Multiple Sclerosis and Related Disorders (2013) 2, 60–63

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CASE REPORT

Case report of anti-glomerular basement membrane disease following alemtuzumab treatment of relapsing–remitting multiple sclerosis David Meyera,n, Alasdair Colesb, Pedro Oyuelac, Annie Purvisc, David H. Margolinc a

Triad Neurological Associates, Cornerstone Health Care, 145 Kimel Park Drive, Suite 100, Winston Salem, NC 27103, USA Department of Neurosciences, University of Cambridge, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 0QQ, UK c Genzyme Corporation, 500 Kendall Street, Cambridge, MA 02142, USA b

Received 15 June 2012; accepted 19 July 2012

KEYWORDS Anti-glomerular basement membrane disease; Goodpasture’s syndrome; Autoimmune disease; Alemtuzumab; Multiple sclerosis; Pulmonary renal syndrome

1.

Abstract Objective: To report a case of anti-glomerular basement membrane disease (anti-GBM disease) during alemtuzumab treatment of a relapsing–remitting multiple sclerosis (RRMS) patient. Design: Case report. Setting: Outpatient neurology research protocol. Patient: A 35-year-old white female receiving alemtuzumab for RRMS in a clinical research protocol developed symptoms leading to diagnosis of anti-GBM disease. Main outcome measure: Patient response to the treatment of anti-GBM disease and RRMS. Results: Early identification and treatment of anti-GBM disease resolved clinical symptoms and preserved renal function. Alemtuzumab treatment of RRMS resolved initial MS symptoms and appears to have controlled active disease to date. Conclusion: Close monitoring for potential side effects of alemtuzumab treatment in RRMS resulted in a positive outcome when anti-GBM disease was recognized and treated early. & 2012 Elsevier B.V. All rights reserved.

Introduction

Multiple sclerosis can occur in association with other autoimmune diseases, including a few cases of anti-glomerular n

basement membrane disease (anti-GBM disease, Goodpasture’s syndrome) (Henderson et al., 2000). Anti-GBM disease is a rare (incidence 0.1 cases per million) and potentially life-threatening organ-specific disorder in which circulating

Corresponding author. Tel.: +1 336 972 3675; fax: +1 336 760 9393 E-mail addresses: [email protected], [email protected] (D. Meyer), [email protected] (A. Coles), pedro.oyuela@gen zyme.com (P. Oyuela), [email protected] (A. Purvis), [email protected] (D.H. Margolin). 2211-0348/$ - see front matter & 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.msard.2012.07.002

Case report of antilomerular basement membrane disease antibodies are directed against the alpha-3 chain of type IV collagen present in the basement membrane of renal glomeruli and pulmonary alveoli (Levy and Pusey, 1997; Ooi et al., 2008). The resulting clinical spectrum ranges from mild or no renal involvement to rapidly progressive glomerulonephritis. Patients may also develop pulmonary hemorrhage. Alemtuzumab is a humanized monoclonal antibody currently in phase 3 trials for the treatment of relapsing– remitting multiple sclerosis (RRMS). Anti-GBM disease was previously reported following alemtuzumab treatment for MS (Coles et al., 2006; Clatworthy et al., 2008). We present a case of anti-GBM disease arising in a phase 2 trial of alemtuzumab for the treatment of RRMS (Coles, 2009; Meyer et al., 2010).

2.

