Rituximab is a chimeric monoclonal antibody directed against the CD20 antigen found on B cells. It works through several mechanisms to induce B cell depletion. It has been used successfully to treat various B cell-mediated diseases with variable levels of response. These include non-Hodgkin's lymphoma, autoimmune diseases such as rheumatoid arthritis, vasculitis, lupus nephritis, and kidney diseases such as membranous nephropathy. It has also been used prior to transplantation to reduce antibody levels and aid transplantation in sensitized patients.

1. Mohammed Adel

2. Rituximab is an engineered chimeric monoclonal antibody that contains
murine heavy and light chain variable regions directed againstCD20 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

3.  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.

4. 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.

5.  ■ 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 affectsT-cell activation by B cells
includes reducedT-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.

6. 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 toT cells, and
proliferate and
differentiate into plasma cells.
Rituximab perturbs these
processes.

7.  Standard
 Four weekly infusions (375 mg/m2) for non-
Hodgkin’s lymphoma, cryoglobulinemia (in
association with hepatitisC virus infection),
systemic lupus erythematosus, idiopathic
Membranous nephropathy and pure red cell
aplasia

8.  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

9.  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

10.  Nephrotic syndrome
 Idiopathic membranous nephropathy
 Focal segmental glomerulosclerosis
 Mixed essential cryoglobulinemia
 Primary systemic vasculitis
 Systemic lupus erythematosus
 Pure red cell aphasiac with anti-
erythropoietin antibodies
 In kidney transplant

11.  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.

12.  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.

13.  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.

14.  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.

15.  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.

16.  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.

17.  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.

18.  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.

19.  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.

20.  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.

21.  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-threateningAASV. 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.

22.  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

23.  Catherine M. et al in 2009 reported 20 pt received
rituximab as induction treatment for an active class IV (15
cases) or classV (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.

24.  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.

25.  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.

26. 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.

27.  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])

28.  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.

29.  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

30.  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.

31.  Hepatitis B may reactivate
 Pneumocystis jirovecii Pneumonia
 MeningoencephalitisCaused 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.

32. System Organ
Class
Very
Common
Common Uncommon Unknown
Infectionsand
infestations
bacterial
infections, viral infections,
+bronchitis
sepsis,
+pneumonia,
+febrile infection,
+herpes zoster,
+respiratory tract infection,
fungal infections,
infectionsof
unknown aetiology, +acute
bronchitis,
+sinusitis
serious viral infection1,
hepatitis B
reactivation1
Blood and lymphatic
system disorders
neutropenia,
leucopenia,
+febrile neutropenia
anaemia,
thrombocytopenia,
+pancytopenia
coagulationdisorders,
aplastic anaemia,
haemolytic anaemia,
lymphadenopathy
Late neutropenia2,
transientincrease in serum
IgM levels2
Immune system disorders infusion
related reactions,
angioedema
hypersensitivity tumour lysis syndrome3,
cytokine release syndrome3,
serum sickness, anaphylaxis
Metabolism and nutrition
disorders
hyperglycaemia, weight
decrease,
peripheral oedema, face
oedema, increased LDH,
hypocalcaemia

33. System Organ
Class
Very
Common
Common Uncommon Unknown
Nervous system disorders paraesthesia,
hypoaesthesia, agitation, ins
omnia, vasodilatation, dizzi
ness, anxiety
Dysgeusia cranial
neuropathy,
peripheral neuropathy
facial nerve palsy4,
loss of other senses4
Eye disorders lacrimation
disorder, conjunctivitis
severe vision loss4
Ear and labyrinth
disorders
tinnitus, ear pain hearing loss4
Cardiac disorders +myocardial
infarction3 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
and
mediastinal
disorders
bronchospasm3,
respiratory disease, chest
pain,
asthma, bronchiolitis
obliterans, 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

34. System Organ
Class
Very
Common
Common Uncommon Unknown
Skin and subcutaneous
tissue disorders
pruritis,
rash,
+alopecia
urticaria,
sweating, night sweats,
+skin disorder
severe bullous
skin reactions, toxic
epidermal necrolysis6
Musculoskeletal,
connective tissue and bone
disorders
hypertonia,
myalgia, arthralgia, back
pain, neck pain, pain
Renal and urinary
disorders
renal failure3
General disorders and
administration
site conditions
fever,
chills, asthenia, headache
tumour pain,
flushing, malaise, cold
syndrome,
+fatigue,
+shivering,
+multi-organ failure3
pain at the infusion site

35.  Idiopathic membranous nephropathy
Anti-PLA2 -related diseases,Overcome dependency on
calcineurin inhibitors
 Autoimmune thrombotic thrombocytopenic purpura
Beneficial in patients with poor response to standard
therapy,Suggestion of benefit as first-line therapy in
acuteTTP
 Focal segmental glomerulosclerosis
Recurrent FSGS in transplanted kidney,Uncertain
benefit in primary FSGS

36.  Lupus nephritis
Induction of remission,Relapsing or refractory disease,Inadequate
data on role as maintenance therapy
 ANCA-associated vasculitides
Induction of remission,Combination therapy with cytoxan for
induction of remission
Poor response in granulomatosis manifestations
,(orbital/pachymeningitis),Inadequate data on role as
maintenance therapy or timing of retreatment to prevent relapse
 Cryoglobulinemic vasculitis
Hepatitis C-related,Non-Hepatitis C-related,Non-cryoglobulinemic
glomerulonephritis

37.  rituximab is proved only in
 Idiopathic membranous nephropathy
 Reduction in preformed alloantibody titers
 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