset of AIRD in 6 cases identified in this study. In conclusion, in order to identify those rare individuals with higher risk for development of biologics-induced AIRD, a baseline testing for ANA, anti-dsDNA and ANCA should be performed in all patients prior to starting biologics together with a careful assessment of pre-existing causes of nephropathy, which in our review resulted associated to the development of AIRD. Moreover, during treatment with biologics all patients must undergo an at least quarterly evaluation of kidney parameters. If impaired renal function or urinary sediment abnormalities are detected, the possible occurrence of AIRD must be investigated through an accurate clinical and laboratory examination, furthermore the eventuality to perform a kidney biopsy should be strictly considered. When AIRD is diagnosed, or even suspected, the biologic agent must be stopped and patient treated according to clinical manifestations and biopsy findings. The management of GNSV and GNLS requires a timely withdrawal of the biologic agent and an early treatment mainly based on administration of high dose corticosteroids and immunosuppressive drugs. By contrast, the variety of renal disorders classified as IARD mirrors the different therapeutic approach and outcomes required in this group of patients, but the first step on their management must be the discontinuation of biologic therapy.
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.
M. Piga et al. / Autoimmunity Reviews 13 (2014) 873–879
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). References [1] Smolen JS, Landewe R, Breedveld FC, Buch M, Burmester G, Dougados M, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis 2014;73:492–509. [2] Smolen JS, Braun J, Dougados M, Emery P, Fitzgerald O, Helliwell P, et al. Treating spondyloarthritis, including ankylosing spondylitis and psoriatic arthritis, to target: recommendations of an international task force. Ann Rheum Dis 2014;73:6–16. [3] Paula FS, Alves JD. Non-tumor necrosis factor-based biologic therapies for rheumatoid arthritis: present, future, and insights into pathogenesis. Biogeosciences 2014; 8:1–12. [4] Noack M, Miossec P. Th17 and regulatory T cell balance in autoimmune and inflammatory diseases. Autoimmun Rev 2014;13:668–77. [5] Dimitroulas T, Nikas SN, Trontzas P, Kitas GD. Biologic therapies and systemic bone loss in rheumatoid arthritis. Autoimmun Rev 2013;12:958–66. [6] Modena V, Bianchi G, Roccatello D. Cost-effectiveness of biologic treatment for rheumatoid arthritis in clinical practice: an achievable target? Autoimmun Rev 2013; 12:835–8. [7] Roccatello D. Novel diagnostic approaches and cost–benefit balance of treatment of immune-mediated and rare disease in the era of biologic drugs: lessons from the 15th Turin Congress on Immune Pathology and Orphan Disease. Autoimmun Rev 2013;12:793–5. [8] Ramos-Casals M, Roberto Perez A, Diaz-Lagares C, Cuadrado MJ, Khamashta MA. Autoimmune diseases induced by biological agents: a double-edged sword? Autoimmun Rev 2010;9:188–93. [9] Perez-Alvarez R, Perez-de-Lis M, Ramos-Casals M. Biologics-induced autoimmune diseases. Curr Opin Rheumatol 2013;25:56–64. [10] Kaneko K, Nanki T, Hosoya T, Mizoguchi F, Miyasaka N. Etanercept-induced necrotizing crescentic glomerulonephritis in two patients with rheumatoid arthritis. Mod Rheumatol 2010;20:632–6. [11] Kaushik P, Rahmani M, Ellison W. Membranous glomerulonephritis with the use of etanercept in ankylosing spondylitis. Ann Pharmacother 2011;45:e62. [12] Maruotti N, Corrado A, Gaudio A, Cantatore FP. Membranous nephropathy in rheumatoid arthritis: a case report. Clin Exp Rheumatol 2009;27:840–2. [13] Stokes MB, Foster K, Markowitz GS, Ebrahimi F, Hines W, Kaufman D, et al. Development of glomerulonephritis during anti-TNF-alpha therapy for rheumatoid arthritis. Nephrol Dial Transplant 2005;20:1400–6. [14] den Broeder AA, Assmann KJ, van Riel PL, Wetzels JF. Nephrotic syndrome as a complication of anti-TNFalpha in a patient with rheumatoid arthritis. Neth J Med 2003;61:137–41. [15] Jacquet A, Francois H, Frangie C, Yahiaoui Y, Ferlicot S, Micelli C, et al. IgA nephropathy associated with ankylosing spondylitis is not controlled by infliximab therapy. Nephrol Dial Transplant 2009;24:3540–2. [16] Matsuo Y, Mizoguchi F, Kohsaka H, Ito E, Eishi Y, Miyasaka N. Tocilizumab-induced immune complex glomerulonephritis in a patient with rheumatoid arthritis. Rheumatology (Oxford) 2013;52:1341–3. [17] Michel M, Henri P, Vincent F, Leon N, Marcelli C. Mesangial immunoglobulin (Ig)A glomerulonephritis in a patient with rheumatoid arthritis treated with abatacept. Joint Bone Spine 2013;80:660–3. [18] Korsten P, Sweiss NJ, Nagorsnik U, Niewold TB, Grone HJ, Gross O, et al. Druginduced granulomatous interstitial nephritis in a patient with ankylosing spondylitis during therapy with adalimumab. Am J Kidney Dis 2010;56:e17–21. [19] Nishimura K, Saegusa J, Kawano S, Morinobu A. Tumor necrosis factor-alpha inhibitor-induced antiglomerular basement membrane antibody disease in a patient with rheumatoid arthritis. J Rheumatol 2012;39:1904–5. [20] Tosovsky M, Bradna P, Laco J, Podhola M, Soukup T, Brozik J. Case 1–2012: ANCA associated glomerulonephritis in combination with IgG4-positive mediastinal mass
