1 Department of Pathology, Columbia University College of Physicians and Surgeons, New York, NY, USA, 2 St Vincent's Hospital, Staten Island, NY, USA, 3 Stamford Nephrology, Stamford, CT, USA, 4 North Shore Medical Group, Huntington, NY, USA, 5 Suffolk Nephrology Consultants, Stony Brook, NY, USA and 6 Fairfax Hospital, VA, USA
Correspondence and offprint requests to: M. Barry Stokes, MD, Department of Pathology, Renal Pathology Laboratory, VC14-224, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA. Email: mbs2101{at}columbia.edu
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Abstract |
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Methods. We report the clinical and pathologic findings in five patients with longstanding rheumatoid arthritis (duration of rheumatoid arthritis, 1030 years; mean, 23 years) who developed new onset of glomerular disease after commencing therapy with anti-TNF agents (duration of therapy, 330 months; median, 6 months).
Results. At presentation, three patients were receiving etanercept, one adalimumab and one infliximab. Two subjects presented with acute renal insufficiency, haematuria, nephrotic-range proteinuria, positive lupus serologies, and hypocomplementemia, and renal biopsies showed proliferative lupus nephritis. Two individuals presented with new onset renal insufficiency, haematuria and proteinuria, and renal biopsies showed pauci-immune necrotizing and crescentic glomerulonephritis. One of these subjects, who had anti-myeloperoxidase autoantibodies, also developed pulmonary vasculitis. The fifth patient presented with nephrotic syndrome and renal biopsy findings of membranous glomerulonephritis, associated with immune complex renal vasculitis. A pathogenic role for anti-TNF therapy is suggested by the close temporal relationship with development of glomerular disease, and by the improvement in clinical and laboratory abnormalities after drug withdrawal and initiation of immunosuppressive therapy in most cases.
Conclusions. Rheumatoid arthritis patients receiving anti-TNF agents may develop glomerulonephritis via the induction of rheumatoid arthritis-related nephropathy or de novo autoimmune disorders.
Keywords: adalimumab; etanercept; glomerulonephritis; infliximab; lupus; TNF
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Introduction |
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Use of anti-TNF agents leads to formation of autoantibodies, including antinuclear antibodies (ANA), anti-double stranded DNA (dsDNA) antibodies, and anticardiolipin antibodies (ACL) in a significant subset of RA patients, suggesting a role for TNF
in normal immune regulation [3,4]. Several cases of a mild, reversible lupus-like syndrome have been reported, none of which had neurological or renal involvement [3,4]. Etanercept has also been linked to other disease manifestations that may have an immunologic basis, including cutaneous leukocytoclastic vasculitis [5], accelerated rheumatoid nodulosis [6] and anti-neutrophil cytoplasmic autoantibodies (ANCA)-related vasculitis [7]. The findings that anti-TNF
therapy may induce flares of autoimmune disease in man [6] are consistent with the converse observation that exogenous administration of TNF
suppresses autoimmune manifestations in murine lupus [8].
Three previous reports have described biopsy-proven glomerular disease in four RA patients while receiving anti-TNF therapy [7,9,10]. One subject, who had perinuclear anti-neutrophil cytoplasmic autoantibodies (pANCA) prior to starting therapy, developed pauci-immune necrotizing and crescentic glomerulonephritis during treatment with etanercept [7]. Another individual, who had previously received gold salts, developed steroid-responsive nephrotic syndrome during treatment with adalimumab and renal biopsy showed advanced membranous nephropathy [9]. Two additional RA patients who developed new onset of renal insufficiency and proteinuria following etanercept therapy showed renal biopsy findings of IgA nephropathy [10]. Whether these cases represent co-incidental disease, RA nephropathy or a drug reaction is unclear.
We report five additional patients with longstanding RA who developed new-onset of glomerular disease while receiving TNF antagonists. The temporal relationship to drug use suggests induction of RA-related nephropathy or de novo autoimmune disorders. The clinical-pathologic features and possible pathogenetic mechanisms of this under-recognized complication are discussed.
