| |
|
|
| Year : 2012 | Volume
: 23
| Issue : 2 | Page : 334-337 |
|
| Rituximab in the treatment of refractory lupus nephritis with vasculitis |
|
|
Huseyin Kadikoy1, Waqar Haque1, Salman Ahmed1, Abdul Abdellatif2
1 Department of Medicine, Baylor College of Medicine, Houston, TX, 77030, USA
2 Department of Medicine and Division of Nephrology, Baylor College of Medicine, Houston, TX, 77030, USA
Click here for correspondence address and email
| Date of Web Publication | 28-Feb-2012 |
|
|
 |
|
 Abstract | | |
Dysfunction of the B lymphocyte, an important component of adaptive immunity, is thought to be important in the pathogenesis of lupus nephritis (LN). There are several novel strategies emerging including B-cell depletion by the monoclonal antibodies to B-cell markers, rituximab. We describe an unusual clinical response of a 22-year-old Hispanic woman with class IV LN with vasculitis while on dialysis to cyclophosphamide (CY) and adjunct rituximab. The patient had a history of class III/V LN and was treated with nine months of CY and maintenance therapy with mycophenolate mofetil (MMF) for three years. While on MMF, the patient developed class IV LN with vasculitis leading to end-stage renal disease (ESRD). While the patient was on peritoneal dialysis, the patient was treated with two doses of rituximab and six doses of intravenous CY. The patient responded to this regimen and recovered kidney function within four months. The kidney function remained stable nine months after discontinuing peritoneal dialysis.
How to cite this article:
Kadikoy H, Haque W, Ahmed S, Abdellatif A. Rituximab in the treatment of refractory lupus nephritis with vasculitis. Saudi J Kidney Dis Transpl 2012;23:334-7 |
How to cite this URL:
Kadikoy H, Haque W, Ahmed S, Abdellatif A. Rituximab in the treatment of refractory lupus nephritis with vasculitis. Saudi J Kidney Dis Transpl [serial online] 2012 [cited 2013 Jun 18];23:334-7. Available from: http://www.sjkdt.org/text.asp?2012/23/2/334/93169 |
| Introduction | |  |
While clinical outcomes for proliferative lupus nephritis (LN) have improved since the 1990s with widespread adoption of the National Institutes of Health treatment strategy using intravenous cyclophosphamide (CY) and cortico-steroids, [1] up to 25% of patients fail to respond to this treatment. [2] In recent years, many new immunosuppressive therapies have been evaluated for LN and many more are under consideration. Rituximab is a chimeric monoclonal antibody that specifically binds to the CD20 molecule on the surface of pre- and mature B-cells. It results in profound depletion of the B-cell subsets through induction of cell lysis that may be mediated by complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, or apoptosis. In a pilot open study of five patients with refractory systemic lupus erythematous (SLE), three of whom had nephritis, a combination of rituximab and CY with high-dose corticosteroid was well tolerated and resulted in improvement of renal parameters in two patients. [3]
| Case Report | | |
A 22-year-old Hispanic woman presented to the emergency room with a 3-day history of shortness of breath, swelling of the legs, and headache. The patient had a history of class III/V LN with interstitial fibrosis and tubular atrophy diagnosed by biopsy two months prior to presentation. She complained of sudden onset of edema in her legs and shortness of breath upon exertion. The patient denied double vision, dizziness, nausea, vomiting, chest pain, or orthopnea. The patient had no history of smoking, drug or alcohol abuse. Family history was significant for a brother with type 1 Diabetes. Physical examination showed bilateral pitting edema. The chest, heart, and abdominal examinations were unremarkable.
On admission, laboratory values included serum creatinine of 4.1 mg/dL, urine protein of 320 mg/dL, albumin of 2.4 mg/dL, C3 of 32 mg/dL, and C4 of 3 mg/dL. Ultrasound guided kidney biopsy was performed, which was consistent with diffuse proliferative glomerulo-nephpritis with some cellular crescents and necrotizing vasculitis, consistent with class IV LN with vasculitis [Figure 1], [Figure 2], and [Figure 3]. | Figure 1: Biopsy of the kidney showing glomerular changes consistent with lupus nephritis class IV with vasculitis. There is global endocapillary proliferation in the glomerulus.
Click here to view |
 | Figure 2: Small artery showing mononuclear infiltration in the vessel wall, limited to the intima.
