Uses of Rituximab in Nephrology

Rituximab in Nephrology

Mohammed Adel

Defintion :

Rituximab is an engineered chimeric monoclonal antibody that contains murine heavy and light chain variable regions directed against CD20 plus a human IgG1 constant region. The CD20 antigen, a transmembrane protein, is found on immature and mature B cells, as well as on malignant B cells; this antigen is found in more than 85% of non-Hodgkin’s lymphoma. CD20 mediates B-cell proliferation and differentiation

Mechanism of action

The CD20 antigen is not internalized upon antibody binding, and is not shed or found in soluble forms. Following treatment with rituximab, B cells are prevented from proliferating, and undergo apoptosis and lysis through complement-dependent and complement-independent mechanisms. These mechanisms include complement-dependent cytotoxicity, antibody-dependent cell cytotoxicity, and activation of tyrosine kinases as a direct effect of the antibody binding to its CD20 ligand. The exact contribution that each of these mechanisms makes in vivo remains unclear.

Figure 1 B-cell development and antigen expression. Surface expression of immunoglobulin chains and B-cell antigens during B-cell development and maturation is shown. CD20 is predominantly expressed on immature and mature B cells (bold). sIgG, surface IgG; sIgM, surface IgM.

Immune effects of B-cell depletion by rituximab.

■ Evidence that rituximab affects production of antibodies and regulation of immunoglobulin maturation by B cells includes reduced levels of IgM (variable), rheumatoid factor and autoantibodies (variable)

■ Evidence that rituximab affects cytokine production by B cells includes reports of cytokine-release syndromes in patients with hematological disease, which potentially accounts for some infusion-related adverse effects. No evidence for alteration in B cell cytokine profiles is available

■ Evidence that rituximab affects T-cell activation by B cells includes reduced T-cell expression of HLA-DR, CD154 and CD69

■ Evidence that rituximab affects lymphocyte homeostasis mediated by B cells includes normalization of lymphocyte subsets in active systemic lupus erythematosus

■ There are few data to support an effect of rituximab on antigen presentation by B cells Note: few data regarding the mechanisms of action of rituximab in autoimmune disease are available.

Figure 2 B-cell functions are inhibited following cell depletion by rituximab. Following activation, B cells produce cytokines, modify immunoglobulin production, process antigen for presentation to T cells, and proliferate and differentiate into plasma cells. Rituximab perturbs these processes.

Rituximab protocols for treatment of renal disease.

Standard Four weekly infusions (375 mg/m2)

for non-Hodgkin’s lymphoma, cryoglobulinemia (in association with hepatitis C virus infection), systemic lupus erythematosus, idiopathic Membranous nephropathy and pure red cell aplasia


Extended Standard dosing regimen plus two or

three monthly infusions (375 mg/m2) for nephrotic syndrome and idiopathic membranous nephropathy

Prolonged Eight weekly infusions (375 mg/m2)

for non-Hodgkin’s lymphoma and cryoglobulinemia


Modified short Two 2-weekly infusions (1 g per infusion) for

anti-neutrophil cytoplasmic autoantibody-associated vasculitis and SLE

Single dose One infusion (50–375 mg/m2) for transplant

rejection, reduction of preformed alloantibodies or anti-blood-group antibodies

Uses

Nephrotic syndrome Idiopathic membranous nephropathy Focal segmental glomerulosclerosisMixed essential cryoglobulinemiaPrimary systemic vasculitisSystemic lupus erythematosusPure red cell aphasiac with anti-

erythropoietin antibodies In kidney transplant

Nephrotic syndrome

Ashima Gulati and colleges in a Multicentric study in 2010 reported

Thirty-three patients with SRNS and 24 with SDNS, were included. Six months after rituximab therapy, 9 (27.2%) patients with SRNS showed complete remission, 7 (21.2%) had partial remission, and 17 (51.5%) had no response. At 21.5 +- 11.5 months, remission was sustained in 15 (complete: 7, partial: 8) patients.

