| Abstract|| |
Although recently completed controlled trials failed to demonstrate a significant effect of rituximab on the clinical outcome in non-renal and renal lupus, there is growing evidence from case reports and open-label trials that the use of this medication is successful in certain subgroups of patients including refractory cases and helps in reducing the dose of steroids. We present a 26-year-old female who failed to respond to a long-course treatment with prednisolone, cyclophosphamide, mycophenolate mofetil and azathioprine and who went on to develop end-stage renal disease requiring commencement of regular maintenance hemodialysis. Ten days before starting dialysis, she was given rituximab, and a second dose was given 17 days after starting dialysis. After 7 months on dialysis, the patient began to regain kidney function and is now off dialysis for 11 months. To the best of our knowledge, this is the first case report of a lupus patient on dialysis treated with rituximab in whom dialysis could be stopped and who remained off this therapy up till now, after an observation period of 1 year.
|How to cite this article:|
Hussein MM, Mooij JM, Al Malki N, Demerdash TM. Late response to rituximab in a dialysis patient with severe lupus nephritis
. Saudi J Kidney Dis Transpl 2013;24:976-80
|How to cite this URL:|
Hussein MM, Mooij JM, Al Malki N, Demerdash TM. Late response to rituximab in a dialysis patient with severe lupus nephritis
. Saudi J Kidney Dis Transpl [serial online] 2013 [cited 2020 May 26];24:976-80. Available from: http://www.sjkdt.org/text.asp?2013/24/5/976/118101
| Introduction|| |
B-cell hyper-reactivity is a hallmark of systemic lupus erythematosus, and methods that deplete B-cells might therefore be effective in the treatment of the disease.  Rituximab, a chimeric monoclonal anti-CD 20 antibody, which depletes B-lymphocytes non-selectively during an average period of 6-9 months, has been used for the treatment of resistant or relapsing lupus since 2002. 
Although there is growing evidence from case reports and open-label trials that the use of this medication is successful in certain sub-groups of patients such as refractory cases ,,, and in reducing the use of steroids, , with a relatively good safety profile,  recently completed controlled trials failed to demonstrate a significant effect of rituximab on the clinical outcome in non-renal  and renal lupus. 
One reason for this negative effect might be the notorious heterogenicity of any lupus population, while some comments suggested that with a longer follow-up, the outcome might have been different. ,,
We present here a 26-year-old female who failed to respond to a long-course treatment with prednisolone, cyclophosphamide, mycophe-nolate mofetil (MMF) and azathioprine and who gradually went on to develop end-stage renal disease requiring commencement of regular maintenance hemodialysis (HD).
Ten days before starting dialysis, she was given rituximab, and a second dose was administered 17 days after starting dialysis. After 7 months on dialysis, the patient began to regain kidney function and is now off dialysis for 11 months.
| Case Report|| |
A 26-year-old female patient presented in the end of 2007 with fever, arthralgia, weight loss and cervical lymphadenopathy. There was anemia [hemoglobin (Hgb): 8.5 g%] and leukopenia; her white blood cell (WBC) count was 2.8 × 10  /L and her platelet count was 280 × 10  /L. Renal function was normal (serum creatinine: 63 μmol/L), but there was proteinuria (5.7 g/24 h). Serum albumin was 29 g/L. Urine sediment showed WBCs: 3-5 per high-power field (hpf), red blood cells (RBC): 0-2/hpf and granular casts: 3-5 per low-power field (lpf).
Anti-nuclear antibodies (ANA) were detectable (titer: 1/320), while the level of anti-desoxynuclear antibodies (anti-DNA) was initially 432 IU/mL and, later, increased to 937 IU/mL (normal: 0-200 IU/L). Anti-Smith (Anti-Sm) and anti-RNP-titers were also elevated. Complement factors 3 and 4 (C3 and C4) were decreased. Circulating lupus anti-coagulant was undetectable.
A renal biopsy was performed in December 2007, which showed diffuse proliferative lupus nephritis and membranous glomerulonephritis (classes IV and V). The patient received three intravenous pulse doses of methylprednisolone (1 g each) followed by a maintenance dose of oral prednisolone 1 mg/kg body weight (60 mg) per day and MMF 500 mg twice per day, in addition to anti-hypertensive treatment, which included angiotensin-converting inhibitor (ACEi) therapy. Because of the deterioration of renal function (serum creatinine rose to 190 μmol/L), renal biopsy was repeated in January 2008, but the histo-pathological features remained the same. She was given three pulse doses, each of 500 mg of methylprednisolone, after which the serum creatinine improved to 130 μmol/L.
In February 2008, she was re-admitted with status epilepticus, abdominal wall edema, ascites and massive bilateral lower limb pitting edema. Serum creatinine was 85 μmol/L and proteinuria was 4.4 g/24 h. Computerized tomography scan and magnetic resonance imaging of the brain showed signs of lupus cerebritis. Anti-cardiolipin antibodies were not detectable. The patient was started on intravenous (i.v.) pulse doses of cyclophosphamide 750 mg each month for 6 months, while MMF was discontinued. Prednisolone was continued at a dose of 60 mg/day, but later gradually reduced. The patient improved and was discharged from the hospital.
Two weeks later, she was re-admitted for abdominal pain and a micro-infarction of the right big toe. Cardiolipin antibodies were again not detectable. After this episode, on 9 March 2008, the patient became stable, had no further seizures and the renal parameters improved as well, with a serum creatinine of 56 μmol/L in June 2008, and proteinuria of 1.28 g/24 h.
