Beneficial effects of rituximab therapy for systemic lupus erythematosus
http://www.100md.com
《美国医学杂志》
Division of Pediatric Nephrology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India
We report an 11-yr-old girl with systemic lupus erythematosus (SLE) with recurrent flares of skin and systemic manifestations, which were poorly controlled with conventional therapy. Treatment with rituximab, a monoclonal antibody against CD20, was associated with remission of symptoms and a steroid sparing effect that persisted for more than 9 months. Therapy with rituximab appears promising in subjects with SLE.
Keywords: B lymphocytes; Lupus nephritis
Systemic lupus erythematosus (SLE) is a multisystem disorder, characterized by production of numerous autoantibodies, some of which have pathogenic consequences and result in considerable morbidity. Medications for treatment include non-steroidal anti-inflammatory drugs, hydroxychloroquine sulfate (HCQS), corticosteroids, azathioprine and cyclophosphamide. Therapy with cyclosporine, mycophenolate mofetil (MMF), intravenous immunoglobulin and plasmapheresis has been used to induce and/or maintain remission, with variable results.[1] We report the efficacy of a novel treatment in an 11-yr old girl with SLE and severe cutaneous and systemic symptoms, which did not respond satisfactorily to standard therapy.
Case report
This 11-yr-old girl was diagnosed with SLE at the age of 7-yr, when she presented with continuous fever, arthritis involving the knee joints and photosensitive facial rash for 2 months. Rest of the systemic examination was normal. Investigations showed hemoglobin level of 8.8 g/dl, white cell count 2500/cu mm, platelet count 100000/cu mm, ESR 45 and serum creatinine 0.7 mg/dl; urinalysis showed microscopic hematuria and 2+ proteinuria by dipstick. Antinuclear antibody was positive, complement (C3) 25 (normal 90-180) mg/dl and double stranded DNA 121 (normal 0-55) IU/ml. Light microscopy of the kidney biopsy showed focal proliferative glomerulonephritis (GN); diffuse mesangial and capillary wall deposits of immunoglobulin (Ig) G, IgM, IgA and C3 were found on immunofluorescence. The findings were suggestive of class III lupus nephritis with high histological activity index. The patient was treated with oral prednisolone (1 mg/Kg daily for 3 months, with later tapering by 2.5 mg every 2 weeks to a dose of 10 mg daily) and IV pulses of cyclophosphamide (500 mg/m 2 once a month) for 6 months [Figure - 1]. Therapy was later continued with oral azathioprine (2 mg/Kg), HCQS (4 mg/Kg), prednisolone (0.5 mg/Kg on alternate days) and sunscreen lotions for the next 18 months.
Two-yr after onset of the disease, the patient showed recurrence of fever, 4+ proteinuria, gross hematuria and extensive erythematous ulcerative rash involving malar area, scalp and trunk, and dorsal and palmar aspects of hands and feet. She also had oral ulcers and arthralgia involving large joints. Investigations showed nephrotic range proteinuria (urine albumin to creatinine ratio 4.4), hematuria with dysmorphic red cells and red cell casts, normal blood counts, ESR 60 mm at 1 hr and normal levels of blood urea and creatinine. Blood levels of C3 were 15 mg/dl and double stranded DNA 200 IU/ml. A repeat kidney biopsy showed features suggestive of diffuse proliferative (class IV) GN. The dose of prednisolone was increased to 1.3 mg/Kg per day and treatment initiated with oral MMF (1000 mg/m 2/day), HCQS and enalapril (0.3 mg/Kg/day); topical application of corticosteroids and sunscreen lotions was continued [Figure - 1].
Despite 4 months therapy, the patient continued to have exacerbations of disease activity (fever, arthralgia, erythematous ulcerative and vasculitic rash on face, trunk and extremities, and nephrotic range proteinuria with microscopic hematuria) causing significant impairment of daily activities. Investigations showed hemoglobin level of 5.3 g/dl, leukocytes 2900/cu mm, platelets 40000/cu mm, ESR 65 mm, albumin 2.7 g/dl, creatinine 1.3 mg/dl, double stranded DNA 160 IU/ml and C3 18 mg/dl; anticardiolipin antibodies were absent and Coombs test was negative. Bone marrow examination showed normal hematopoietic cell lines with no abnormal cells or hemophagocytes. Urinalysis showed nephrotic range proteinuria (albumin/creatinine ratio 5.2), 10-15 red cells and 10-15 leukocytes/HPF. The SLE disease activity index (SLEDAI) score was 34.[2] In view of persistent leukopenia and thrombocytopenia treatment with MMF and HCQS was discontinued. Oral dapsone (3 mg/Kg/day) was administered for the skin rash, for 6 months without satisfactory response.