Click here to view |
 | Figure 3. Small vessel with mononuclear inflammatory cells in the media and fibrin deposition within the lumen.
Click here to view |
Initially, the patient received three days i.v. methylprednisone, and was initiated on a six month course of i.v. CY. Rituximab was added as an adjunct therapy, at 350 mg/m [2] for two doses two weeks apart. During the first two weeks of therapy, the patient's kidney function deteriorated and creatinine peaked at 6.0 mg/ dL prior to initiation of dialysis. The patient was continued on hemodialysis and then transferred to peritoneal dialysis. At this point it was decided to continue with aggressive therapy of CY and steroids in the outpatient setting. The patient was followed in clinic once per month. Her creatinine improved from 6.0 mg/dL to 1.1 mg/dL within four months [Table 1]. She was taken off of peritoneal dialysis after 16 weeks of follow-up due to improvement in kidney function. Her renal function remained stable at a creatinine of 1.1 mg/dL one year after the initial insult, and was maintained on MMF and steroids.
| Discussion | | |
The prevalence of clinical renal involvement is between 30% and 90% of SLE patients, with LN being more common in certain ethnic groups and in children, and vasculitis is one of the poorest prognostic factors in any patient. [4]
In LN, usually patients present with worsening kidney function, hypertension, edema, and nephritic/nephrotic syndrome. Patients with LN usually also display characteristics of systemic SLE including skin manifestations, synovitis, and serositis. Upon presentation, our patient had hypertension, worsening kidney function, edema and nephritic range proteinuria with hypoalbuminemia.
The etiology of autoimmunity in SLE may be due to loss of self-tolerance as a result of incomplete silencing or deletion of autoreac-tive lymphocytes. [5] Another possible mechanism for autoimmunity is dysfunctional apop-tosis characterized by incomplete removal of nuclear remnants, which leads to increased exposure to the immune system and subsequent recognition. [6] In addition, there are certain genetic linkages in SLE that predispose individuals to renal disease and influence the severity of glomerular disease. [7]
B cells have a central role in the genesis of SLE, as shown by the presence of pathogenic autoantibodies such as anti-double stranded DNA. However, the influence of B cells on SLE is not limited to production of pathogenic autoantibodies. A model of LN in mice showed that a decreased number of B cells prevented the development of SLE, but animals with normal B cell count that were not able to produce antibodies still had occurrence of SLE and LN. [8]
The damage to the kidney in SLE is due to either direct antibody-induced cytotoxicity, immune complex lodging in the glomeruli, or in situ immune complex formation. [9],[10],[11] The three criteria for clinical lupus nephritis are 30% decrease in creatinine clearance, protei-nuria greater than 1000 mg/day, and renal biopsy consistent with active lupus nephrititis. The staging of LN was revised by the International Society of Nephrology/Renal Pathology Society in 2003, and is shown in [Table 2]. [12] | Table 2: Abbreviated International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification of lupus nephritis (2003).
Click here to view |
Several novel treatments for LN involve the strategy of inhibiting B cell activity, other than rituximab, such as LJP-394 (Abetimus so-dium), [13],[14] which was shown in a retrospective observation to improve renal function as it reduced proteinuria. [15] Another anti-B cell drug, Belimumab (LymphoStat-B), [16] showed improved disease activity and quality of life scores in patients with moderate disease, [17] and is currently in phase III trials for treatment of SLE. [18] The use of the renal biopsy enables more patient-directed therapy based on histo-logic examination. [19]
Our case supports the aggressive treatment of LN with vasculitis, even if renal replacement therapy is initiated. We aggressively treated our patient to salvage any remaining kidney function. Fortunately, our patient showed impressive recovery of kidney function to a creatinine near her baseline. Rituximab may be a beneficial adjunct therapy in class IV LN with vasculitis even though recent trials have been negative for rituximab role in therapy for lupus nephritis with vasculopathy but without vasculitis. Further studies are required to verify the use of aggressive pharmacologic therapy in patients who are dialysis dependent secondary to LN with vasculitis.
| References | | |
| 1. | Fiehn C, Hajjar Y, Mueller K, et al. Improved clinical outcome of lupus nephritis during the past decade: importance of early diagnosis and treatment. Ann Rheum Dis 2003;62:435-9. 