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Subjects and methods |
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Results |
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Renal biopsy findings
Light microscopy revealed 64 glomeruli, 28 of which showed global sclerosis. Nineteen glomeruli contained cellular or fibrocellular crescents. Glomerular tufts displayed diffuse mesangial and endocapillary proliferation with segmental duplication of glomerular basement membranes, leukocyte infiltration, and rare subendothelial wire-loop deposits. Several glomeruli showed segmental fibrinoid necrosis or karyorrhexis. There was moderate tubular atrophy, interstitial fibrosis, and interstitial inflammation, and red cell casts were noted. Arterioles were severely occluded by eosinophilic intimal deposits, mucoid intimal edema and concentric fibroplasia. One arteriole contained intraluminal fibrin but no arteritis was noted. Immunofluorescence microscopy disclosed granular mesangial and glomerular capillary wall staining for IgG and C3, and focal staining for fibrinogen. Glomeruli were negative for IgM, IgA and C1q. Arterioles stained for IgG, C3 and C1q. Electron microscopy confirmed the presence of diffuse mesangial, segmental subendothelial, and rare subepithelial immune-type electron-dense deposits. No endothelial tubuloreticular inclusions were seen. The final diagnosis was diffuse proliferative immune complex glomerulonephritis with immune complex vasculopathy, consistent with diffuse proliferative lupus nephritis (class IV) [12].
Post-biopsy clinical course
Following biopsy, etanercept was discontinued and the patient received prednisone 60 mg QD, tapering to 5 mg/day over 4 months, followed by mycophenolate mofetil. At last follow up (16 months post-biopsy), serum creatinine had fallen to 1.6 mg/dl (141 µmol/l) and 24 h urinary protein excretion had decreased to 0.6 g. ANA remained positive, albeit with reduced titre (1:160, speckled), and dsDNA antibody was positive. C3 and C4 had returned to normal levels.
Case 2
A 52-year-old female with a 22-year history of RF-positive RA, leading to joint replacement surgery in both hands, presented with gross haematuria and acute renal failure 1 week after receiving her third monthly dose of adalimumab (40 mg sc). Other medications included prednisone 5 mg/day, mycophenolate mofetil, procrit, valdecoxib, folic acid, aciphex and ambien. Infliximab therapy had been initiated 1 year before, but this was discontinued after 1 month when the patient developed hypertension and angioedema. In the past year, she had also received methotrexate and plaquenil, and in the remote past she had received penicillamine and gold. Of note, proteinuria and renal insufficiency were never detected prior to the current admission. She had never had a history of malar rash or other clinical evidence to suggest overlap with SLE. Multiple tests for ANA and anti-dsDNA in previous years were negative. Serum creatinine on admission was 1.7 mg/dl (150 µmol/l), [baseline 1.1 mg/dl (97 µmol/l) 2 months previously] and urinalysis showed 3+ protein, >20 red blood cells (RBC)/high power field and granular casts. Twenty-four hour urinary protein excretion was 3.8 g. Serologic testing revealed positive RF, positive ANA (1:640, homogenous pattern), and positive anti-dsDNA IgG antibody (1:25). Both complement C3 and C4 components were decreased. Tests for pANCA, cANCA and cryoglobulin were negative; however, an atypical ANCA of undetermined specificity was detected. Serum creatinine rose to 3.7 mg/dl (327 µmol/l) over the next 2 weeks, and a renal biopsy was performed.
Renal biopsy findings
Light microscopy revealed 14 glomeruli, two of which were globally sclerotic. Glomeruli displayed mild diffuse mesangial proliferation; five glomeruli also showed segmental endocapillary proliferation with infiltrating neutrophils and focal fibrinoid necrosis, and four glomeruli showed cellular crescents. Segmental subendothelial fuchsinophilic deposits and focal intraluminal hyaline thrombi were seen. There was marked diffuse interstitial inflammation, with focal red blood cell casts. Moderate arteriosclerosis was noted, but no arteritis was seen. Immunofluorescence microscopy revealed full-house global granular mesangial and segmental glomerular capillary wall staining for IgG, IgM, IgA, C3 and C1q. Tubular basement membranes stained focally for IgG and C3. Electron microscopy disclosed widespread mesangial and segmental subendothelial immune-type electron-dense deposits. Endothelial tubuloreticular inclusions were noted. The final diagnosis was focal proliferative lupus nephritis (class III) [12].
Post-biopsy clinical course
Following biopsy, adalimumab was discontinued and the patient received pulse solumedrol, followed by a tapering dose of oral steroids for 1 month. At last follow-up (4 months post-biopsy) serum creatinine had fallen to 1.1 mg/dl (97 µmol/l) and urinary protein excretion declined to 1.7 g/day. ANA titre had decreased to 1:160 and complement levels had returned to normal.