In view of lupus activity and class IV GN, not responsive to therapy with high dose prednisolone, the patient was administered three IV pulses of methylprednisolone (500 mg/m 2) every other day; followed by oral prednisolone at a dose of 1.5 mg/Kg per day. Three weeks later the leukocyte and platelet counts were 5500/cu mm and 140000/cu mm respectively. Administration of the first monthly pulse of IV cyclophosphamide (500 mg/m 2) resulted in hospitalization for systemic sepsis, lower respiratory tract infection and oral candidiasis.
In presence of clinical and laboratory features of active lupus, and exacerbation of severe infections following immunosuppressive treatment, the authors considered the use of rituximab (Mabthera, Roche) for this patient. After informed written consent, the patient received four doses of rituximab, at a dose of 375 mg/m 2, at weekly intervals with prednisolone 0.7 mg/Kg per day. Premedication with oral paracetamol (15 mg/Kg) and oral diphenhydramine (0.5 mg/Kg) was given before each infusion. Except for transient rise in blood pressure to 134/90 mmHg during the first infusion, no other adverse events were noted.
A significant reduction in the extent and severity of rash and remission from joint pains and fever was seen by the fourth dose of rituximab. Four weeks following the last dose, the rash had completely subsided, leukocyte count was 5600/cu mm, platelet count 165000/cu mm, creatinine 0.8 mg/dl and C3 70 mg/dl; nephrotic range proteinuria (albumin/creatinine ratio 3) and microscopic hematuria persisted. Eight months later proteinuria decreased (albumin/creatinine ratio 0.4) and urine microscopy showed 4-6 red cells/HPF. Despite low dose of prednisolone (0.2 mg/Kg/d), there was no recurrence of systemic symptoms, SLEDAI score was 6 and she was attending school for the first time in 3 yr.
Nine months after the last dose of rituximab, the patient showed recurrence of rash, fever and oral ulcers. This was managed with increase in the dose of daily prednisolone to 0.5 mg/Kg per day, HCQS and sunscreen lotions.
Discussion
The present patient had severe and recurrent flares of lupus, which were difficult to manage with standard medications including corticosteroids, HCQS, dapsone, cyclophosphamide, azathioprine and MMF. Intense immunosuppression was effective in controlling symptoms but resulted in life threatening infections, requiring multiple hospital admissions. Administration of 4-doses of rituximab resulted in steroid sparing, satisfactory improvement in skin rash, fever, leukopenia and thrombocytopenia, and decrease in lupus activity score. The improvement in renal symptoms, chiefly proteinuria and hematuria was partial.
Rituximab is a chimeric mouse-human monoclonal antibody against a transmembrane protein, the CD20 antigen, present on B lymphocytes. Treatment with rituximab results in inhibition of B cell proliferation, and their apoptosis and lysis through complement-dependent and complement-independent mechanisms.[3] Since the CD20 antigen is present on all stages of B cell development except plasma cells,[3] immunoglobulin production is not affected and the risk of infections is not increased.