Of 24 patients with SDNS, remission was sustained in 20 (83.3%) at 12 months and in 17 (71%) at follow-up of 16.8 5.9 months. The mean difference in relapses before and 12 months after treatment with rituximab was 3.9 episodes/patient per year.

Nephrotic syndrome

Most of the literature comes from pediatric experience becausepediatricians are most often confronted with this disease, either in the form of steroid dependency and frequent relapses or as steroid-resistant NS. A study on 70 children treated with rituximab reported a response rate of 82% in steroid-dependent NS, 44% in steroid-resistant NS and 60% in recurrent posttransplant NS. Another report on 57 patients showed sustained remission in 83% of the steroid-dependent NS cases and in 21% of the steroid-resistant NS cases at 12 months. Both reports showed good results in cases in which rituximab was used as rescue therapy. Nevertheless, questions about how early or laterituximab should be administered, the duration of remission and the indications for retreatment are still open.

Focal segmental glomerulosclerosis

Gema Fernandez-Fresnedo and colleges in 2009 Studied eight adult patients who had severe nephrotic syndrome (due to FSGS)that was unresponsive to several other immunosuppressive therapies, only two patients showed a sustained positive response, with renal function improvement and a remarkable reduction of proteinuria,whereas another patient showed a beneficial but transitory effect of rituximab.

Membranous Nephropathy

Twenty-one articles were included for reviewby Andrew S. et al ;from (2002 to 2008) all were either case reports or case series without controls.More than half of the published cases (50 of 85) came from one center where rituximab was used as primary immunosuppression for idiopathic MN. The available data suggest that rituximab, dosed either as 375 mg/m2 once weekly for 4 wk or as 1 g on days1 and 15, achieves a 15 to 20% rate of complete remission and a 35 to 40% rate of partial remission. The drug was well tolerated with minimal adverse events.

Membranous Nephropathy Segarra et al. in 2009 treated 13 patients who had

idiopathic MN and preserved renal function and were deemed dependent on a CNI with four weekly doses of rituximab (375 mg/m2 each dose). After rituximab treatment, withdrawal of CNI and other immunosuppressant drugs (MMFand corticosteroids) was possible for all patients.

At 12 mo, four patients remained in complete and nine in partial remission. Three patients experienced a relapse of nephrotic-range proteinuria 19, 23, and 28 mo after rituximab treatment and were successfully treated with a second course of rituximab. All patients remained in partial remission after a minimum follow-up period of 30 mo.

Membranous Nephropathy

The authors concluded that in patients who have MN who are CNI dependent, rituximab therapy offers an effective tool to overcome CNI dependence. Rituximab allows the avoidance of the nephrotoxicity that is associated with the prolonged use of CNI while at the same time maintains a long-lasting remission of proteinuria.

Mixed essential cryoglobulinemia

Roccatello et al. in 2004 reported on six patients with HCV-associated MEC (renal involvement in five) who were treated with a prolonged regimen of rituximab (four weekly pulses followed by two monthly pulses) and no other immunosuppressive agents. Four of the six patients had already failed to respond to conventional immunosuppressive agents.Overall there was no change in viral load, but symptoms improved markedly, complement levels recovered, and IgM levels were reduced. In addition, bone marrow abnormalities normalized. Proteinuria declined in all cases, and renal function improved in all but one patient, at 12–18 months of follow-up. No adverse effects were reported.

Mixed essential cryoglobulinemia

Zaja et al. in 2003 described their experience of 15 patients with type II MEC (12 with HCV) treated with standard protocol rituximab. At follow-up of between 9 and 31 months, there was significant improvement of symptoms (arthralgias, fevers, skin manifestations) and laboratory parameters (increasing C4, and decreasing IgM and rheumatoid factor). Two patients experienced possible adverse effects; one had a retinal artery thrombosis, and the other panniculitis (possibly related to the underlying cryoglobulinemia). Only two patients in this series had nephritis; the urinary sediment of one of these patients normalized, but the second did not complete the course because of the retinal artery thrombosis. Rituximab treatment permitted steroid usage to be significantly reduced in all but one patient.