Case 3
A 55-year-old male with a 10-year history of severe RF-positive RA involving multiple joints presented with new onset of renal failure, 4 months after initiation of etanercept therapy. Previous tests of renal function and urinalyses were normal. There was no prior history of rheumatoid nodules, skin rash, eye abnormalities, hypertension or diabetes. In the past, he had been treated with methotrexate but had never received gold or penicillamine. On admission, the patient was noted to have alopecia, an upper body maculo-papular rash, and signs of lower extremity sensory neuropathy. Laboratory testing revealed a serum creatinine of 3.0 mg/dl (265 µmol/l), 24 urinary protein excretion 1 g/day, and serum albumin 2.2 g/dl (22 g/l). Urinalysis revealed 1+ protein, >5 RBCs/high power field, >5 white blood cells/high power field and no cellular casts. ANA (1:320) and anti-myeloperoxidase pANCA (>300) were positive; anti-dsDNA antibody and cANCA were negative. C3 and C4 complement levels were within normal limits, and serologic testing for hepatitis C virus, human immunodeficiency virus, and hepatitis B surface antigen, were all negative. ANA or ANCA serologies prior to the current presentation were not known.
Renal biopsy findings
Light microscopy revealed 27 glomeruli, 19 of which displayed global sclerosis, including some with evidence of fibrous crescents. Four of the remaining eight glomeruli showed segmental fibrinoid necrosis, including two with cellular crescents. Three additional glomeruli showed tuft adhesions to Bowman's capsule, including one with a fibrocellular crescent. The remaining glomerulus was histologically unremarkable. There was mild tubular atrophy, interstitial fibrosis, and interstitial inflammation. There was mild arteriosclerosis and no evidence of arteritis. Immunofluorescence stains for IgG, IgM, IgA, C3, C1q , and
light chains were negative, and electron microscopy disclosed no immune-type electron-dense deposits or endothelial tubuloreticular inclusions. The final diagnosis was pANCA-associated focal segmental necrotizing and crescentic glomerulonephritis.
Post-biopsy clinical course
Following renal biopsy, intravenous cytoxan was initiated. Etanercept therapy was continued for 4 more months. During this period, the patient developed haemoptysis and an open lung biopsy revealed alveolar haemorrhage with capillaritis, consistent with pulmonary vasculitis. Immunofluorescence studies for immunoglobulins and complement revealed no evidence of granular or linear deposits, providing evidence against lupus pneumonitis and Goodpasture's syndrome, and supporting the diagnosis of pauci-immune pulmonary vasculitis. Etanercept was discontinued, but over the next 5 months the patient developed multiple severe infections, including shingles and septic arthritis. HIV testing was negative. The last serum creatinine, measured 8 months post-biopsy, was 2.3 mg/dl (203 µmol/l). The patient expired 9 months following the renal biopsy. No autopsy was performed.
Case 4
A 64-year-old female with a 30-year history of ANA-negative RA, characterized by deforming arthritis of all hand and feet joints, was noted to have microhematuria and 2+ dipstick proteinuria, 10 months after starting infliximab therapy. She had well controlled hypertension for 30 years and diet-controlled type II diabetes mellitus for 1 year. There was no history of rheumatoid nodules, eye disease or pulmonary disease. Current medications included enalapril, prednisone 5 mg qd and acetaminophen-propoxyphene napsylate. She had received a 6-month course of gold salts and penicillamine more than 10 years previously. Methotrexate had been used for 1 year but was discontinued due to gastrointestinal upset. Non-steroidal anti-inflammatory drugs (NSAID) and azathioprine had been used continuously for 20 and 10 years, respectively. The patient had previously received etanercept for 16 months but this was discontinued when a rash developed; during this time, serum creatinine was stable [0.60.7 mg/dl (5362 µmol/l)] and urinalyses were consistently negative for protein and blood. Following infliximab therapy, injection site reactions were noted for the first 5 months. Blood pressure was normal and no peripheral edema or rash were noted. Ten months after starting infliximab, urinalysis revealed trace proteinuria and 2+ heme. Five months later, repeat urinalysis revealed 2+ protein and RBC casts. Serum creatinine was 1.0 mg/dl (88 µmol/l) [baseline 0.7 mg/dl (62 µmol/l) several months previously] and urinary protein excretion was 1.8 g/day. Serologic tests revealed positive RF and negative ANA, anti-dsDNA, anti-Smith, anti-ribonucleoprotein, anti-myeloperoxidase, and anti-proteinase 3 antibodies. C3 and C4 complement levels were normal. A renal biopsy was performed.