Report of case

MS was diagnosed at age 31 with a history of Z2 prior neurological events. 11 months earlier, the patient reported numbness of the right side of her mouth and tongue and gait imbalance; symptoms resolved without treatment. Several months later, she experienced similar symptoms on the left side of her face, again associated with ataxia, all of which resolved without treatment. Prior to study entry, MRI scan showed multiple T2hyperintense lesions with 2 gadolinium-enhancing lesions in the brainstem. Prior medical history included endometriosis; medications included naproxen sodium, tramadol hydrochloride with acetaminophen, and ibuprofen. As part of the phase 2 CAMMS223 trial (ClinicalTrials.gov NCT00050778), the patient received 2 annual cycles of intravenous alemtuzumab 12 mg/day (5 days at Month 0 and 3 days at Month 12) for a cumulative dose of 96 mg (Coles et al. 2008). Baseline Expanded Disability Status Scale (EDSS) score was 0 and creatinine was normal (71 mmol/L, 0.8 mg/dL). At Month 23, she became pregnant. At Month 24 she developed mild and asymptomatic hypothyroidism. Treatment with 100 mcg levothyroxine was initiated at Month 31. At Month 32, the patient delivered a healthy baby. Thyroid function tests normalized on treatment; anti-TSH receptor antibodies remained positive at 40 IU/L at Month 48. At Month 51, routine quarterly blood chemistry monitoring identified an increase in serum creatinine to 163.0 mmol/L (1.8 mg/dL, normal range 0.6–1.1 mg/dL) (Fig. 1). At approximately the same time, the patient experienced but did not report an upper respiratory infection, rash on her thighs, and hematuria. At Month 52, she had a nephrology consultation, where she retrospectively reported the symptoms above. Creatinine was 185.6 mmol/L (2.1 mg/dL, unscheduled lab not reflected in figure). Nine days later, she was admitted to the hospital for CT-guided renal biopsy. The biopsy revealed moderately increased cellularity with both mesangial and segmental endocapillary proliferation (Fig. 2a). Some glomeruli showed segmental cellular crescent formation with occasional associated segmental necrotizing capillary loop lesions. The tubulo-interstitial region showed mild to moderate interstitial inflammation and edema and no evidence of extraglomerular vasculitis. In

61 the immuno-fluorescence examination (Fig. 2b), the glomerular basement membranes showed linear positivity for IgG and kappa and lambda light chains. Two glomeruli showed segmental positivity for fibrinogen. Electron microscopy revealed an injury pattern characterized by segmental areas of basement membrane thinning and occasional segmental areas of new basement membrane formation. The epithelial foot processes showed segmental areas of mild effacement estimated at 20%. No electron dense deposits were identified. The biopsy diagnosis was necrotizing and crescentic glomerulonephritis, consistent with anti-GBM disease. Creatinine was 229.8 mmol/L (2.6 mg/dL, unscheduled lab not reflected in figure). There was no evidence of pulmonary hemorrhage. The patient’s blood was tested for anti-GBM IgG with ELISA and immunofluorescent antibody (IFA) assays; both were negative. Anti-GBM disease treatment included plasmapheresis every other day for 3 weeks, cyclophosphamide at a cumulative dose of 13.5 g over 6 months, and 60 mg prednisone per day for 3 months followed by a slow taper over an additional 3 months. The patient tolerated treatment well but developed leukopenia, which responded well to decreased cyclophosphamide dose. 26 months after diagnosis of anti-GBM disease, the patient remained in remission without clinical sequelae. Serum creatinine was normal at 88.4 mmol/L (1.0 mg/dL) and estimated glomerular filtration rate was normal at 460 mL/min. The patient also continued to be MS relapse-free with an EDSS score of 0.

3.

Comment

We describe a case of anti-GBM disease following alemtuzumab treatment of an RRMS patient in the CAMMS223 trial. Two other cases of anti-GBM disease in alemtuzumab-

Fig. 1 Creatinine trends and treatment of anti-GBM disease. Solid vertical lines indicate alemtuzumab cycles; dashed vertical line indicates anti-GBM disease diagnosis; horizontal solid line indicates ULN for creatinine; green arrow indicates antiGBM disease treatment: P plasmapheresis, PR prednisone, C cyclophosphamide. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

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D. Meyer et al.