Rituximab was initially approved for therapy of non Hodgkin B cell lymphomas. Later reports showed its efficacy in patients with rheumatoid arthritis, idiopathic thrombocytopenic purpura and Wegener's granulomatosis.[3],[4] Perturbations in humoral and cellular immunity are described in SLE with formation of autoantibodies and immune complexes that result in apoptosis, complement activation and tissue injury.[5] Preliminary results of treatment with rituximab confirm its efficacy and safety in adult subjects with SLE.[6],[7],[8] In a retrospective analysis, 2 out of 4 patients with nephritis and 7 of 9 without nephritis showed significant reduction in SLEDAI scores and 70.4% reduction in steroid dosage following treatment with this agent.[6] Leandro et al reported significant clinical improvement in 19 patients and sustained remission in 13 patients with severe SLE.[7] In another study, 10 of 17 subjects showed depletion of B cells and reduced disease activity scores, which persisted for 12 months.[8]
Rituximab has also been used in children with SLE, refractory to standard therapy with cyclophosphamide and steroids [Table - 1].[7],[9],[10],[11],[12],[13] Review of these case series suggests that joint and cutaneous manifestations respond better to treatment than other features.[6],[7],[8],[11],[12] The clinical response usually corresponds to selective depletion of B lymphocytes, seen after a mean duration of 4 weeks.[3] B cells reappear 6-9 months after treatment although it is not known whether this reappearance results in reactivation of the disease.[3],[7],[12] A similar course was seen in the present patient who showed remission of symptoms following the fourth dose of rituximab. The improvement persisted despite significant reduction in the dose of prednisolone and discontinuation of other immunosuppressive agents for over 9 months, before recurrence of the rash. While authors speculate that a repeat course of treatment with rituximab might be effective, experience in this regard is limited.[3]
Infusion of rituximab has been associated with the occurrence of chills, fever and hypotension, related to release of cytokines including tumor necrosis factor-a and interleukin-6.[14] These complications are usually observed in treatment of B-cell lymphomas and are perhaps related to the load of circulating tumor cells. A similar risk is not seen in non-malignant conditions, and might be further reduced by concomitant administration of corticosteroids.[12],[15] While patients treated with rituximab are at a higher risk of infections, most reports are anecdotal and there is no clear evidence of increased risk of viral, bacterial and fungal pathogens. Protective titers against immunized pathogens are preserved in most instances.[15]
Treatment of SLE with rituximab seems attractive, since its specific binding to the CD20 antigen mediates B lymphocyte lysis, preventing renewal of autoantibodies and antigen presentation by pathogenic B cells. While its prohibitive cost (a 4-week course for a 35 Kg child costs Rs. 200000) is currently a constraint to its use, this medication offers considerable promise for targeted therapy of severe SLE without the risks of immunosuppression and drug toxicity. Randomized trials comparing treatment with rituximab and conventional immunosuppressants are, however, required before this drug is accepted as standard therapy for SLE.
Contributor's credits: SM, AB and PH planned, organized and coordinated the treatment protocol, work up and management of the patient. SM and AB prepared the manuscript. AB will act as guarantor of the paper.
Competing interests: None
Acknowledgements
Mabthera (rituximab) was partly provided by Roche (India) Ltd.
References
1.Ardoin SP, Schanberg LE. The management of pediatric systemic lupus erythematosus. Nature Clin Prac Rheum 2005; 1: 82-92. [PUBMED] [FULLTEXT]
2.Bombardier C, Gladman DD, Urowitz MB, Caron D, Chang CH. Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE. Arthritis Rheum 1992; 35 : 630-640.
3.Salama AD, Pusey CD. Drug insight: rituxumab in renal disease and transplantation. Nature Clin Prac Nephrol 2006; 2: 221-230. [PUBMED] [FULLTEXT]
4.Leandro MJ, Cambridge G, Ehrenstein MR, Edwards JC. Reconstitution of peripheral blood B cells after depletion with rituximab in patients with rheumatoid arthritis. Arthritis Rheum 2006; 54: 613-620. [PUBMED] [FULLTEXT]
5.Lipsky PE. Systemic lupus erythematosus: an autoimmune disease of B cell hyperactivity. Nature Immunol 2001; 2: 764-766. [PUBMED] [FULLTEXT]
6.Gottenberg J-E, Guillevin L, Lambotte O, et al. Tolerance and short term efficacy of rituximab in 43 patients with systemic autoimmune diseases. Ann Rheum Dis 2005; 64: 913-920.
7.Leandro MJ, Cambridge G, Edwards JC, Ehrenstein MR, Isenberg DA. B cell depletion in the treatment of patients with systemic lupus erythematosus: A longitudinal analysis of 24 patients. Rheumatology (Oxford) 2005; 44: 1542-1545 [PUBMED] [FULLTEXT]
8.Looney RJ, Anolik JH, Campbell D, et al. B cell depletion as a novel treatment for systemic lupus erythematosus: a phase I/II dose-escalation trial of rituximab. Arthritis Rheum 2004; 50: 2580-2589.