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Contents lists available at ScienceDirect
Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev
Review
Biologics-induced autoimmune renal disorders in chronic inflammatory rheumatic diseases: Systematic literature review and analysis of a monocentric cohort Matteo Piga ⁎, Elisabetta Chessa, Valentina Ibba, Valentina Mura, Alberto Floris, Alberto Cauli, Alessandro Mathieu Rheumatology and Rheumatology Unit, University and AOU of Cagliari, Cagliari, Italy
a r t i c l e
i n f o
Article history: Received 15 April 2014 Accepted 2 May 2014 Available online 16 May 2014 Keywords: Rheumatic diseases Biologic drugs Drug-induced glomerulonephritis Lupus nephritis Systemic vasculitis Anti-TNF-alpha
a b s t r a c t 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. © 2014 Elsevier B.V. All rights reserved.
Contents 1. 2.
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Introduction . . . . . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Systematic review . . . . . . . . . . . . . . . . . . 2.2. Longitudinal cohort analysis . . . . . . . . . . . . . 2.3. Case classification . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Literature search . . . . . . . . . . . . . . . . . . 3.2. Cohort study . . . . . . . . . . . . . . . . . . . . 3.3. Pooled cases from systematic review and cohort analysis 3.3.1. Demographic features . . . . . . . . . . . . 3.3.2. Clinical, serologic and histopathological features 3.3.3. Treatment and outcomes . . . . . . . . . . 3.3.4. Causality assessment . . . . . . . . . . . .
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⁎ Corresponding author at: Rheumatology Unit, University Clinic AOU of Cagliari, SS 554-09 042 Monserrato, Cagliari, Italy. Tel.: +39 070 5109 6381; fax: +39 070 5109 6382/513157. E-mail address: [email protected] (M. Piga).
http://dx.doi.org/10.1016/j.autrev.2014.05.005 1568-9972/© 2014 Elsevier B.V. All rights reserved.
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4. Discussion . . Take-home message Acknowledgment . References . . . .
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1. 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 CD20positive 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 [5–7]. 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.
2. Methods 2.1. 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, Ankylosing”[Mesh]) OR (“Arthritis, Psoriatic”[Mesh]) AND (“Interleukin 1 Receptor Antagonist Protein”[Mesh]) OR (“infliximab” [Supplementary Concept]) OR (“TNFR-Fc fusion protein” [Supplementary Concept]) OR (“adalimumab” [Supplementary Concept]) OR (“golimumab” [Supplementary Concept]) OR (“certolizumab pegol” [Supplementary Concept]) OR (“rituximab” [Supplementary Concept]) OR (“tocilizumab” [Supplementary Concept]) OR (“abatacept” [Supplementary Concept]) AND (“Glomerulonephritis”[Mesh]) OR (“Nephrotic Syndrome”[Mesh]) OR (“Nephrosis, Lipoid”[Mesh]). Additional papers were obtained by checking the references from the selected studies as well as from review articles and other sources
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known to the authors. All type of studies were allowed, but only full publications reporting on adult patients and written in English were included in the literature search. Once investigators have independently selected the articles, initially on the basis of titles and abstracts then if necessary on the full texts, eligibility assessment was performed independently in a blinded standardized manner. Disagreements between reviewers were solved by consensus. Whenever papers reported duplicate data, the most recent article was selected. To be included in the review, the retrieved papers had to provide the descriptive features of each reported case of biologics-induced AIRD. In particular, demographic, clinical, histopathologic (if performed), treatment and outcome data must be provided. In an attempt to clarify if AIRD are specific adverse reactions for biologic drugs, the WHO-UMC system for standardized case causality assessment (http://who-umc.org/Graphics/24734.pdf) was applied and the reported adverse drug reactions were classified in a six categories scale ranging from “certain” to “unassessable/unclassifiable”. Case reports classified in the last two categories of the scale, “conditional/unclassified” and “unassessable/unclassifiable”, were excluded from the analysis of results. Causality assessment was performed independently in a blinded standardized manner by the two reviewers. Disagreements between reviewers were solved by consensus. When retrieved studies did not report the characteristics required for case classification we tried to contact the authors asking them to notify us the lacking features. 