rituximab in nephrology adult nephrology panel · 2018. 9. 8. · rituximab in nephrology dr....

Rituximab in nephrologyadult nephrology panel

Dr. Mojgan Mortazavi

Professor of Nephrology

Dr. Firouzeh Moeinzadeh Dr. Mohammad Matinfar

Assisstant professor of Nephrology

Isfahan Kidney Diseases Research Center

Isfahan University of Medical Sciences

Introduction

Rituximab is a chimeric anti-CD20 monoclonal antibody .

The CD20 antigen is a transmembrane nonglycosylatedphosphoprotein, expressed on immature and mature B cells.

It is associated with transmembrane calcium

conductance and the regulation of cell proliferation

and differentiation.

2013 European Society for Organ Transplantation. Published by Blackwell Publishing Ltd 26 (2013) 563–575

Rituximab is a chimeric anti-CD20 monoclonal antibody

Rituximab causes a reduction in B cells in the peripheral

blood within 1–3 days of administration, and complete

B cell depletion in the majority of patients within

1–6 weeks .

It does not have a direct effect on plasma cells.


Indications of Rituximab in nephrology

Although the approved indication for rituximab treatment is limited to B-cell lymphoma and rheumatoid arthritis, rituximab has been used for various indications in :

Glomerulonephritis

transplantation including induction therapy

treatment of renal allograft rejection .

Indications for immunoadsorption in nephrology and kidney transplantation

Membranous nephropathy

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Dr. Mortazavi/ Dr. Moeinzadeh/Dr. Matinfar8

Idiopathic membranous nephropathy



• All currently recommended regimens have a 25% to 30% primary failure rate.

• Rituximab efficacy in observational studies has indicated a similar or even higher short-term success rate associated with reduced AEs.

• Dose exposure has varied from 375 mg/m2 weekly for 4 weeks to 1 g every 15 days 2 to a single 1-g i.v. dose, all with similar response rates.



• Most assessed a treatment regime of Rituximab 375mg/m2, four doses at weekly intervals, but some used the alternative regime of two doses of 1000mg on day 1 and 15.

• The results can be summarised:

• Reduction in proteinuria at 12 months 48-66%• Remission at 12 months 45-75%• Insufficient data to report on progression to ERF



• Ruggenenti et al. analyzed 132 MN patients treated with rituximab, monitoring 24-h proteinuria and anti-PLA2R antibodies

• The lower baseline anti-PLA2R titer and a complete antibody reduction 6 months after the treatment were found to be the best predictors of disease remission.

• Moreover, the reduction of antibody titer preceded the improvement of 24h proteinuria, as well as the increase of anti-PLA2R after a complete or partial remission preceded the worsening of proteinuria



Rituximab in idiopathic membranous nephropathy



ANCA ASSOCIATED VASCULITIS

GLOMERULONEPHRITIS

ANCA Associated GN/Vasculitis

• Necrotizing inflammation of the small vessels

• No deposition of immune complexes

• Medium or large vessels may be involved

• Subtypes :Granulomatosis with polyangitis (Wegener’s)

Microscopic polyangiitis

Churg-Strauss syndrome

• Necrotizing and crescentic glomerulonephritis (NCGN)

KDIGO Clinical Practice Guideline for Glomerulonephritis 2012



ANCA Associated GN/Vasculitis

•Circulating ANCA

•NCGN may without extrarenal manifestations

•ANCA, directed primarily to the neutrophil granule proteins myeloperoxidase (MPO) or proteinase 3 (PR3)

• NCGN may persistently ANCA-negative Treated similarly to ANCA-positive patients




Therapeutic Options

• Immunosuppressive therapy :In all cases of ANCA vasculitis and GN

Exception :Severe kidney-limited disease

Absence of extrarenal manifestations

Pauci-immune NCGN requiring dialysis

Risks of therapy > than the likelihood of recovering

• No level of kidney function to avoid treatment

Remission in 57% in GFR of 10 ml/min or less




Therapeutic Options • Cyclophosphamide and corticosteroids as initial treatment. (1A)