9.Perrotta S, Locatelli F, La Manna A, Cennamo L, De Stefano P, Nobili B. Anti-CD20 monoclonal antibody (rituximab) for life-threatening autoimmune hemolytic anemia in a patient with systemic lupus erythematosus. Br J Hematol 2002; 116: 465-467. [PUBMED]
10.ten Cate R, Smiers FJ, Bredius RG, Lankester AC, van Suijlekom-Smit LW, Huizinga TW, et al. Anti-CD20 monoclonal antibody (rituximab) for refractory autoimmune thrombocytopenia in a girl with systemic lupus erythematosus. Rheumatology (Oxford) 2004; 43: 244. [PUBMED] [FULLTEXT]
11.Edelbauer M, Jungraithmayr T, Zimmerhackl LB. Rituximab in childhood systemic lupus erythematosus refractory to conventional immunosuppression: case report. Pediatr Nephrol 2005; 20: 811-813. [PUBMED] [FULLTEXT]
12.Marks SD, Patey S, Brogan PA, Hasson N, Pilkington C, Woo P et al. B lymphocyte depletion therapy in children with refractory systemic lupus erythematosus. Arthritis Rheum 2005; 52: 3168-3174.
13.Willems M, Haddad E, Niaudet P, Kone-Paut I, Bensman A, Cochat P et al. French Pediatric-Onset SLE Study Group. Rituximab therapy for childhood-onset systemic lupus erythematosus. J Pediatr 2006; 148: 623-627.
14.Kunzmann V, Ruediger T, Hallek M, Mueller-Hermelink HK, Wilhelm M. Tumor cell agglutination and not solely cytokine release as mechanism of adverse reactions during anti-CD20 monoclonal antibody (IDEC-C2B8, rituximab) treatment. Blood 2001; 98: 1991-1992. [PUBMED] [FULLTEXT]
15.Pescovitz MD. Rituximab, an anti-CD20 monoclonal antibody: History and mechanism of action. Am J Transpl 2006; 6: 859-866.(Menon Shina, Hari Pankaj, Bagga Arvind)
We report an 11-yr-old girl with systemic lupus erythematosus (SLE) with recurrent flares of skin and systemic manifestations, which were poorly controlled with conventional therapy. Treatment with rituximab, a monoclonal antibody against CD20, was associated with remission of symptoms and a steroid sparing effect that persisted for more than 9 months. Therapy with rituximab appears promising in subjects with SLE.
Keywords: B lymphocytes; Lupus nephritis
Systemic lupus erythematosus (SLE) is a multisystem disorder, characterized by production of numerous autoantibodies, some of which have pathogenic consequences and result in considerable morbidity. Medications for treatment include non-steroidal anti-inflammatory drugs, hydroxychloroquine sulfate (HCQS), corticosteroids, azathioprine and cyclophosphamide. Therapy with cyclosporine, mycophenolate mofetil (MMF), intravenous immunoglobulin and plasmapheresis has been used to induce and/or maintain remission, with variable results.[1] We report the efficacy of a novel treatment in an 11-yr old girl with SLE and severe cutaneous and systemic symptoms, which did not respond satisfactorily to standard therapy.
Case report
This 11-yr-old girl was diagnosed with SLE at the age of 7-yr, when she presented with continuous fever, arthritis involving the knee joints and photosensitive facial rash for 2 months. Rest of the systemic examination was normal. Investigations showed hemoglobin level of 8.8 g/dl, white cell count 2500/cu mm, platelet count 100000/cu mm, ESR 45 and serum creatinine 0.7 mg/dl; urinalysis showed microscopic hematuria and 2+ proteinuria by dipstick. Antinuclear antibody was positive, complement (C3) 25 (normal 90-180) mg/dl and double stranded DNA 121 (normal 0-55) IU/ml. Light microscopy of the kidney biopsy showed focal proliferative glomerulonephritis (GN); diffuse mesangial and capillary wall deposits of immunoglobulin (Ig) G, IgM, IgA and C3 were found on immunofluorescence. The findings were suggestive of class III lupus nephritis with high histological activity index. The patient was treated with oral prednisolone (1 mg/Kg daily for 3 months, with later tapering by 2.5 mg every 2 weeks to a dose of 10 mg daily) and IV pulses of cyclophosphamide (500 mg/m 2 once a month) for 6 months [Figure - 1]. Therapy was later continued with oral azathioprine (2 mg/Kg), HCQS (4 mg/Kg), prednisolone (0.5 mg/Kg on alternate days) and sunscreen lotions for the next 18 months.