2.2. Longitudinal cohort analysis The retrospective analysis of a prospectively followed-up population of adult with chronic IRD was performed. Data was retrieved using the database dedicated to patients treated with biological drugs at the Centre of Rheumatology of the University Hospital of Cagliari, Italy. For the purposes of the study, cases under investigation were defined as adult patients suffering from chronic IRD that had developed renal abnormalities following treatment with biotechnological drugs. The aim was to identify those patients that developed AIRD secondary to biologics treatment. Renal abnormalities were defined as: a) increased levels of blood urea nitrogen and serum creatinine; b) reduction of glomerular filtration rate; c) alterations of renal sediment (erythrocytes, leukocytes, casts); d) the appearance/worsening of proteinuria. To be included in the study a patient should have had blood tests and urine analysis at least three times per year and must have been followed-up for at least 12 months. Cases in which renal changes were explained by diseases (e.g. IRD by itself, infectious disease, diabetes, hypertension) or other drugs (e.g. gold salts, vaccination) were excluded. The diagnosis of AIRD was defined and reassessed according to kidney biopsy and clinical judgment. The WHO-UMC system for standardized case causality assessment was retrospectively applied to the identified cases. This study was performed according to the principles of Good Clinical Practice and the Declaration of Helsinki. 2.3. Case classification According to clinical manifestations and kidney histology the identified cases were classified as: a) glomerulonephritis associated with systemic vasculitis (GNSV), b) glomerulonephritis in lupus-like syndrome (GNLS), c) isolated autoimmune renal disorders (IARD). Clinical outcomes were defined as i) complete resolution (i.e. inactive urinary
M. Piga et al. / Autoimmunity Reviews 13 (2014) 873–879
sediment, absent proteinuria and normal or stable renal function), ii) partial resolution (i.e. significant improvement of proteinuria, urinary sediment and renal function but they did not return to normal values) and iii) worsening of clinical conditions (i.e. worsening of proteinuria and/or urinary sediment, deterioration of renal function even until end stage renal disease or death). Results from systematic review and cohort analysis have been pooled and will be presented together.
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RA during follow-up was: Adalimumab (ADA) 46.5%, Etanercept (ETN) 35.8%, Tocilizumab (TCZ) 7.9%, Abatacept (ABA) 4.4%, Rituximab (RTX) 3.8%, Golimumab (GOL) b 1.0%, Infliximab (IFX) b1.0%, Certolizumab (CTZ) b1.0%. Among AS patients (56 F, 112 M; follow-up 4.8 ± 2.4 years; 722.7 patient-years) the 48.1% were on ADA, 36.1% on ETN, 15.0% on IFX and b 1.0% on GOL. During a mean follow-up of 5.4 ± 2.3 years (488.3 patient-years) patients with PsA (48 F, 64 M) received: ETN 59.3%, ADA 37.2% and IFX 3.5%.
3. Results 3.3. Pooled cases from systematic review and cohort analysis 3.1. 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 AIRD, leading to a “unclassified” or “unclassifiable” evaluation according to the WHO-UMC criteria 3.2. Cohort study Three out of 707 adult patients with IRD identified through the monocentric retrospective analysis was classified as suffering with biologics induced AIRD (Table 1). The cohort study included 427 Rheumatoid Arthritis (RA), 168 Ankylosing Spondylitis (AS) and 112 Psoriatic Arthritis (PsA), treated with biologics between January 2004 and January 2014. All patients were treated with biologics because of inadequate response to first line drugs and after screening for detection of latent chronic infectious diseases (i.e. tuberculosis) and exclusion of connective tissue diseases (i.e. SLE) according to local and international guidelines. Patients affected with RA, 326 Female (F) and 111 Male (M), showed a mean follow-up on biologics treatment of 5.6 ± 6.2 years for a total of 2116.8 patient-years. The distribution of biologic drugs in patients with
3.3.1. Demographic features 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 ETN (15 cases, 51.7%) followed by ADA (9 cases, 31.0%) and IFX (3 cases, 10.3%) while TCZ and ABA were reported in 1 case (3.4%) for each. AIRD usually appeared within 18 months since the beginning of treatment, but in 8 cases (27.5%) it was diagnosed later. Thirteen out of 29 cases were classified as affected by IARD (Table 1) [10–18], 12 with GNSV (Table 2) [10,13,19–28] and 4 with GNLS (Table 3) [13,29,30]. Patients reported as developing GNLS showed younger age at onset (mean age 37.0 years; range 22–52) than patients with GNSV (mean age 49.7 years; range 28–69) and IARD (mean age 55.0 years; range 29–64). No major differences were identified on disease duration at the time of AIRD development between GNLS (mean 15.0 years; range 7–23) and GNSV (mean 13.4 years; range 1–30) while patients with IARD showed longer disease duration (mean 17.9 years; range 5–30). 3.3.2. Clinical, serologic and histopathological features Clinical presentation was represented by cutaneous lesions, mostly purpura, or other organ manifestations in patients with GNSV (66.6% and 41.6% respectively) and GNLS (50% and 75% respectively), while patients with IARD mainly presented with lower limbs edema (38.5%) and no or few systemic involvement. Impaired renal function with increased serum creatinine was more frequent in GNSV (83.3%) and GNLS (75%) than in IARD (37.5%). Urinary sediment changes were reported in
Fig. 1. Flow diagram illustrating the results of the literature search.