Segmental Crescent

Linear IgG

Fig. 2 Histology of renal biopsy showing (A) crescentic glomerulonephritis and (B) linear deposition of IgG, a staining pattern pathognomonic for anti-GBM disease. Images courtesy of Alexander Hadley, MD.

treated MS patients occurred outside this trial and both had progressed to chronic renal failure by the time of diagnosis and required renal transplantation; neither developed pulmonary manifestations of anti-GBM disease. The first patient, reported by Coles et al. (2006) and Clatworthy et al. (2008) was a 40-year-old female participating in pilot studies of alemtuzumab for MS. She received 1 cycle of alemtuzumab 20 mg/day for a cumulative dose of 100 mg. 10 months following treatment, she developed flulike symptoms and presented with right heart failure from fluid overload. Creatinine was 45 mg/dL and high-titer anti-GBM serum antibodies were present. She was treated with plasmapheresis, pulsed cyclophosphamide, and corticosteroids. The patient required dialysis and ultimately renal transplantation. Her anti-GBM disease remains in remission. The second patient was a 35-year-old female receiving alemtuzumab treatment for MS outside of a clinical protocol (data on file). She received 2 cycles of alemtuzumab 20 mg/ day for a cumulative dose of 160 mg. 36 months after first alemtuzumab exposure and 24 months after last exposure,

she presented with fever, flu-like illness, and hematuria and a creatinine of 10.5 mg/dL. She was diagnosed with antiGBM disease and treated with plasmapheresis, mycophenolate, and steroids prior to renal transplantation. Her antiGBM disease also remains in remission. Anti-GBM disease has also been identified in untreated MS (Henderson et al., 2000). Henderson et al. (1998) described the case of an untreated primary progressive MS patient who developed fatal anti-GBM disease (Henderson et al., 1998). This patient had the human leukocyte antigen haplotype (DRB1n1501-DQA1n0102-DQB1n0602) frequently associated with both diseases, which was also found in the first case of anti-GBM disease described above and in a case of anti-GBM disease following alemtuzumab treatment for ANCA-associated vasculitis (Clatworthy et al., 2008). After presentation of anti-GBM disease, 75–90% of patients survive for Z1 year but only 40% maintain independent renal function (Levy and Pusey, 1997). In a retrospective review of 71 patients treated for anti-GBM disease over 25 years, Levy et al. found that patients presenting with creatinine o500 mmol/L (o5.7 mg/dL) had 100% survival at year 1 and 94% survival at year 5; renal survival was 95% at year 1 and 94% at year 5 (Levy et al., 2001). These data highlight the importance of early identification and treatment. Our case illustrates both the detectable nature of antiGBM disease and the benefit of early intervention. This patient’s anti-GBM disease was identified by routine quarterly blood chemistry monitoring. Following this event, an expert panel of nephrologists was convened and the trial’s monitoring program was improved with enhanced education regarding anti-GBM disease signs and symptoms and intensified renal surveillance (monthly urinalysis and serum creatinine, with more frequent monitoring triggered by abnormal results). Based on the observation that autoimmune disorders in general and glomerular nephropathy and anti-GBM disease in particular usually occur within 40 months following the last dose (data on file), patients receiving alemtuzumab for MS should be monitored for 48 months following the last exposure. While both ELISA and IFA assays for anti-GBM IgG have a high degree of sensitivity, false negative results have been reported (Litwin et al., 1996; Sinico et al., 2006). Negative results in this case may have been due to undetectable titers of the circulating antibodies or to antibodies directed against a different domain than the Goodpasture’s antigen (alpha-3(IV) NC1 proteins) (Charytan et al., 2005). Renal biopsy remains the gold standard of diagnosis for anti-GBM disease and should be performed when possible. In addition to preserved renal function and remission of anti-GBM disease, this patient continues to do well with her MS. More than 5 years following last exposure to alemtuzumab, she has not had any relapse and disability is minimal according to her most recent EDSS of 0. Anti-GBM disease in this patient does not appear to have affected alemtuzumab’s efficacy. Two phase 3 trials comparing alemtuzumab to interferon beta-1a in treatment-naı¨ve patients (ClinicalTrials.gov NCT00530348) and patients who have relapsed on therapy with glatiramer acetate or interferon (ClinicalTrials.gov NCT00548405) will contribute important data on the efficacy and safety of alemtuzumab in RRMS, including risk of anti-GBM

Case report of antilomerular basement membrane disease disease. The relationship between the mechanism of action of alemtuzumab and secondary autoimmunity remains an area of active research (Jones et al., 2009), as does the pathogenesis of anti-GBM disease (Pedchenko et al., 2010).