• Rituximab&corticosteroids as an alternative initial treatment in

Patients without severe disease

Cyclophosphamide is contraindicated (1B)

• Plasmapheresis :

Requiring dialysis or rapidly increasing SCr (1C)

Diffuse pulmonary hemorrhage(2C)

Overlap syndrome of ANCA vasculitis and anti-GBM GN (2D)

• Discontinuing cyclophosphamide after 3 months in :

Patients who remain dialysis-dependent & no extrarenalmanifestations (2C)




Rituximab in ANCA-Associated Vasculitis

• In 2011, RTX was approved for patients with GPA and MPA ( 375 mg/m2 on a weekly basis for 4 weeks)along with GC

• CYC -- gold standard therapy for many decades

• RTX proved to be non-inferior in inducing remission in AAV

• Suggestive evidence of superiority in patients with ANCA PR3+ with relapsing or severe disease

• Evidence of superiority to AZA to maintain remission

• RITUXVAS failed to show RTX superiority to CYC, but it was not inferior




Therapeutic Recommendation




Randomized controlled trials



Membranoproliferative glomerulonephritis



IMMUNE COMPLEX-MEDIATED MPGN

• Results from chronic antigenemia and/or circulating immune complexes and can be seen in:

• Chronic infections

• Autoimmune diseases

• Monoclonal gammopathies



Nephrotic syndrome, normal or near normal creatinine

• Prednisone 1 mg/kg per day (maximum dose 60 to 80 mg/day) for 12 to 16 weeks. If the patient responds, prednisone is gradually tapered to alternate day therapy over six to eight months.

• If there is less than a 30 percent reduction in proteinuria after 12 to 16 weeks, we recommend tapering and discontinuation of prednisone. We initiate angiotensin inhibition therapy at the same time.

• Calcineurin inhibitors may be considered in patients who do not respond to or tolerate glucocorticoids.



Elevated serum creatinine, with or without nephrotic syndrome and/or hypertension, and

without crescents

• Initial therapy with Prednisone (1 mg/kg per day, maximum dose 60 to 80 mg/day).

• we would add Cyclophosphamide (2 mg/kg per day, reduced to 1.5 mg/kg per day in patients with a serum creatinine greater than 2.5 mg/dL or age greater than 60 years) for three to six months If there is no response or there are increases in the serum creatinine and/or proteinuria.



MPGN

• We recommend that patients with rapidly progressive crescentic MPGN be treated with glucocorticoids and cyclophosphamide

• Cessation of cyclophosphamide and a trial of Rituximab recommended In patients with persistent disease activity despite cyclophosphamide.



MPGN

• Current guidelines suggest treatment with steroids, cytotoxic agents with or without plasmapheresis only for subjects with progressive disease, that is, nephrotic range proteinuria and decline of renal function.

• Data on the use of rituximab in MPGN, C3GN, and DDD are limited to case reports and retrospective case series.



MPGN

• Patients with immunoglobulin-associated and idiopathic MPGN who were treated with rituximab showed partial and complete responses in the majorities of cases.

• However, rituximab was not effective in few cases of C3GN and DDD.

• Despite promising results in immunoglobulin-associated and idiopathic MPGN, current evidence on this treatment remains weak, and controlled and prospective data are urgently needed.



• In patients with a HCV-related renal disease (presumably MPGN) and cryoglobulinemia with nephrotic proteinuria and evidence of progressive kidney disease, treatment with plasmapheresis, rituximab, or cyclophosphamide in conjunction with steroids and antiviral therapy may be most useful, but data are limited and treatment approaches have to be individualized



• The efficacy of Rituximab in patients without underlying leukemia was evaluated in six adults with MPGN type I; the MPGN was idiopathic in four and associated with cryoglobulinemia in two .

• The rituximab dose was 1000 mg intravenously on days 1 and 15; the patients were followed for one year. The mean serum creatinine was 1.7 mg dL at baseline. The primary outcome was the change in proteinuria from baseline (mean 3.9 g/day).