876
Table 1 Demographic and clinical features of biologics-induced isolated autoimmune renal disorders. Age/sex
IRD (duration)
Drug
Latency
Associated features
Renal abnormalities
Kidney biopsy
Treatment
Outcome
WHO-UMC assessment
[10]
64/F
RA (20 years)
ETN
18 months
Bucillamine induced MN.
NCGN
Possible
60/F
AS (40 years)
ETN
2 months
Anasarca
Complete resolution
Certain
[12] [13]
61/F 53/F
RA (12 years) RA, sSS (30 years)
ADA ETN
48 months 6 months
Complete resolution Partial resolution
Possible Probable
[13]
64/F
RA (30 years)
IFX
10 months
RF Peripheral neuropathy, lower limbs edema. RF, ANA 1:160, anti-SSA anti-SSB RF, type II diabetes mellitus
Worsened
Possible
[14]
64/M
RA (21 years)
ADA
12 months
Gold's salt nephropathy. RF
Complete resolution
Certain
[15]
37/M
AS (16 years)
IFX
36 months
ANA 1:80
ETN withdrawal. Iv MPRE, PRE. ETN withdrawal. Switch to ADA. Iv MPRE, PRE. ETN withdrawal. PRE, CyA. IFX withdrawal. CY, PRE ADA withdrawal. CY, PRE. IFX withdrawal.
Partial resolution
[11]
RBC, WBC, ↑ s-Cr, ↑ u-Prt (10 g/day) RBC, WBC, casts, ↑ u-Prt (10 g/day) RBC, ↑ u-Prt (6 g/day) RBC, WBC, ↑ s-Cr, ↑ u-Prt (7.9 g/day) RBC, casts, ↑ u-Prt (1.8 g/day) ↑ u-Prt (16.7 g/day)
Partial resolution
Possible
[15]
61/F
RA (13 years)
TCZ
16 months
Lower limbs edema RF, ANA 1:40
Complete resolution
Probable
[17]
47/F
RA (5 years)
ABA
4 months
Partial resolution
Possible
[18]
42/M
AS (6 years)
ADA
18 months
Partial resolution
Certain
Present study
29/M
PsA (7 years)
ADA
11 months
Partial resolution
Certain
Present study
58/M
RA (7 years)
ADA
60 months
Complete resolution
Possible
Present study
75/F
RA, sSS (26 years)
ETN
8 months
Complete resolution
Certain
MGN MGN MGN and IC mediated renal vasculitis NCGN and amyloidosis MGN
RBC, ↑ s-Cr, ↑ u-Prt (1.7 g/day) RBC, ↑ u-Prt (2.0 g/day)
mGN
RF, aCCP, pre-existing hematuria and proteinuria Hilar adenopathy, bilateral uveitis, ANA 1:320 ANA 1:40
RBC, ↑ u-Prt (2.9 g/day)
IgA mGN
↑ s-Cr
Granulomatous interstitial nephritis mGN
Lower limbs edema, type II diabetes mellitus Lower limbs edema RF
RBC, casts, ↑ s-Cr, ↑ u-Prt (3.7 g/day) Casts, ↑ s-Cr, ↑ u-Prt (5.7 g/day)
↑ u-Prt
IgA mGN
NA
TCZ withdrawal. PRE ABA withdrawal. PRE ADA withdrawal. PRE. ADA withdrawal. PRE. ADA withdrawal.
Minimal change disease
ETN withdrawal. Iv MPRE, PRE.
F: female. M: male. IRD: inflammatory rheumatic disease. AS: Ankylosing Spondylitis. RA: Rheumatoid Arthritis. PsA: Psoriatic Arthritis. sSS: secondary Sjogren Syndrome. ETN: Etanercept. ADA: Adalimumab. IFX: Infliximab. TCZ: Tocilizumab. ABA: Abatacept. RF: Rheumatoid Factor. ANA: antinuclear antibodies. aCCP: anti cyclic citrullinated peptides. RBC: red blood cells. WBC: white blood cells. ↑ S-Cr: increased serum creatinine. ↑ U-Prt: increased proteinuria. MGN: membranous glomerulonephritis. NCGN: necrotizing crescentic glomerulonephritis. mGN: mesangial glomerulonephritis. NA: not available. Iv: intravenous. MPRE: metil-prednisolone. PRE: prednisone.
M. Piga et al. / Autoimmunity Reviews 13 (2014) 873–879
Ref.