Two-yr after onset of the disease, the patient showed recurrence of fever, 4+ proteinuria, gross hematuria and extensive erythematous ulcerative rash involving malar area, scalp and trunk, and dorsal and palmar aspects of hands and feet. She also had oral ulcers and arthralgia involving large joints. Investigations showed nephrotic range proteinuria (urine albumin to creatinine ratio 4.4), hematuria with dysmorphic red cells and red cell casts, normal blood counts, ESR 60 mm at 1 hr and normal levels of blood urea and creatinine. Blood levels of C3 were 15 mg/dl and double stranded DNA 200 IU/ml. A repeat kidney biopsy showed features suggestive of diffuse proliferative (class IV) GN. The dose of prednisolone was increased to 1.3 mg/Kg per day and treatment initiated with oral MMF (1000 mg/m 2/day), HCQS and enalapril (0.3 mg/Kg/day); topical application of corticosteroids and sunscreen lotions was continued [Figure - 1].
Despite 4 months therapy, the patient continued to have exacerbations of disease activity (fever, arthralgia, erythematous ulcerative and vasculitic rash on face, trunk and extremities, and nephrotic range proteinuria with microscopic hematuria) causing significant impairment of daily activities. Investigations showed hemoglobin level of 5.3 g/dl, leukocytes 2900/cu mm, platelets 40000/cu mm, ESR 65 mm, albumin 2.7 g/dl, creatinine 1.3 mg/dl, double stranded DNA 160 IU/ml and C3 18 mg/dl; anticardiolipin antibodies were absent and Coombs test was negative. Bone marrow examination showed normal hematopoietic cell lines with no abnormal cells or hemophagocytes. Urinalysis showed nephrotic range proteinuria (albumin/creatinine ratio 5.2), 10-15 red cells and 10-15 leukocytes/HPF. The SLE disease activity index (SLEDAI) score was 34.[2] In view of persistent leukopenia and thrombocytopenia treatment with MMF and HCQS was discontinued. Oral dapsone (3 mg/Kg/day) was administered for the skin rash, for 6 months without satisfactory response.
In view of lupus activity and class IV GN, not responsive to therapy with high dose prednisolone, the patient was administered three IV pulses of methylprednisolone (500 mg/m 2) every other day; followed by oral prednisolone at a dose of 1.5 mg/Kg per day. Three weeks later the leukocyte and platelet counts were 5500/cu mm and 140000/cu mm respectively. Administration of the first monthly pulse of IV cyclophosphamide (500 mg/m 2) resulted in hospitalization for systemic sepsis, lower respiratory tract infection and oral candidiasis.
In presence of clinical and laboratory features of active lupus, and exacerbation of severe infections following immunosuppressive treatment, the authors considered the use of rituximab (Mabthera, Roche) for this patient. After informed written consent, the patient received four doses of rituximab, at a dose of 375 mg/m 2, at weekly intervals with prednisolone 0.7 mg/Kg per day. Premedication with oral paracetamol (15 mg/Kg) and oral diphenhydramine (0.5 mg/Kg) was given before each infusion. Except for transient rise in blood pressure to 134/90 mmHg during the first infusion, no other adverse events were noted.
A significant reduction in the extent and severity of rash and remission from joint pains and fever was seen by the fourth dose of rituximab. Four weeks following the last dose, the rash had completely subsided, leukocyte count was 5600/cu mm, platelet count 165000/cu mm, creatinine 0.8 mg/dl and C3 70 mg/dl; nephrotic range proteinuria (albumin/creatinine ratio 3) and microscopic hematuria persisted. Eight months later proteinuria decreased (albumin/creatinine ratio 0.4) and urine microscopy showed 4-6 red cells/HPF. Despite low dose of prednisolone (0.2 mg/Kg/d), there was no recurrence of systemic symptoms, SLEDAI score was 6 and she was attending school for the first time in 3 yr.