Primary systemic vasculitis

Keogh and co-workers in 2006reported on an open label trial of 10 patients with refractory Wegener’s granulomatosis treated with steroids and rituximab only. Seven had renal involvement (biopsy proven in three), three had lung nodules and one had retro-orbital pseudotumor. All achieved remission within 3 months. Return of ANCA or B cells prompted pre emptive therapy with rituximab. Patients remained in remission while B cells were depleted. One patient relapsed at 9 months, the point at which he was due to undergo preemptive therapy.

Primary systemic vasculitis Conventional immunosuppression has changed the fatal

course of primary systemic AASV to a chronic disease with remission periods and relapses. However, therapy-related toxicity (especially infections), primary treatment failures inup to 20% and a relapse rate of >50% at 5 years together with a persistently high mortality rate reflect the unmet needs in the standard of care of these patients. The therapeutic limitations of standard immuno suppression and the accumulating evidence of the importance of ANCA in the pathogenesis of this disease constitute the rationale for rituximab use in AASV. From the standpoint of efficacy, rituximab is effective in AASV. In small case series and open-label trials, a clinical response occurred in the majority of patients, with the exception of those with refractory granulomatous manifestations.

Primary systemic vasculitis Recently, two randomized trials using rituximab as induction therapy in

AASV have been published:. In the European RITUXVAS trial, 44patients were randomly assigned to receive corticosteroids plus either rituximab or cyclophosphamide as induction therapy for AASV with severe renal involvement. After 12 months, there was no difference, neither in remission rates (76 vs. 82%, p = 0.68) nor in the serious adverse event rates (42 vs. 36%). Both treatment arms had an early mortality of 18%.

The RAVE-ITNtrial, conducted in the USA, is a noninferiority trial directly comparing rituximabto oral cyclophosphamide as induction therapy in 197 patients with severe but not life-threatening AASV. Rituximab was not inferior to cyclophosphamide for induction of remission at 6 months and it even showed superiority in patients with frequent relapses. Adverse event rates, however, were comparable. In both trials, rituximab showed no superiority in termsof safety, but both were shortterm trials and therefore not designed to detect possible advantages of cyclophosphamide avoidance translating into lower long-term mortality.

Systemic lupus erythematosus

An open label study of 10 patients with proliferative nephritis (four WHO class III, six class IV) treated with standard protocol rituximab and oral steroids was reported by Sfikakis and colleagues in 2005 reported Seven of the 10 patients had already experienced episodes of nephritis requiring steroids plus cyclophosphamide or mycophenolate mofetil. Four patients achieved complete remission (normalization of serum creatinine and serum albumin, inactive urinary sediment and proteinuria <0.5 g/day) at 1 year.

Only IgM levels decreased significantly; levels of anti-double-stranded DNA antibodies declined in all patients, as did antinuclear antibodies in eight out of ten patients

Systemic lupus erythematosus Catherine M. et al in 2009 reported 20 pt received

rituximab as induction treatment for an active class IV (15 cases) or class V (5 cases) lupus nephritis. Rituximab was given for lupus nephritis refractory to standard treatment (12 cases), for relapsing disease (6 cases), or as first-line treatment (2 cases). Three patients received cyclophosphamide concomitantly with rituximab.

Ten received new injections of rituximab as maintenance therapy.

After a median follow-up of 22 mo, complete or partial renal remission was obtained in 12 patients (60%). Lupus nephritis relapsed in one patient, who responded to a new course of rituximab.

Systemic lupus erythematosus

Boletis JN, and colleges conculded that : the addition of rituximab to MMF is effective for the treatment of relapsing proliferative lupus nephritis .