7 months 3 months 5 months 11 months 84 months 6 months ETN ETN ETN ETN ETN ETN 32/F 60/F 28/F 57/M 58/F 61/M [23] [24] [25] [26] [27] [28]
RA (3 years) RA (20 years) RA (16 years) PsA (20 years) RA (13 years) AS (30 years)
6 months 8 months 48 months ADA IFX ADA 47/M 31/M 62/F [20] [21] [22]
AS (14 years) RA (8 years) RA (15 years)
4 months ADA 69/F [19]
RA (1 years)
4 months ETN RA (10 years) 55/M [13]
F: female. M: male. IRD: inflammatory rheumatic disease. AS: Ankylosing Spondylitis. RA: Rheumatoid Arthritis. PsA: Psoriatic Arthritis. ETN Etanercept. ADA: Adalimumab. IFX: Infliximab. RF: Rheumatoid Factor. ANA: antinuclear antibodies. ANCA: Anti-neutrophil cytoplasmic antibody. RBC: red blood cells. WBC: white blood cells. ↑ S-Cr: increased serum creatinine. ↑ U-Prt: increased proteinuria. NCGN: necrotizing crescentic glomerulonephritis. mGN: mesangial glomerulonephritis. HSP: Henoch–Shonlein Purpura. NA: not available. Iv: intravenous. MPRE: metil-prednisolone. PRE: prednisone. CY: cyclophosphamide. PEX: plasma exchange. AZA: Azathioprine. MMF: mycophenolate mofetil.
Possible Certain Certain Certain Unlikely Certain NCGN IgA and C3 mGN (HSP) NCGN NA (HSP) NGN IgA and C3 mGN (HSP) RBC, ↑ s-Cr, ↑ u-Prt (3.5 g/day) RBC ↑ s-Cr, ↑ u-Prt (4.5 g/day) RBC, casts, ↑ s-Cr, ↑ u-Prt ↑ s-Cr RBC, ↑ s-Cr, ↑ u-Prt
Complete resolution Complete resolution Dialysis Complete resolution Dialysis Complete resolution
Probable Certain Probable NCGN CGN NCGN RBC, ↑ s-Cr, ↑ u-Prt (2.6 g/day) RBC, ↑ s-Cr, ↑ u-Prt (1.5 g/day) RBC, ↑ s-Cr, ↑ u-Prt (N6 g/day)
Partial resolution Partial resolution Partial resolution
Probable
ADA withdrawal. Iv MPRE, 6 PEX, PRE, CY. ADA withdrawal. Iv MPRE, PRE, CY. IFX withdrawal. Iv MPRE, CY. ADA withdrawal. Iv MPRE, 8 PEX, hemodialysis PRE, CY. ETN withdrawal. Iv MPRE, CY ETN withdrawal. Iv MPRE, CY ETN withdrawal. PRE, AZA (later MMF) ETN withdrawal. Iv MPRE, PRE ETN withdrawal. PRE ETN withdrawal. Iv MPRE, PRE NA RBC, casts, ↑ s-Cr
Dialysis
Certain Continued ETN. CY NCGN RBC, WBC. ↑ s-Cr, ↑ u-Prt (1 g/day)
Death
Probable Complete resolution ETN withdrawal. PRE. NCGN RBC, casts, ↑ u-Prt (2.1 g/day)
Organizing pneumonia. RF, ANA 1:80, p-ANCA Alopecia, rash, neuropathy. RF, ANA 1:320, p-ANCA Lower limbs edema, purpura. p-ANCA, aCCP, antiGBM IgG4 + ve mediastinic mass. c-ANCA Purpura. RF, ANA 1:320, c-ANCA Lower limbs edema, purpura, oral ulcer, anemia. RF, ANA 1:640, c-ANCA RF, p-ANCA Purpura, sinusitis. RF, ANA 1:640 Rash. RF, ANA 1:3200 Purpura, abdominal pain c-ANCA Lower limbs edema, purpura, fatigue. ANA 1:80, anti-histone 24 months 36/F [10]
RA (11 years)
ETN
Associated features Latency Drug IRD (duration) Age/Sex Ref.
Table 2 Demographic and clinical features of biologics-induced glomerulonephritis associated with systemic vasculitis.