Nine months after the last dose of rituximab, the patient showed recurrence of rash, fever and oral ulcers. This was managed with increase in the dose of daily prednisolone to 0.5 mg/Kg per day, HCQS and sunscreen lotions.
Discussion
The present patient had severe and recurrent flares of lupus, which were difficult to manage with standard medications including corticosteroids, HCQS, dapsone, cyclophosphamide, azathioprine and MMF. Intense immunosuppression was effective in controlling symptoms but resulted in life threatening infections, requiring multiple hospital admissions. Administration of 4-doses of rituximab resulted in steroid sparing, satisfactory improvement in skin rash, fever, leukopenia and thrombocytopenia, and decrease in lupus activity score. The improvement in renal symptoms, chiefly proteinuria and hematuria was partial.
Rituximab is a chimeric mouse-human monoclonal antibody against a transmembrane protein, the CD20 antigen, present on B lymphocytes. Treatment with rituximab results in inhibition of B cell proliferation, and their apoptosis and lysis through complement-dependent and complement-independent mechanisms.[3] Since the CD20 antigen is present on all stages of B cell development except plasma cells,[3] immunoglobulin production is not affected and the risk of infections is not increased.
Rituximab was initially approved for therapy of non Hodgkin B cell lymphomas. Later reports showed its efficacy in patients with rheumatoid arthritis, idiopathic thrombocytopenic purpura and Wegener's granulomatosis.[3],[4] Perturbations in humoral and cellular immunity are described in SLE with formation of autoantibodies and immune complexes that result in apoptosis, complement activation and tissue injury.[5] Preliminary results of treatment with rituximab confirm its efficacy and safety in adult subjects with SLE.[6],[7],[8] In a retrospective analysis, 2 out of 4 patients with nephritis and 7 of 9 without nephritis showed significant reduction in SLEDAI scores and 70.4% reduction in steroid dosage following treatment with this agent.[6] Leandro et al reported significant clinical improvement in 19 patients and sustained remission in 13 patients with severe SLE.[7] In another study, 10 of 17 subjects showed depletion of B cells and reduced disease activity scores, which persisted for 12 months.[8]
Rituximab has also been used in children with SLE, refractory to standard therapy with cyclophosphamide and steroids [Table - 1].[7],[9],[10],[11],[12],[13] Review of these case series suggests that joint and cutaneous manifestations respond better to treatment than other features.[6],[7],[8],[11],[12] The clinical response usually corresponds to selective depletion of B lymphocytes, seen after a mean duration of 4 weeks.[3] B cells reappear 6-9 months after treatment although it is not known whether this reappearance results in reactivation of the disease.[3],[7],[12] A similar course was seen in the present patient who showed remission of symptoms following the fourth dose of rituximab. The improvement persisted despite significant reduction in the dose of prednisolone and discontinuation of other immunosuppressive agents for over 9 months, before recurrence of the rash. While authors speculate that a repeat course of treatment with rituximab might be effective, experience in this regard is limited.[3]
Infusion of rituximab has been associated with the occurrence of chills, fever and hypotension, related to release of cytokines including tumor necrosis factor-a and interleukin-6.[14] These complications are usually observed in treatment of B-cell lymphomas and are perhaps related to the load of circulating tumor cells. A similar risk is not seen in non-malignant conditions, and might be further reduced by concomitant administration of corticosteroids.[12],[15] While patients treated with rituximab are at a higher risk of infections, most reports are anecdotal and there is no clear evidence of increased risk of viral, bacterial and fungal pathogens. Protective titers against immunized pathogens are preserved in most instances.[15]
Treatment of SLE with rituximab seems attractive, since its specific binding to the CD20 antigen mediates B lymphocyte lysis, preventing renewal of autoantibodies and antigen presentation by pathogenic B cells. While its prohibitive cost (a 4-week course for a 35 Kg child costs Rs. 200000) is currently a constraint to its use, this medication offers considerable promise for targeted therapy of severe SLE without the risks of immunosuppression and drug toxicity. Randomized trials comparing treatment with rituximab and conventional immunosuppressants are, however, required before this drug is accepted as standard therapy for SLE.