[PUBMED] [FULLTEXT] |
| 2. | Illei GG, Austin HA, Crane M, et al. Combination therapy with pulse CY plus pulse methylprednisolone improves long-term renal outcome without adding toxicity in patients with lupus nephritis. Ann Intern Med 2001;135:248-57.
[PUBMED] [FULLTEXT] |
| 3. | Leandro MJ, Edwards JC, Cambridge G, Ehrenstein MR, Isenberg DA. An open study of B lymphocyte depletion in systemic lupus erythematosus. Arthritis Rheum 2002;46:2673-7.
[PUBMED] [FULLTEXT] |
| 4. | Pasquali S, Banfi G, Zucchelli A, Moroni G, Ponticelli C, Zucchelli P. Lupus membranous nephropathy: long-term outcome. Clin Nephrol 1993;39:175-82.
[PUBMED] |
| 5. | Mecklenbrauker I, Saijo K, Zheng NY, et al. Protein kinase C delta controls self- antigen-induced B-cell tolerance. Nature 2002;416: 860-5.
|
| 6. | Stuart L, Hughes J. Apoptosis and autoimmunity. Nephrol Dial Transpl 2002;17:697-700.
|
| 7. | Lea, J. Lupus Nephritis in African Americans. Am J Med Sci 2002;323:85-9.
|
| 8. | Grammer AC, Lipsky PE. B cell abnormalities in systemic lupus erythematosus. Arthritis Res Ther 2003;5:S22-7.
[PUBMED] [FULLTEXT] |
| 9. | Clynes R, Dumitru C, Ravetch JV. Uncoupling of immune complex formation and kidney damage in autoimmune glomerulonephritis. Science 1998;279:1052-4.
[PUBMED] |
| 10. | Berden JH. Lupus Nephritis. Kidney Int 1997; 52:538-58.
[PUBMED] |
| 11. | Daugas E, Nocy D, Huong du LT, et al. Anti-phospholipid syndrome nephropathy in systemic lupus erythematosus. Am J Kidney Dis 1997;29:119-24.
|
| 12. | Yokoyama H, Wada T, Hara A, et al. The outcome and a new ISN/ RPS 2003 classification of lupus nephritis in Japanese. Kidney Int 2004;66:2382-8.
[PUBMED] [FULLTEXT] |
| 13. | Cordeiro AC, Isenberg DA. Novel therapies in lupus-focus on nephritis. Acta Rheumatol Portuguesa 2008;33:157-69.
|
| 14. | Alarcon-Segovia D, Tumlin JA, Furie RA, et al. LJP394 for the Prevention of Renal Flare in Patients with Systemic Lupus Erythematosus. Arthritis Rheum 2003;48:442-54.
|
| 15. | Cardie MH, Tumlin JA, Furie RA, et al. Abetimus sodium for renal flare in systemic lupus erythematosus: results of a randomized, controlled phase III trial. Arthritis Rheum 2008;58:2470-80.
|
| 16. | Bhat P, Radhakrishnan J. B lymphocytes and lupus nephritis: New insights into pathogenesis and targeted therapies. Kidney Int 2008;73: 261-8.
[PUBMED] |
| 17. | Furie RLJ, Merrill JT, Petri M, et al. Multiple SLE disease activity measures in a multicenter phase 2 SLE trial demonstrate belimumab (fully human monoclonal antibody to B-lymphocyte stimulator [BLYS]) improves or stabilizes SLE activity. Ann Rheum Dis 2006;65:63.
|
| 18. | Belimumab: anti-BLyS human monoclonal antibody, anti-BLyS monoclonal antibody, BmAb, human monoclonal antibody to B-lymphocyte stimulator. Drugs R D 2008;9: 197-202.
|
| 19. | Tumlin, JA. Lupus Nephritis: Histology, Diagnosis, and Treatment. Bull NYU Hosp Jt Dis 2008;66:188-94.
|
Correspondence Address:
Abdul Abdellatif
Assistant Professor of Medicine, Division of Nephrology, Department of Medicine, Baylor College of Medicine, One Baylor Plaza, BCM 620, Houston, TX 77030
USA
PMID: 22382230
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2] |
|
|
|
|
|
|
|
|
|
|
|
|
|
| Article Access Statistics | | | Viewed | 1550 | | | Printed | 48 | | | Emailed | 0 | | | PDF Downloaded | 407 | | | Comments | [Add] | | |
|
|