Treatment Kidney biopsy Renal abnormalities
Outcome
WHO-UMC assessment
M. Piga et al. / Autoimmunity Reviews 13 (2014) 873–879
877
almost all patients; hematuria was the most frequent sediment abnormality being present in 100% GNLS, 83.3% GNSV and 69.2% IARD. Proteinuria in nephrotic range (N3 g in 24 h) was prevalent in GNLS (75%) and IARD (53.8%) than in GNSV (25%), while 50% of patients with GNSV showed a 24-hour urinary protein excretion less than 3 g (IARD 38.5%, GNLS 25%). As regards to histopathologic findings, patients affected with GNLS showed class IV lupus nephritis in 3 cases and class III in 1 case; all of them had high titer of ANA (≥ 1:640) and anti-dsDNA while antihistone antibodies were reported in only 1 case. In patients with GNSV the most frequent histopathological finding was necrotizing GN with crescents (70%) followed by mesangial GN (20%). Necrotizing crescentic GN (NCGN) was associated with clinical and serological picture of ANCA-associated vasculitis, with detection of p-ANCA in 3 and c-ANCA in 4 cases of biopsy proven NCGN. Mesangial GN was associated with the typical clinical features of Henoch–Shönlein Purpura (HSP). In the group with IARD, 4 cases were defined as affected by membranous GN, 4 by mesangial GN (with IgA deposits in 2 cases), 2 by NCGN, 1 by minimal change disease and 1 by granulomatous interstitial nephritis in the picture of TNF-alpha induced sarcoidosis. The search for possible predisposing or precipitating factors has revealed the presence of infection immediately prior to the onset of AIRD in 6 cases [13,17,21,22,24,29]. Previous autoantibodies positivity was reported in 3 cases with GNSV, 2 p-ANCA and 1 ANA, but the systematic search of autoantibodies before the start of biological therapy was performed only in a few cases among those identified in the literature. Moreover, in at least five IARD cases retrieved from literature [10, 15,26,29] and in 1 case identified in the monocentric cohort, other possible pre-existing causes of nephropathy were identified namely pre-existing urinary sediment abnormalities, past drug-induced nephropathy and long-standing diabetes mellitus.
3.3.3. Treatment and outcomes In almost all described cases, biologics were discontinued at the time of AIRD clinical presentation and only in 2 cases [12,13] were continued during treatment for the acquired autoimmune kidney disorder. All GNSV and GNLS patients were treated with corticosteroids and/or immunosuppressant, more frequently cyclophosphamide, while only in most severe cases plasma-exchange and/or hemodialysis were required. Corticosteroids were frequently administered in IARD but immunosuppressive drugs were less used and in few cases the withdrawal of biologic drug alone lead to resolution of clinical manifestations. A complete resolution of AIRD was reported in 46.1% IARD, 41.7% GNSV and 25% GNLS, while partial resolution account for 75% in GNLS, 46.1% in IARD and 25% in GNSV. Worsening of clinical conditions was reported in 4 cases with GNSV (33.3%) and 1 with IARD (7.7%); end stage renal failure was reported in 3 cases with GNSV and 1 with IARD, 1 death was reported in GNSV.
3.3.4. Causality assessment The case causality assessment for GNSV and GNLS identified a high rate of cases classified in the categories “certain” (GNSV 50%, GNLS 50%, IARD 38.5%) and “probable” (GNSV 33.3%, GNLS 50.0%, IARD 15.4%), with stronger evidence for an etiologic role for biologic drugs in inducing AIRD. By contrast 46.2% IARD cases were defined as “possible” (GNSV 8.3%, GNLS 0%), therefore with a weaker evidence of causality between biologics treatment and AIRD development. Major reason for classifying cases in this category was the presence of other equally likely explanation for AIRD development, namely pre-existing or co-occurring causes of nephropathy. Among 29 identified cases only 1 (8.3%) GNSV was defined as “unlikely” due to the very long latency (84 months) between biologic intake and AIRD development.
878
M. Piga et al. / Autoimmunity Reviews 13 (2014) 873–879
Table 3 Demographic and clinical features of glomerulonephritis in lupus-like syndrome. Ref.
Age/ IRD Drug Latency Sex (duration)
[13] 30/F [13] 52/F [29] 22/F
[30] 44/F
RA ETN (23 years) RA ADA (22 years) JRA ETN (8 years) RA (7 years)
ETN
Associated Features
30 months Recurrent pleurisy and cutaneous vasculitis. RF, ANA 1:640, anti dsDNA, IgG ACL. 3 months RF, ANA 1:640, anti dsDNA, atypical ANCA 48 months Family history of SLE, lower limbs edema, purpura. ANA 1:320, anti dsDNA, anti-histone, anti-SSA 9 months Oral ulcers, rash, headache, fatigue, lower limbs edema. RF, ANA 1:2560, anti dsDNA, p-ANCA
Renal abnormalities
Kidney Treatment biopsy
Outcome
WHO-UMC assessment
RBC, casts, ↑ s-Cr, ↑ u-Prt (7 g/day) RBC, casts, ↑ s-Cr, ↑ u-Prt (3.8 g/day) RBC, WBC, casts, ↑ s-Crs, ↑ u-Prt (3.6 g/day) RBC, ↑ u-Prt (3 g/day)
Class IV Class III Class IV
ETN withdrawal. PRE, MMF ADA withdrawal. Iv MPRE, PRE ETN withdrawal. Iv MPRE
Partial resolution Partial resolution Complete resolution
Probable
Class IV
ETN withdrawal. CY (later Partial MMF), PRE. PEX, dialysis. resolution
Certain Probable
Certain
F: female. IRD: inflammatory rheumatic disease. RA: Rheumatoid Arthritis. ETN: Etanercept. ADA: Adalimumab. RF: Rheumatoid Factor. ANA: antinuclear antibodies. ANCA: Antineutrophil cytoplasmic antibody. ACL: anticardiolipin. RBC: red blood cells. WBC: white blood cells. ↑ S-Cr: increased serum creatinine. ↑ U-Prt: increased proteinuria. NA: not available. Iv: intravenous. MPRE: metil-prednisolone. PRE: prednisone. CY: cyclophosphamide. PEX: plasma exchange. MMF: mycophenolate mofetil.
