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Table of Contents
Year : 2020  |  Volume : 9  |  Issue : 2  |  Page : 124-127

Anti-glomerular basement membrane-antibody disease in a patient treated with adalimumab for rheumatoid arthritis

1 Renal Services, Toowoomba Hospital, Darling Downs Hospital and Health Service, Toowoomba, Australia
2 Department of Anatomical Pathology, Royal Brisbane and Women’s Hospital, Metro North Hospital and Health Service, Brisbane, Queensland, Australia

Date of Submission12-Jun-2018
Date of Decision17-Jun-2019
Date of Acceptance17-Aug-2019
Date of Web Publication4-Aug-2020

Correspondence Address:
Sree Krishna Venuthurupalli
Senior Consultant, Nephrology Services, Ipswich Hospital, West Moreton Health, Ipswich, Queensland
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/JCSR.JCSR_15_20

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Ttumour necrosis factor-alpha (TNF-α) blockade has been linked to the induction of autoimmunity, including autoimmune renal disorders. To our knowledge, there have been no cases of anti-TNF-α therapy associated with anti-glomerular basement membrane (GBM)-antibody disease reported. A 63-year-old male presented with anuric acute renal failure and was found to have a rapidly progressive glomerulonephritis secondary to anti-GBM-antibody disease. This occurred in the setting of 4 years of adalimumab treatment for rheumatoid arthritis and normal baseline renal function. This was preceded by a gastrointestinal illness and nonsteroidal anti-inflammatory use. His anti-GBM titre was >1000 chemiluminescent units at presentation. A renal biopsy revealed a crescentic necrotising glomerulonephritis with linear staining of immunoglobulin G in the GBM. He was treated with pulse intravenous methylprednisolone and later changed to high-dose prednisolone and cyclophosphamide. Four weeks of plasma exchange was completed. He remains dialysis dependent. There is a known association between TNF-α blockade and occurrence of autoimmune renal diseases. Given the rarity of anti-GBM-antibody disease, it is plausible that there could be an association between treatment with adalimumab and anti-GBM-antibody disease., the present case highlights the ongoing need for monitoring of renal function, urinary sediment and proteinuria in patients exposed to these novel therapies.

Keywords: Adalimumab, anti-glomerular basement membrane-antibody disease, rheumatoid arthritis

How to cite this article:
Heron V, Nicholson M, Wilkinson S, Young A, Govindarajulu S, Stewart A, Venuthurupalli SK. Anti-glomerular basement membrane-antibody disease in a patient treated with adalimumab for rheumatoid arthritis. J Clin Sci Res 2020;9:124-7

How to cite this URL:
Heron V, Nicholson M, Wilkinson S, Young A, Govindarajulu S, Stewart A, Venuthurupalli SK. Anti-glomerular basement membrane-antibody disease in a patient treated with adalimumab for rheumatoid arthritis. J Clin Sci Res [serial online] 2020 [cited 2020 Oct 31];9:124-7. Available from: https://www.jcsr.co.in/text.asp?2020/9/2/124/291368

  Introduction Top

As the use of anti–tumour necrosis factor-alpha (TNF-α) treatments for rheumatic and systemic autoimmune disorders increases, so does our understanding of their adverse effects. TNF-α blockade has been linked to the induction of autoimmunity, including autoimmune renal disorders. To our knowledge there have been no cases of anti-TNF-α therapy associated with anti-glomerular basement membrane (GBM) antibody disease reported. We present a case of rapidly progressive glomerulonephritis secondary to anti-GBM antibody disease.

  Case Report Top

A 63-year-old male was transferred to a regional referral hospital with a 48-h history acute anuric renal failure. He had initially presented to his general practitioner with 1 week of vomiting and diarrhoea following a cruise trip and was found to have an acute kidney injury (AKI). Initial investigations showed a creatinine of 275 umol/L (compared with 88 μmol/L 2 months prior) and an estimated glomerular filtration rate (eGFR) of 20 mL/min/1.732 (previously 80 mL/min/1.73 m2). On arrival to his local hospital, he was found to have a worsening AKI with a creatinine of 1170 μ mol/L and an eGFR of 4 mL/min/1.732. Renal ultrasonography showed no obstruction or structural abnormality. A catheter urine specimen showed >500 erythrocytes with a protein-to-creatinine ratio of 1400 g/mol (reference value <15).

The patient's medical history was notable for seronegative rheumatoid arthritis (RA) and hypertension. His medications at the time of his admission that were administered orally, daily were leflunomide (20 mg), atenolol (50 mg), esomeprazole (40 mg), pregabalin (25 mg), perindopril (8 mg), prednisolone (2 mg), tramadol (200 mg) and celecoxib (200 mg). Further, he was being treated with adalimumab (40 mg fortnightly) for the management of his RA which was commenced 4 years prior to his presentation. Perindopril and celecoxib were stopped on presentation to the hospital.