Recent recommendations suggest the use of rituximab either inaddition to mycophenolic acid or to cyclophosphamide in refractory cases of proliferative lupus nephritis.

Pure red cell aplasia with anti-erythropoietin antibodies

Pure red cell aplasia can develop as a result of therapy with certain recombinant forms of erythropoietin (EPO), probably because of produc tion of antibodies that cross-react with native EPO. Mandreoli et al.in 2004 described an 80-year-old man with chronic renal failure, treated with subcutaneous EPO-α, in whom neutralizing anti-EPO antibodies developed after 8 months of therapy, in association with profound anemia. The patient was transfusion-dependent, with evidence of impaired erthyropoiesis. Treatment with four doses of rituximab was followed by an increase in his EPO levels and a decline in anti-EPO antibody titer. The patient was rechallenged with recombinant EPO (intravenously). His hemoglobin levels increased significantly, and were maintained at this higher level for 1 year of follow-up.

Cellular and humoral rejection

The presence of CD20+ B cells in transplant biopsy infiltrates is associated with poorer outcome and less steroid responsiveness.

Thus, there is a rationale for the use of rituximab in acute rejection episodes characterized by heavy CD20+ infiltrates. Such a case of acute renal allograft rejection unresponsive to steroids or antithymocyte globulin, but successfully treated with rituximab, has recently been reported.

Cellular and humoral rejection Becker et al.in 2004 reported on the use of

rituximab in humoral rejection resistant to conventional treatment with pulsed steroids, plasmapheresis, intravenous immunoglobulins and anti-lymphocyte globulin. Twenty seven patients were treated, and graft function improved significantly in 24 (mean serum creatinine 495 μmol/l pretreatment to 84 μmol/l post-treatment [5.60 and 0.95 mg/dl, respectively])

Reduction in preformed alloantibody titers

In ABO-incompatible grafts, Tyden and coworkers in 2005 showed that a protocol including single dose ritixumab allowed successful kidney transplantation of all 11 patients, without splenectomy.

These results were reproduced by Sonnenday et al.50 in six ABO-incompatible recipients.

Sawada et al. in 2004 successfully utilized rituximab, splenectomy and plasmapheresis in four patients resistant to plasmapheresis alone.


Used as a means of reducing the titer of preformed anti-HLA alloantibodies prior to kidney transplantation, Sidner et al. 2004 showed that single dose rituximab reduced panel-reactive antibodies in all nine patients studied. Vieira and colleaguesin 2004 demonstrated that, of nine patients, rituximab altered the specificity and titer of panel-reactive antibodies in six. In one patient in

Post-transplantation lymphoproliferative disorder

Rituximab has been successfully used to treat lymphoproliferative disorder following solid organ transplantation. In a trial by Choquet S et al. (2005) 46 patients with this disorder (of whom 18 were renal transplant recipients) were treated with rituximab; immuno-suppression was also reduced. The response rate at 80 days was 44% and more than half the patients achieved complete remission. Survival at 1 year was 67%. Importantly, in about 20% of patients, transplant rejection (acute and chronic) was precipitated by the immuno suppression reduction strategy.

Similar response and overall survival rates were reported for two other smaller cohorts with shorter follow-up. Oertel SH et al. (2005 and Jain AB et al. (2005) , Further investigation of a rituximab-based strategy for treatment of post-transplantation lympho proliferative disorder is warranted.

Complication of thearpy

Hepatitis B may reactivate Pneumocystis jirovecii Pneumonia Meningoencephalitis Caused by

Enterovirus Other Infections like Babesiosis, a

zoonosis caused by the parasite Babesia microti, has been particularly difficult to eradicate in patients who have received rituximab.