4. 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 related to the use of NSAIDs, synthetic DMARDs, such as gold salts, D-penicillamine and bucillamine, and more recently has been linked to anti-TNF-alpha therapy. Since the first report by Kemp and colleagues [34], describing the development of GN in 2 patients suffering with RA after being treated with ETN, several cases have been reported in literature, both in IRD [6–26] and in other conditions such as psoriasis and inflammatory bowel diseases [35–39]. This study shows that the paradoxical development of biologicsinduced AIRD in patients affected by IRD is rare, but not exceptional, and apparently unpredictable. It is worthy of mention that AIRD could be life-threatening and may lead to renal failure and death. They may occur as part of induced autoimmune systemic disease, such as systemic vasculitis and rarely SLE, or as an induced autoimmune process limited to the kidney. Cases of AIRD and especially GNSV and GNLS have been overwhelmingly related to the administration of the most frequently used anti-TNF-alpha agents (ETN, ADA and IFX). This could be due to TNF-alpha blocking or to the longer availability of these agents as compared with the newer ones. In support to the latter explanation, two cases of isolated GN has been recently associated to the use of Tocilizumab [16], a humanized monoclonal antibody directed against the IL6R, and Abatacept [17], a fusion protein capable of binding to CD80 and CD86. The real incidence of biologics-induced AIRD is unknown, but they are supposed to be very rare. A French nationwide survey on more than 10.000 patients treated with biologics identified 22 patients with induced SLE, of whom none developed GNLS, and 39 with induced vasculitis complicated by GNSV in 7 cases [40,41]. Systematic reviews reported the incidence of biologics-induced SLE to be less than 1% and that of GNLS in these patients to be 7–9% [42,43] while GNSV was present in 13% of patients with biologics-induced systemic vasculitis [44]. The cohort analysis performed in this study did not identify cases with GNLS or GNSV, but estimated the prevalence of IARD at 0.5% and the incidence rate at 0.9 cases per 1000 patient-years. To our knowledge, these are the first data available in the literature on the epidemiology of IARD, which has never been specifically addressed in previous studies. When AIRD occur as GNSV and GNLS their clinical, serological and histopathological findings are similar to those of the primitive disorders, suggesting that they mostly represent a true drug-induced vasculitis or drug-induced SLE rather than a systemic reaction against the biologic
drug, as hypothesized in isolated hypersensitivity cutaneous vasculitis and lupus-like syndrome. By contrast, the variety of renal disorders classified as IARD may mirror different underlying pathogenetic mechanisms. Such an observation is partly confirmed by the different time of induction, response to treatment and outcomes observed between the various AIRD subgroups. Despite still debated, the pathogenetic mechanisms suggested for AIRD development range from self-limited reaction against the drug, resulting in immuno-complex deposition and kidney damage, to the direct effect of biologic agents on cytokine production and lymphocyte functions. As an example, it has been suggested that anti-TNF-alpha drugs may favor the drifting of the immune system to a Th-2 profile, thus up-regulating production of antibodies such as ANA, anti-dsDNA and ANCA in susceptible subjects [45]. Alternatively, an increase in viral or bacterial infections in the setting of biologic treatment, mainly anti-TNF-alpha, might promote autoimmune reactions by different mechanisms such as molecular mimicry, bystander activation or epitope spreading [46]. In agreement with this hypothesis is the finding of infection prior to the onset of AIRD in 6 cases identified in this study. In conclusion, in order to identify those rare individuals with higher risk for development of biologics-induced AIRD, a baseline testing for ANA, anti-dsDNA and ANCA should be performed in all patients prior to starting biologics together with a careful assessment of pre-existing causes of nephropathy, which in our review resulted associated to the development of AIRD. Moreover, during treatment with biologics all patients must undergo an at least quarterly evaluation of kidney parameters. If impaired renal function or urinary sediment abnormalities are detected, the possible occurrence of AIRD must be investigated through an accurate clinical and laboratory examination, furthermore the eventuality to perform a kidney biopsy should be strictly considered. When AIRD is diagnosed, or even suspected, the biologic agent must be stopped and patient treated according to clinical manifestations and biopsy findings. The management of GNSV and GNLS requires a timely withdrawal of the biologic agent and an early treatment mainly based on administration of high dose corticosteroids and immunosuppressive drugs. By contrast, the variety of renal disorders classified as IARD mirrors the different therapeutic approach and outcomes required in this group of patients, but the first step on their management must be the discontinuation of biologic therapy.