Initially, he was treated for a presumed prerenal AKI in the setting of dehydration with concomitant nephrotoxin use, although the presence of microscopic glomerular haematuria and proteinuria warranted further workup. His glomerulonephritis screen showed an anti-GBM antibody titre of >1000 chemiluminescent units (reference value <20). The anti-nuclear antibody (ANA), anti-double-stranded DNA (anti-dsDNA) and antineutrophil cytoplasmic antibody results were negative.

He was immediately commenced on high-dose methylprednisolone (1000 mg IV daily), cyclophosphamide and therapeutic plasma exchange (TPE), and a renal biopsy was performed.

The renal biopsy revealed a severe crescentic necrotising glomerulonephritis with up to eight cellular crescents, one fibrocellular crescent and at least four segmental lesions of glomerular tuft fibrinoid necrosis. Almost complete loss of normal glomerular architecture was present in at least three glomeruli and partial glomerular tuft collapse was present in approximately a third of the sampled glomeruli. There was a moderate linear staining in the glomerular basement membrane (GBM) for immunoglobulin (Ig) G and with negative staining for Igs, complement and light chains consistent with a diagnosis of anti-GBM disease.

With the confirmed diagnosis of anti-GBM-antibody disease, the patient continued on regular TPE, in conjunction with 3 days of intravenous methylprednisolone followed by high-dose oral prednisolone. Serial titres of anti-GBM antibodies showed a declining trend; however, due to severe upper gastrointestinal bleeding from duodenal and gastric ulcers, plasma exchange was ceased after 4 weeks. The patient continues on cyclophosphamide as well as 5 mg of prednisolone. He remains dialysis dependant. He is being worked up for a renal transplant, and tissue typing found the presence of the HLA DRB1*15 alleles.

  Discussion Top

Anti-GBM-antibody disease is an autoimmune condition whereby autoantibodies target Type IV collagen which is present in the glomerular and alveolar basement membrane. In Australia and New Zealand, it accounts for <1% of cases of end-stage kidney disease.[1] When presenting with acute renal impairment requiring renal replacement therapy, the disease portends a poor renal prognosis with 3% of cases of anti-GBM disease recovering to be dialysis independent in the Australasian cohort.[1]

TNF-α is a pro-inflammatory cytokine which is implicated in both the innate and adaptive immune response. It plays a role in many rheumatic and systemic autoimmune disorders and therefore has been used as a target for drug therapy. Anti-TNF-α treatments have redefined the management of inflammatory rheumatic diseases and are being more frequently used. Adalimumab is a fully humanised monoclonal antibody which binds to soluble and membrane-bound TNF-α.[2],[3],[4] While these medications are often well tolerated, the growth in their use as well as longer follow-up times means that adverse effects are being more frequently reported and better understood.[5]

The paradoxical development of autoimmune disease with the use of TNF-α inhibitors has been known and investigated for sometime.[6],[7] These reports range from induction of autoantibodies, including ANA, anti-dsDNA and anticardiolipin antibody,[2],[5] to life-threatening systemic disorders.[6] Specifically, renal diseases associated with TNF-blockade include renal vasculitis, lupus nephritis, Henoch–Schonlein purpura, membranous glomerulonephritis, IgA nephritis, minimal change disease, granulomatous interstitial nephritis and renal sarcoidosis.[2],[4],[5],[6],[7],[8],[9] To date, we are unaware of a case of anti-GBM disease associated with TNF-α inhibition being reported in the literature. However, a report documented two cases with anti-GBM-antibody disease in patients treated with the anti-CD52 monoclonal antibody, alemtuzumab, which is also known to potentiate autoimmune disease. Both the patients carried the anti-GBM susceptibility allele HLA DRB1*15 which was also present in this case.[10] Other factors thought to precipitate anti-GBM-antibody disease include preceding infection, which was present in this case, hydrocarbons and cigarette smoking.[11]

The understanding of the association between TNF-α inhibition and autoimmunity is incomplete. These medications may favour Th-2 cytokine production and this imbalance may induce antibody production.[4],[6],[7],[12] Alternatively, it has been hypothesised that alterations to immune regulation which increase susceptibility to infection may encourage molecular mimicry.[6],[13] Finally, autoantigens may be released following inflammatory cell apoptosis due to the binding of TNF-α which subsequently promote the production of autoantibodies.[2],[6],[12]

While a substantial proportion of TNF-α-associated autoimmune renal disorders (AIRD) have been reported as case reports, there are cohort studies which have examined the association between the use of these medications and autoimmune diseases.[5],[6],[7],[9] Similar to our case, in these studies, RA was the most frequent disease associated with the development of autoimmune disorders.[5],[6],[7],[9] Piga et al. performed a review of the literature of patients with rheumatic diseases treated with biologics who developed an AIRD. Interestingly, 22 of 29 cases were RA patients, with etanercept being the cause in about 51% of cases, followed by adalimumab (31.0%), infliximab (10.3%), tocilizumab and abatacept (3.4% each).[6]

Many reports have found a temporal relationship between the commencement of anti-TNF-α medications and onset of autoimmune disease; however, examining the literature, the duration of therapy prior to disease onset ranged from 2 to 72 months.[2],[4],[7],[12] The 4-year duration of treatment preceding the onset of disease in this case was longer than other case reports. This and the preceding infection, which could have been a trigger for the disease,[5],[12] are arguments against the association of adalimumab and anti-GBM-antibody disease in this case. Nevertheless, anti-TNF-α treatments are known to potentiate the development of autoantibodies and the presence of the HLA DRB1*15, which is a known susceptibility allele, favour the association between the disease and medication. Using the World Health Organisation–Uppsala Monitoring Centre causality assessment scale, this association falls into the category of “possible.”[14] However, given the sporadic nature of anti-GBM-antibody disease, it is difficult to prove a causal relationship between it and adalimumab therapy; however, this could proabably be the first reported case.