Complication of thearpy System Organ

ClassVery

CommonCommon Uncommon Unknown

Infections and infestations

bacterialinfections , viral infections ,+bronchitis

sepsis,+pneumonia,+febrile infection,+herpes zoster,+respiratory tract infection, fungal infections,infections ofunknown aetiology, +acute bronchitis,+sinusitis

serious viral infection1, hepatitis B reactivation1

Blood and lymphaticsystem disorders

neutropenia,leucopenia,+febrile neutropenia

anaemia,thrombocytopenia,+pancytopenia

coagulation disorders,aplastic anaemia, haemolytic anaemia, lymphadenopathy

Late neutropenia2,transient increase in serum IgM levels2

Immune system disorders infusionrelated reactions, angioedema

hypersensitivity tumour lysis syndrome3, cytokine release syndrome3, serum sickness, anaphylaxis

Metabolism and nutritiondisorders

hyperglycaemia, weight decrease,peripheral oedema, face oedema, increased LDH,hypocalcaemia


ClassVery


Nervous system disorders paraesthesia,hypoaesthesia, agitation, insomnia, vasodilatation, dizziness, anxiety

Dysgeusia cranialneuropathy, peripheral neuropathy facial nerve palsy4,loss of other senses4

Eye disorders lacrimationdisorder, conjunctivitis

severe vision loss4

Ear and labyrinthdisorders

tinnitus, ear pain hearing loss4

Cardiac disorders +myocardialinfarction3 and 5, arrhythmia, +atrial fibrillation, tachycardia,+cardiac disorder

+left ventricular failure,+supraventricular tachycardia,+ventricular tachycardia, +angina,+myocardial ischaemia,

heart failure3 and 5,severe cardiac events 3

and 5

Vascular disorders hypertension,Orthostatic hypotension, hypotension

vasculitis(predominately cutaneous), leukocytoclastic vasculitis

Respiratory, thoracic andmediastinaldisorders

bronchospasm3,respiratory disease, chest pain,

asthma, bronchiolitisobliterans, lung disorder, hypoxia

respiratory failure3, pulmonary infiltrates, interstitial pneumonitis

Gastrointestinal disorders nausea vomiting ,diarrhoea, abdominal pain, stomatitis, constipation, dyspepsia, anorexia, throat irritation

abdominal enlargement gastro-intestinal perforation6


ClassVery


Skin and subcutaneoustissue disorders

pruritis,rash,+alopecia

urticaria,sweating, night sweats, +skin disorder

severe bullousskin reactions, toxic epidermal necrolysis6

Musculoskeletal, connective tissue and bone disorders

hypertonia,myalgia, arthralgia, back pain, neck pain, pain

Renal and urinarydisorders

renal failure3

General disorders and administrationsite conditions

fever ,chills, asthenia, headache

tumour pain,flushing, malaise, cold syndrome,+fatigue,+shivering,+multi-organ failure3

pain at the infusion site

Conclusion

Idiopathic membranous nephropathyAnti-PLA2 -related diseases,Overcome dependency

on calcineurin inhibitors

Autoimmune thrombotic thrombocytopenic purpuraBeneficial in patients with poor response to standard

therapy,Suggestion of benefit as first-line therapy in acute TTP

Focal segmental glomerulosclerosisRecurrent FSGS in transplanted kidney,Uncertain

benefit in primary FSGS

Conclusion

Lupus nephritisInduction of remission,Relapsing or refractory

disease,Inadequate data on role as maintenance therapy

ANCA-associated vasculitidesInduction of remission,Combination therapy with cytoxan for

induction of remissionPoor response in granulomatosis manifestations

,(orbital/pachymeningitis),Inadequate data on role as maintenance therapy or timing of retreatment to prevent relapse

Cryoglobulinemic vasculitisHepatitis C-related,Non-Hepatitis C-related,Non-

cryoglobulinemic glomerulonephritis

Conclusion

rituximab is proved only in

Idiopathic membranous nephropathy


allograft rejection unresponsive to steroids or ATG

But can be can be used safely in SDNS ,SRNS ,FSGS ,MEC , LN class III ,IV, V , AAV

Uses of Rituximab in Nephrology

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