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.
M. Piga et al. / Autoimmunity Reviews 13 (2014) 873–879
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). References [1] Smolen JS, Landewe R, Breedveld FC, Buch M, Burmester G, Dougados M, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis 2014;73:492–509. [2] Smolen JS, Braun J, Dougados M, Emery P, Fitzgerald O, Helliwell P, et al. Treating spondyloarthritis, including ankylosing spondylitis and psoriatic arthritis, to target: recommendations of an international task force. Ann Rheum Dis 2014;73:6–16. [3] Paula FS, Alves JD. Non-tumor necrosis factor-based biologic therapies for rheumatoid arthritis: present, future, and insights into pathogenesis. Biogeosciences 2014; 8:1–12. [4] Noack M, Miossec P. Th17 and regulatory T cell balance in autoimmune and inflammatory diseases. Autoimmun Rev 2014;13:668–77. [5] Dimitroulas T, Nikas SN, Trontzas P, Kitas GD. Biologic therapies and systemic bone loss in rheumatoid arthritis. Autoimmun Rev 2013;12:958–66. [6] Modena V, Bianchi G, Roccatello D. Cost-effectiveness of biologic treatment for rheumatoid arthritis in clinical practice: an achievable target? Autoimmun Rev 2013; 12:835–8. [7] Roccatello D. Novel diagnostic approaches and cost–benefit balance of treatment of immune-mediated and rare disease in the era of biologic drugs: lessons from the 15th Turin Congress on Immune Pathology and Orphan Disease. Autoimmun Rev 2013;12:793–5. [8] Ramos-Casals M, Roberto Perez A, Diaz-Lagares C, Cuadrado MJ, Khamashta MA. Autoimmune diseases induced by biological agents: a double-edged sword? Autoimmun Rev 2010;9:188–93. [9] Perez-Alvarez R, Perez-de-Lis M, Ramos-Casals M. Biologics-induced autoimmune diseases. Curr Opin Rheumatol 2013;25:56–64. [10] Kaneko K, Nanki T, Hosoya T, Mizoguchi F, Miyasaka N. Etanercept-induced necrotizing crescentic glomerulonephritis in two patients with rheumatoid arthritis. Mod Rheumatol 2010;20:632–6. [11] Kaushik P, Rahmani M, Ellison W. Membranous glomerulonephritis with the use of etanercept in ankylosing spondylitis. Ann Pharmacother 2011;45:e62. [12] Maruotti N, Corrado A, Gaudio A, Cantatore FP. Membranous nephropathy in rheumatoid arthritis: a case report. Clin Exp Rheumatol 2009;27:840–2. [13] Stokes MB, Foster K, Markowitz GS, Ebrahimi F, Hines W, Kaufman D, et al. Development of glomerulonephritis during anti-TNF-alpha therapy for rheumatoid arthritis. Nephrol Dial Transplant 2005;20:1400–6. [14] den Broeder AA, Assmann KJ, van Riel PL, Wetzels JF. Nephrotic syndrome as a complication of anti-TNFalpha in a patient with rheumatoid arthritis. Neth J Med 2003;61:137–41. [15] Jacquet A, Francois H, Frangie C, Yahiaoui Y, Ferlicot S, Micelli C, et al. IgA nephropathy associated with ankylosing spondylitis is not controlled by infliximab therapy. Nephrol Dial Transplant 2009;24:3540–2. [16] Matsuo Y, Mizoguchi F, Kohsaka H, Ito E, Eishi Y, Miyasaka N. Tocilizumab-induced immune complex glomerulonephritis in a patient with rheumatoid arthritis. Rheumatology (Oxford) 2013;52:1341–3. [17] Michel M, Henri P, Vincent F, Leon N, Marcelli C. Mesangial immunoglobulin (Ig)A glomerulonephritis in a patient with rheumatoid arthritis treated with abatacept. Joint Bone Spine 2013;80:660–3. [18] Korsten P, Sweiss NJ, Nagorsnik U, Niewold TB, Grone HJ, Gross O, et al. Druginduced granulomatous interstitial nephritis in a patient with ankylosing spondylitis during therapy with adalimumab. Am J Kidney Dis 2010;56:e17–21. [19] Nishimura K, Saegusa J, Kawano S, Morinobu A. Tumor necrosis factor-alpha inhibitor-induced antiglomerular basement membrane antibody disease in a patient with rheumatoid arthritis. J Rheumatol 2012;39:1904–5. [20] Tosovsky M, Bradna P, Laco J, Podhola M, Soukup T, Brozik J. Case 1–2012: ANCA associated glomerulonephritis in combination with IgG4-positive mediastinal mass
[21] [22] [23]
[24] [25]
[26] [27] [28] [29]
[30] [31] [32]
[33]
[34]
[35] [36] [37]
[38]
[39]
[40]
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[43] [44] [45]
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