Renal biopsy findings
Light microscopy showed seven glomeruli, two of which were globally sclerotic. Two glomeruli showed fibrocellular crescents and segmental fibrinoid necrosis. Three glomeruli (including the two with crescents) showed small segmental mesangial accumulations of Congophilic material that stained immunohistochemically for amyloid A protein. Two glomeruli appeared histologically normal. There was mild tubular atrophy and interstitial fibrosis and moderate arteriosclerosis. Immunofluorescence microscopy revealed no significant staining for IgG, IgM, IgA, C3, C1q or or
light chains. Electron microscopy demonstrated focal mesangial accumulations of randomly oriented non-branching fibrils measuring 12 nm in diameter. No immune-type electron-dense deposits or endothelial tubulo-reticular inclusions were seen. The final diagnoses were pauci-immune focal segmental necrotizing and crescentic glomerulonephritis and mild secondary (AA) amyloidosis.
Post-biopsy clinical course
Following renal biopsy, infliximab was discontinued. The patient received cytoxan 100 mg qd, followed by IV cytoxan, and prednisone dose was increased to 40 mg/day. At 8 months post-biopsy, urinary protein excretion had increased to 8.5/day and serum creatinine was 1.3 mg/dl (115 µmol/l).
Case 5
A 53-year-old woman with a 30 year history of severe deforming rheumatoid arthritis and Sjogren's syndrome presented with generalized weakness and peripheral sensory neuropathy, 6 months after starting etanercept therapy. She reported foamy urine for several months and a recent episode of herpes zoster infection but denied any history of alopecia, rash, haemoptysis or dry eyes. Medications on admission included etanercept, cytoxan and methrotrexate. Past medication history included use of gold salts 24 years previously. Physical examination revealed pitting lower extremity edema. Laboratory investigations revealed urinary protein excretion of 7.9 g/day, serum albumin 2.6 g/dl (26 g/l) and serum creatinine 0.7 mg/dl (62 µmol/l). She had a low titre ANA (1:160) that had also been noted prior to beginning etanercept. Other tests revealed positive RF and SSA and SSB antibodies, negative cryoglobulins, pANCA, cANCA, and anti-dsDNA antibody, and normal C3, C4 and CH50 complement levels. Chest X-ray showed no evidence of pulmonary haemorrhage or pulmonary infiltrates. A renal biopsy was performed.
Renal biopsy findings
Light microscopy showed 23 glomeruli, one of which was globally sclerotic. There was moderate mesangial hypercellularity and diffuse thickening of glomerular capillary walls with numerous, small, subepithelial, fuchsinophilic deposits, separated by basement membrane spikes. No endocapillary proliferation, necrotizing features, or crescents were identified. There was mild tubular atrophy and interstitial fibrosis, affecting 10% of the cortical area. Arterial vessels showed moderate intimal sclerosis. Two small arteries showed mild endovasculitis and fuchsinophilic deposits, consistent with immune deposits. Immunofluorescence microscopy showed diffuse glomerular capillary wall and mesangial staining for IgG, IgM, C3 and C1q, and focal vessel wall staining for these reagents. Electron microscopy revealed numerous mesangial and subepithelial electron-dense deposits separated by spikes. Endothelial tubuloreticular inclusions were not seen. The final diagnosis was membranous glomerulonephritis (stage 2) and immune complex-mediated renal vasculitis.
Post-biopsy clinical course
Following renal biopsy, etanercept was discontinued and oral prednisone dose was increased to 60 mg daily. After 2 months, cyclosporine was added because of persistent peripheral edema. At last follow-up, 3 months post-biopsy, urinary protein excretion had declined to 1.06 g/day and serum albumin was 2.6 g/dl (26 g/l), with stable renal function (serum creatinine 0.6 mg/dl) (53 µmol/l).
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Discussion |
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In the present report, an etiologic role for anti-TNF therapy in the initiation of glomerulonephritis is supported by the temporal association of drug use with new-onset of nephropathy, often accompanied by new serologic abnormalities, in individuals who had no prior evidence of renal disease. All patients had longstanding RA (range, 1030 years) and none had prior history of systemic lupus, although one patient had a history of rheumatoid vasculitis and one had overlap with Sjogren's syndrome. Three patients were receiving etanercept, one adalimumab, and one infliximab (for 3 to 30 months, median 6 months), indicating that the renal complications are not specific to any one drug formulation and develop following months of therapy. Three subjects had newly detected autoantibodies at the time of onset of renal disease, consistent with drug-induced autoimmunity. In three patients, clinical and/or serologic manifestations improved following discontinuation of anti-TNF
therapy and initiation of immunosuppressive therapy. The single patient in whom etanercept was not discontinued progressed to multisystem vasculitis and subsequently died, despite cytotoxic therapy. One subject reported here (case 4) developed ANCA-negative pauci-immune necrotizing and crescentic glomerulonephritis following infliximab therapy, consistent with induction of RA nephropathy. The worsening proteinuria in this case might have been related to the presence of co-existent secondary (AA) amyloidosis in the renal biopsy. In one case (case 5), the findings of membranous glomerulonephritis and renal vasculitis might be related to RA and/or Sjogren's syndrome. In both of these cases, the new onset of renal disease, following many years of rheumatologic disease without renal involvement, suggest a pathogenic role for anti-TNF
agents in induction of RA-related nephropathy. Taken together, the clinical, serologic and pathologic findings in these cases suggest a pathogenic role for anti-TNF
therapy-related immune dysregulation.