Following the sixth dose of i.v. cyclophosphamide, she was put on a maintenance dose of azathioprine 100 mg daily as she could not tolerate MMF. On 26 November 2008, she presented to the emergency room of our hospital with uncontrolled hypertension, oliguria, lower limb edema and deterioration of renal function (serum creatinine 252 μmol/L). The ANA titer was 1/160, homogeneous; anti-DNA antibodies were strongly positive (1320 U/mL). C3 and C4 levels were decreased. Testing for anti-cardiolipin antibodies (both IgM and IgG) was negative.
The patient was given three pulse doses of 1 g methylprednisolone each, followed by a bolus of 750 mg i.v. cyclophosphamide (the seventh dose; on 29 November 2008). Renal biopsy was not repeated in view of prolonged bleeding time. Because the patient's renal parameters continued to deteriorate, she was given 1 g rituximab i.v. (on 3 December 2008).
The patient was subsequently discharged on request on 5 December 2008, but was re-admitted on 13 December 2008 with anuria, anasarca, uncontrolled hypertension and deterioration of kidney function (serum creatinine 620 μmol/L). The patient needed urgent ultrafiltration on 14 December 2008, and was started on regular HD since then.
The second dose of i.v. rituximab (1 g) was scheduled for 17 December 2008, but postponed in view of fever, and given on 31 December 2008, while the patient continued to be on regular, two-times weekly HD.
After discharge on 3 January 2009, she was re-admitted on 26 January 2009 with fever and cardiomegaly. Echocardiogram showed a moderate to large pericardial effusion for which pericardiocentesis was performed on 7 February 2009. One and a half liters of hemorrhagic fluid was aspirated, after which a pig-tail catheter was inserted, through which about 500 mL was drained. The pericardial fluid did not show growth of microorganisms, including Mycobacterium tuberculosis. The blood culture grew, surprisingly, Brucella More Details militensis. She was treated with doxycycline, ciprofloxacin and cotrimoxazole administered orally, after which the fever disappeared. The pericardial catheter was removed on 11 February 2009 with no further re-accumulation of fluid.
The patient was discharged on 14 February 2009 and continued HD twice weekly as an outpatient. The maintenance immunosuppressive treatment at that time consisted of prednisolone 30 mg and azathioprine was added (patient refused both MMF and mycofenolate sodium). She remained stable and did not need any admission since then.
After a few months, an increase of the urine output was noted followed later by an improvement of the pre-dialysis renal parameters. In July 2009, the measured urine output was 1015 mL per 24 h, while the pre-dialysis serum creatinine had decreased to 364 μmol/L (it was around 500-600 μmol/L earlier).
It was decided to hold the dialysis and to follow the patient in the outpatient clinic while continuing conservative treatment. Since then, there has been a continuous improvement in the urine output and proteinuria, as well in the serum creatinine values [Figure 1]. The dose of prednisolone was gradually reduced and, presently, she is on 5 mg along with azathioprine 50 mg/day and anti-hypertensive medication, including ACEi therapy. She was last seen in the outpatient clinic on 18 May 2010. At that time, the blood pressure was 116/75 mmHg, WBC was 7.7 × 10  /L, Hgb was 11.5 g/100 mL, serum creatinine was 136 μmol/L, total protein was 63 g/L and albumin was 36 g/L. Urinalysis showed protein 1+; microscopy showed WBC: 5-6/hpf and RBC: 18-20/hpf. The 24-h urine for protein was 768 mg per 24 h. The ANA-titer was 1:160, homogenous; anti-DNA was 433 IU/mL; C3 level was 0.79 (normal: 0.80-1.80 g/L) and C4 level was 0.13 g/L (normal: 0.10-0.40 g/L).
The patient did not experience any episode of leukopenia after rituximab.
|Figure 1. Clinical parameters in the study patient from December 2008|
RTX1: 1st dose of Rituximab, RTX2: 2nd dose of Rituximab
Click here to view
| Discussion|| |
The present case study reports on a patient with renal and extra-renal lupus for about 1 year and who subsequently had a severe relapse of lupus nephritis, which necessitated initiation of dialysis treatment.
She was initially given three pulse doses of i.v. methylprednisolone and seven pulse doses of i.v. cyclophosphamide. In view of the possible toxicity of the cumulative dose of cyclophosphamide in this patient, who was of child-bearing age, it was decided not to continue this drug but to change to rituximab instead, as several case reports and uncontrolled studies had reported successful outcomes with this medication. ,,,
She was given two doses of rituximab, 1 g each, the first dose of which was given just before and the second dose 3 weeks after starting dialysis treatment, combined with low-dose prednisolone (0.25 mg/kg) and azathioprine (1 mg/kg).
Six months after the second dose of rituximab, the patient's renal parameters had improved such that she could be weaned off from HD, after which her kidney function continued to improve.
This improvement occurred after discontinuation of cyclophosphamide and administration of rituximab, and was seen 6 months after the second dose of the latter drug was given. A delayed effect of rituximab has been observed in other studies,  with Catapano et al reporting a time from use of rituximab to remission of 1- 9 months (median: 4 months).  This suggests that the improvement in our case was largely due to the effect of rituximab.
To the best of our knowledge, this is the first report of a patient with lupus on dialysis treated with rituximab in whom dialysis could be stopped and who remained off HD after an observation period of 1 year. Nadri described a dialysis patient who was relieved from her extra-renal lupus activity following rituximab treatment but needed to remain on dialysis. 
Although the present study is a single case report with its inherent limitations, it adds to the growing number of publications supporting the use of rituximab in relapsing or difficult to treat lupus nephritis.  As long as controlled studies in this group of patients are not feasible or too problematic to design, we need to rely on carefully selected case histories and open-label trials for scientific progress. 
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Magdi M Hussein
Head, Department of Nephrology, Al Hada Armed Forces Hospital, P.O. Box 1347, Taif