Cessation of the medication, sometimes in addition to immunosuppression was often, but not always, associated with improvement in disease.[2],[3],[4],[6]

While AIRD associated with TNF-α blockade remains rare, the rising use of these medications and the increased length of follow-up mean that more cases will present. This is a case of anti-GBM-antibody disease in a patient on adalimumab therapy for RA. While the duration of therapy was longer than previously reported cases, given the association between TNF-α blockade and autoimmune renal diseases, monitoring of blood pressure, renal function, urine sediment and the autoantibody profile should be regularly undertaken in any patient prior to commencement and while on this therapy. This is particularly important because delayed diagnosis of anti-GBM disease impairs renal recovery.


A part of this work “Heron V, Nicholson M, Wilkinson S, Young A, Govindarajulu S, Venuthurupalli S. Anti-glomerular basement membrane antibody disease in a patient treated with adalimumab for rheumatoid arthritis”was presented as a poster at the 2018 Annual Scientific Meeting of the Australian and New Zealand Society of Nephrology, Society of Nephrology, Sydney, Australia, September, 2018.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Tang W, McDonald SP, Hawley CM, Badve SV, Boudville NC, Brown FG, et al. Anti-glomerular basement membrane antibody disease is an uncommon cause of end-stage renal disease. Kidney Int 2013;83:503-10.  Back to cited text no. 1
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.  Back to cited text no. 2
Li X, Ma J, Zhao Y, Wang HY, Li XM. Development of crescentic immunoglobulin a nephritis and multiple autoantibodies in a patient during adalimumab treatment for rheumatoid arthritis. Chin Med J (Engl) 2015;128:2555-6.  Back to cited text no. 3
Wei SS, Sinniah R. Adalimumab (TNF? inhibitor) therapy exacerbates IgA glomerulonephritis acute renal injury and induces lupus autoantibodies in a psoriasis patient. Case Rep Nephrol 2013;2013:1-4.  Back to cited text no. 4
Ramos-Casals M, Brito-Zerón P, Muñoz S, Soria N, Galiana D, Bertolaccini L, et al. Autoimmune diseases induced by TNF-targeted therapies: Analysis of 233 cases. Medicine (Baltimore) 2007;86:242-51.  Back to cited text no. 5
Piga M, Chessa E, Ibba V, Mura V, Floris A, Cauli A, et al. Biologics-induced autoimmune renal disorders in chronic inflammatory rheumatic diseases: Systematic literature review and analysis of a monocentric cohort. Autoimmun Rev 2014;13:873-9.  Back to cited text no. 6
Sokumbi O, Wetter DA, Makol A, Warrington KJ. Vasculitis associated with tumor necrosis factor-α inhibitors. Mayo Clin Proc 2012;87:739-45.  Back to cited text no. 7
LaConti JJ, Donet JA, Cho-Vega JH, Sussman DA, Ascherman D, Deshpande AR. Henoch-Schönlein purpura with adalimumab therapy for ulcerative colitis: A case report and review of the literature. Case Rep Rheumatol 2016;2016:2812980.  Back to cited text no. 8
De Bandt M, Sibilia J, Le Loët X, Prouzeau S, Fautrel B, Marcelli C, et al. Systemic lupus erythematosus induced by anti-tumour necrosis factor alpha therapy: A French national survey. Arthritis Res Ther 2005;7:R545-51.  Back to cited text no. 9
Clatworthy MR, Wallin EF, Jayne DR. Anti-glomerular basement membrane disease after alemtuzumab. N Engl J Med 2008;359:768-9.  Back to cited text no. 10
Pusey CD. Anti-glomerular basement membrane disease. Kidney Int 2003;64:1535-50.  Back to cited text no. 11
McAdoo SP, Pusey CD. Is there a role for TNFa blockade in ANCA-associated vasculitis and glomerulonephritis? Nephrol Dial Transplant 2017;32:i80-8.  Back to cited text no. 12
Prinz JC. Autoimmune-like syndromes during TNF blockade: Does infection have a role? Nat Rev Rheumatol 2011;7:429-34.  Back to cited text no. 13
Uppsala Monitoring Centre. The Use of the WHO-UMC System for Standardized Case Causality Assessment. Uppsala Monitoring Centre; 2018. Available from: https://www.who-umc.org/media/164200/who-umc-causality-assessment_new-logo.pdf. [Last updated on 2018 Apr 06; Last accessed on 2019 Feb 23].  Back to cited text no. 14


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