In clinical trials with infliximab for RA, 11% of patients became positive for ANA (vs 5% of controls) and up to 15% developed anti-dsDNA antibodies (vs 4% of controls) [14]. Most of these anti-dsDNA antibodies were of IgM isotype and most were not associated with clinical manifestations of lupus; the one patient who developed a reversible lupus-like syndrome had IgG anti-dsDNA antibodies [14]. Several studies have documented the new onset of a mild lupus-syndrome that resolved following discontinuation of infliximab [3] and etanercept [4]. Both etanercept and infliximab have also been associated with increased formation of anticardiolipin antibodies, with clinically significant thrombotic events occurring in some patients [15]. In the present report, two patients with longstanding RA developed newly positive anti-dsDNA serologies and proliferative lupus nephritis after starting anti-TNF therapy. One of these individuals (case 1) also developed IgG anticardiolipin antibodies that may have contributed pathogenetically to the vascular lesions seen on renal biopsy. Discontinuation of anti-TNF
agent and initiation of immunosuppressive therapy led to improvement in serologic abnormalities and renal function in both patients, supporting a pathogenic role for anti-TNF
-induced autoimmunity.
The mechanisms of anti-TNF induced autoimmunity remain unknown. Charles et al. [14] have proposed that binding of infliximab to TNF
on the plasma membranes of immune cells might induce apoptosis, releasing immunogenic nucleosomal antigens that promote anti-dsDNA antibody formation. Anti-TNF
-treated individuals have lower levels of C reactive protein, which normally clears apoptotic debris, possibly contributing to a higher immunogenic load [16]. In the (NZB/NZW) F1 model of murine SLE, characterized by low levels of endogenous TNF
production, administration of exogenous TNF
delays onset and slows progression of disease in these mice, suggesting a protective role for TNF
[8]. On the other hand, elevated serum levels of both TNF
and soluble TNF
receptors have been shown to correlate with disease activity in patients with SLE [17] and a recent clinical study described amelioration of disease, including nephritis, in SLE patients undergoing treatment with infliximab, despite induction of anti-dsDNA antibodies and ACL in most patients [18]. Although induction of ANCA was not reported in clinical trials with anti-TNF
agents, the case of pANCA-associated vasculitis reported herein (case 3), together with one other reported case of ANCA-related necrotizing crescentic glomerulonephritis in an RA patient receiving etanercept [7], suggest that anti-TNF
therapy may induce or exacerbate ANCA-related vasculitis in some individuals. Interestingly, both hydralazine or propylthiouracil, which are known to induce ANCA-related glomerulonephritis [19], may also induce ANA, anti-dsDNA, and a lupus-like syndrome [13]. Given the frequent induction of autoantibodies following anti-TNF
therapy, it seems reasonable to hypothesize that this phenomenon may give rise to either lupus-like immune complex glomerulonephritis or ANCA-related necrotizing and crescentic glomerulonephritis in susceptible individuals [20].
In summary, RA patients undergoing therapy with anti-TNF agents who develop new-onset of renal disease manifest a variety of renal pathologic findings, including proliferative lupus glomerulonephritis, pauci-immune necrotizing and crescentic glomerulonephritis (with or without anti-MPO ANCA), and membranous glomerulonephritis with renal vasculitis. An etiologic role for anti-TNF
agents is supported by (i) the temporal relation of new onset glomerular disease to drug use in patients with long-standing RA of many years' duration and no prior renal disease, and (ii) the improvement of clinical symptoms and laboratory abnormalities after drug withdrawal and addition of immunosuppressive therapy in the majority of patients. New onset of glomerular disease following anti-TNF
therapy may reflect induction of RA-related nephropathy or de novo autoimmune disorders secondary to immune dysregulation. Baseline testing for ANA, anti-dsDNA, and ANCA should be performed in all RA patients prior to commencing anti-TNF
therapy to facilitate the identification of new, drug-induced autoimmune phenomena in those rare individuals who subsequently develop glomerular disease.
Conflict of interest statement. None declared.
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References |
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