Financial disclosure Dr. Meyer reports serving on speaker bureaus and advisory boards and receiving consulting fees from Genzyme, Pfizer, Novartis, Biogen Idec, EMD Serono, and Teva. Dr. Alasdair J. Coles reports receiving consulting fees, lecture fees, and institutional grant support from Genzyme, Merck Serono, and UCB-Celltech. Dr. Pedro Oyuela, Ms. Annie Purvis, and Dr. David H. Margolin receive personal compensation as employees of Genzyme (a sanofi company). Funding/Support: Genzyme and Bayer Schering Pharma participated in the design of the initial study and provided financial support. Genzyme participated in data analysis and interpretation, and preparation of this report. The corresponding author had full access to all the data. The decision to submit for publication was made by the corresponding author and Genzyme.

Acknowledgement The authors wish to thank Alexander Hadley, MD, who provided helpful guidance on the patient’s renal course. Jenna Hollenstein, MS, ELS, a medical writer employed by Genzyme, provided writing and editorial assistance to the first author.

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63 25th Congress of the European Committee for Treatment and Research in Multiple Sclerosis; Dusseldorf, Germany; 2009. Coles AJ, Compston DA, Selmaj KW, Lake SL, Moran S, Margolin DH, et al. Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. New England Journal of Medicine 2008;359(17):1786–801. Coles AJ, Cox A, Le Page E, Jones J, Trip SA, Deans J, et al. The window of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy. Journal of Neurology 2006;253(1):98–108. Henderson RD, Bain CJ, Pender MP. The occurrence of autoimmune diseases in patients with multiple sclerosis and their families. Journal of Clinical Neuroscience 2000;7(5):434–7. Henderson RD, Saltissi D, Pender MP. Goodpasture’s syndrome associated with multiple sclerosis. Acta Neurologica Scandinavica 1998;98(2):134–5. Jones JL, Phuah CL, Cox AL, Thompson SA, Ban M, Shawcross J, et al. IL-21 drives secondary autoimmunity in patients with multiple sclerosis, following therapeutic lymphocyte depletion with alemtuzumab (Campath-1H). Journal of Clinical Investigation 2009;119(7):2052–61. Levy JB, Pusey CD. Anti-GBM antibody mediated disease. In: Wilkinson R JR, editor. Nephrology. London: Chapman and Hall; 1997. p. 599–615. Levy JB, Turner AN, Rees AJ, Pusey CD. Long-term outcome of antiglomerular basement membrane antibody disease treated with plasma exchange and immunosuppression. Annals of Internal Medicine 2001;134(11):1033–42. Litwin CM, Mouritsen CL, Wilfahrt PA, Schroder MC, Hill HR. Antiglomerular basement membrane disease: role of enzyme-linked immunosorbent assays in diagnosis. Biochemical and Molecular Medicine 1996;59(1):52–6. Meyer D, Coles A, on behalf of the CAMMS223 Study Group. Case report of anti-glomerular basement membrane disease following alemtuzumab treatment. Presented at the 26th Congress of the European Committee for Treatment and Research in Multiple Sclerosis; Gothenburg, Sweden; 2010. Ooi JD, Holdsworth SR, Kitching AR. Advances in the pathogenesis of Goodpasture’s disease: from epitopes to autoantibodies to effector T cells. Journal of Autoimmunity 2008;31(3): 295–300. Pedchenko V, Bondar O, Fogo AB, Vanacore R, Voziyan P, Kitching AR, et al. Molecular architecture of the Goodpasture autoantigen in anti-GBM nephritis. New England Journal of Medicine 2010;363(4):343–54. Sinico RA, Radice A, Corace C, Sabadini E, Bollini B. Anti-glomerular basement membrane antibodies in the diagnosis of Goodpasture syndrome: a comparison of different assays. Nephrology Dialysis Transplantation 2006;21(2):397–401.

Case report of anti-glomerular basement membrane disease following alemtuzumab treatment of relapsing-remitting multiple sclerosis.

To report a case of anti-glomerular basement membrane disease (anti-GBM disease) during alemtuzumab treatment of a relapsing-remitting multiple sclero...
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