Contributor's credits: SM, AB and PH planned, organized and coordinated the treatment protocol, work up and management of the patient. SM and AB prepared the manuscript. AB will act as guarantor of the paper.
Competing interests: None
Acknowledgements
Mabthera (rituximab) was partly provided by Roche (India) Ltd.
References
1.Ardoin SP, Schanberg LE. The management of pediatric systemic lupus erythematosus. Nature Clin Prac Rheum 2005; 1: 82-92. [PUBMED] [FULLTEXT]
2.Bombardier C, Gladman DD, Urowitz MB, Caron D, Chang CH. Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE. Arthritis Rheum 1992; 35 : 630-640.
3.Salama AD, Pusey CD. Drug insight: rituxumab in renal disease and transplantation. Nature Clin Prac Nephrol 2006; 2: 221-230. [PUBMED] [FULLTEXT]
4.Leandro MJ, Cambridge G, Ehrenstein MR, Edwards JC. Reconstitution of peripheral blood B cells after depletion with rituximab in patients with rheumatoid arthritis. Arthritis Rheum 2006; 54: 613-620. [PUBMED] [FULLTEXT]
5.Lipsky PE. Systemic lupus erythematosus: an autoimmune disease of B cell hyperactivity. Nature Immunol 2001; 2: 764-766. [PUBMED] [FULLTEXT]
6.Gottenberg J-E, Guillevin L, Lambotte O, et al. Tolerance and short term efficacy of rituximab in 43 patients with systemic autoimmune diseases. Ann Rheum Dis 2005; 64: 913-920.
7.Leandro MJ, Cambridge G, Edwards JC, Ehrenstein MR, Isenberg DA. B cell depletion in the treatment of patients with systemic lupus erythematosus: A longitudinal analysis of 24 patients. Rheumatology (Oxford) 2005; 44: 1542-1545 [PUBMED] [FULLTEXT]
8.Looney RJ, Anolik JH, Campbell D, et al. B cell depletion as a novel treatment for systemic lupus erythematosus: a phase I/II dose-escalation trial of rituximab. Arthritis Rheum 2004; 50: 2580-2589.
9.Perrotta S, Locatelli F, La Manna A, Cennamo L, De Stefano P, Nobili B. Anti-CD20 monoclonal antibody (rituximab) for life-threatening autoimmune hemolytic anemia in a patient with systemic lupus erythematosus. Br J Hematol 2002; 116: 465-467. [PUBMED]
10.ten Cate R, Smiers FJ, Bredius RG, Lankester AC, van Suijlekom-Smit LW, Huizinga TW, et al. Anti-CD20 monoclonal antibody (rituximab) for refractory autoimmune thrombocytopenia in a girl with systemic lupus erythematosus. Rheumatology (Oxford) 2004; 43: 244. [PUBMED] [FULLTEXT]
11.Edelbauer M, Jungraithmayr T, Zimmerhackl LB. Rituximab in childhood systemic lupus erythematosus refractory to conventional immunosuppression: case report. Pediatr Nephrol 2005; 20: 811-813. [PUBMED] [FULLTEXT]
12.Marks SD, Patey S, Brogan PA, Hasson N, Pilkington C, Woo P et al. B lymphocyte depletion therapy in children with refractory systemic lupus erythematosus. Arthritis Rheum 2005; 52: 3168-3174.
13.Willems M, Haddad E, Niaudet P, Kone-Paut I, Bensman A, Cochat P et al. French Pediatric-Onset SLE Study Group. Rituximab therapy for childhood-onset systemic lupus erythematosus. J Pediatr 2006; 148: 623-627.
14.Kunzmann V, Ruediger T, Hallek M, Mueller-Hermelink HK, Wilhelm M. Tumor cell agglutination and not solely cytokine release as mechanism of adverse reactions during anti-CD20 monoclonal antibody (IDEC-C2B8, rituximab) treatment. Blood 2001; 98: 1991-1992. [PUBMED] [FULLTEXT]
15.Pescovitz MD. Rituximab, an anti-CD20 monoclonal antibody: History and mechanism of action. Am J Transpl 2006; 6: 859-866.(Menon Shina, Hari Pankaj, Bagga Arvind)