• Protein excretion fell at all time points with a mean minimum of 1.4 g/day at nine months. There was no change in creatinine clearance and there were no adverse effects.

• Rituximab has also led to long-lasting complete or partial remissions in seven of eight patients with MPGN associated with a monoclonal gammopathy .



Focal Segmental Glomerulosclerosis

•One of the most common patterns of glomerular injury

• It is the most common cause of proteinuria in the African-American &Hispanic populations

•Primary & Secondary type




Treatment Options• Corticosteroid and immunosuppressive only in idiopathic FSGS &

features of the nephrotic syndrome (1C)

1mg/kg (max80mg) or alternate-day 2 mg/kg( max120mg) (2C)Initial high dose for at least of 4 weeks

High-dose corticosteroids ,max of 16 weeks, as tolerated, or until complete remission (2D)

Tapered slowly over a period of 6 months after achieving CR (2D)

• CNIs as first-line therapy for relative contraindications or intolerance to high-dose corticosteroids (2D)

• Steroid-resistant , who do not tolerate cyclosporine:

Combination of MMF and high-dose dexamethasone. (2C)




• Eight patients biopsy-proven FSGS ,4 women, 4 men)

• High dose (8 weekly -375 mg/m2) follow for at least 2 years

• Failed to improve proteinuria in 7 out of 8 patients, whit persistent nephrotic proteinuria.

• In one , a rapidly deteriorating renal function was also observed



RITUXIMAB & FSGS

Several case reports :

Successful use of in adult patients with

steroid-dependent but not steroid-resistant

In steroid-resistant FSGS did not induce

remission

Uptodate5/11/1397

rituximab in nephrology Dr. Mortazavi/ Dr. Moeinzadeh/Dr. Matinfar

46

Systemic lupus erythematosis

• Recently, clinical trials suggest RTX as a more effective treatment for LN. Nevertheless, its effectiveness is still controversial among studies which either demonstrate a trending superiority or non inferiority compared to conventional treatment.

• RTX remains a common off-label prescription for the treatment of SLE despite the conflicting evidence from clinical studies.

• Our findings suggest a potential therapeutic efficacy of RTX in both SLE and LN patients.

• RTX achieved up to 73% global response rate, 51% complete remission, and 34% partial remission in SLE and LN patients




• In patients with worsening SCr and/or proteinuria after completing one of the initial treatment regimens, consider performing a repeat kidney biopsy to distinguish active LN from scarring.

• Treat patients with worsening SCr and/or proteinuria who continue to have active LN on biopsy with one of the alternative initial treatment regimens

• We suggest that non responders who have failed more than one of the recommended initial regimens may be considered for treatment with rituximab, i.v. immunoglobulin, or CNIs.




• Rituximab may be considered as a ‘‘rescue therapy’’ when usual therapeutic options have been exhausted.

• This use of rituximab is in contrast to its lack of utility as add-on therapy to an initial standard regimen (Regimen D) for proliferative LN.



RTX is chosen only for patients for whom all reasonable conventional options have been exhausted. Moreover, RTX is used in patients with high disease activity and a significant burden of SLE-related damage. As such, the current usage of RTX in SLE may be considered conservative, representing an appropriately used medication of last resort for those with the highest medical need within the larger patient population with SLE.



RITUXIMAB & KIDNEY TRANSPLANTATION

Induction

Desensitization in antibody incompatible Transplantation

Treatment of renal allograft rejection





Induction &pretreatment :

ABO blood group incompatibility

HLA donor specific antibodies




Desensitization : Combined regimen of IVIG therapy and plasmapheresis Rituximab and Bortezumab

Protocol:Rituximab with high-dose IVIG (2 g/kg with max dose 140 g)

Combination of plasmapheresis with low-dose IVIG (100 mg/kg)




Antibody mediated allograft rejection:High-dose(2 g/kg ) IVIG or low-dose (100mg/kg) with plasmapheresis

(Plasmapheresis plus IVIG is performed every other day )

Continue until:

Levels of donor-specific antibodies are brought under control

Serum creatinine has improved to within 30% of previous baseline



RITUXIMAB &KIDNEY TRANSPLANTATION



IgG4 disease

• IgG4-related disease (IgG4-RD) is a recently recognized, frequently multi-organ disorder characterized by organ enlargement, elevated serum IgG4 concentrations, and peculiar histological features including dense lymphoplasmacytic infiltrate enriched with IgG4+ plasma cells, a storiform pattern of fibrosis, and obliterative phlebitis



IgG4 disease

• Laboratory investigations show some very frequent, albeit non specific, abnormalities including hypergammaglobulinemia (80–90% of cases), elevated (>135 mg/dl) serum IgG4 levels (50–70%), elevated serum IgE levels (60–70%), C3 and/or C4 hypocomplementemia (50–70%), peripheral eosinophilia (35–50%), antinuclear antibodies (30%) and rheumatoid factor (20–30%).



IgG4 disease

• The kidney is involved in approximately 15% of patients.

• Renal involvement, termed IgG4- related kidney disease (IgG4-RKD), may include a wide range of manifestations such as tubulointerstitialnephritis (TIN), membranous glomerulonephropathy (MGN), pyelitis, and hydronephrosis due to retroperitoneal fibrosis (RPF) . Compared to general IgG-RD patients, IgG4-RKD patients (especially those with TIN) more frequently show hypocomplementemia and elevated serum IgG4 levels



• Glucocorticoids are the first line of therapy for both IgG4-RD and IgG4-RKD , but disease relapse after tapering or discontinuing treatment is very high, and long-term use of glucocorticoids is associated with various adverse events.

• Rituximab (RTX) has rarely been used as induction therapy but is frequently used as second-line therapy, especially in refractory cases



• RTX has been shown to be effective in improving clinical and serologic features of IgG4-RD patients with active inflammation , even without concomitant steroid therapy .

• Treatment with RTX can decrease serum IgG4, with serum IgG4 concentrations remaining low (and disease quiescent) even after B cell reconstitution



Standard infusion1

• Administer only as an intravenous (IV) infusion

• Do not administer as an intravenous push or bolus

• Premedicate patients with an antihistamine and acetaminophen prior to dosing

• Pneumocystis jiroveci pneumonia (PCP) and anti-herpetic viral prophylaxis is recommended for patients with CLL during treatment and for up to 12 months following treatment as appropriate

• Depending on the severity of the infusion reaction and the required interventions, temporarily or permanently discontinue Ritoximab• Resume infusion at a minimum 50% reduction in rate after symptoms have resolved

• Institute medical management (eg, glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion reactions as needed

• Closely monitor the following patients: those with preexisting cardiac or pulmonary conditions, those who experienced prior cardiopulmonary adverse reactions, and those with high numbers of circulating malignant cells (≥25,000/mm3)

SELECT IMPORTANT SAFETY INFORMATION

• Infusion Reactions

• RITUXIMAB can cause severe, including fatal, infusion reactions. Severe reactions typically occurred during the first infusion, with time to onset of 30 to 120 minutes

• RITUXIMAB-induced infusion reactions and sequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, anaphylactoid events, or death

complication

• headache,

• fever,

• chills,

• stomach pain,

• nausea,

• diarrhea,

• heartburn,

• flushing,

• night sweats,

• weakness,

• muscle or joint pain,

• back pain, or

• dizziness.

https://www.rxlist.com/heartburn/drugs-condition.htm

https://www.rxlist.com/script/main/art.asp?articlekey=7875

https://www.medicinenet.com/weakness/symptoms.htm

https://www.medicinenet.com/joint_pain/symptoms.htm

https://www.rxlist.com/script/main/art.asp?articlekey=25125

Complication

• increased thirst or urination,

• swelling of the hands or feet, or

• tingling of the hands or feet.

https://www.medicinenet.com/thirst/symptoms.htm

THANK YOU

rituximab in nephrology adult nephrology panel · 2018. 9. 8. · rituximab in nephrology dr....

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