**Background**

Rituximab is an immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that
targets the CD20 antigen, a protein expressed most B cells surface results in
B--cell depletion. Initially used for anti-neoplastic therapy, it has been
licensed for use in several autoimmune disorders. Rituximab has been used off-
label for a multitude of indications (1). Rituximab carries a black-box
warning about the following risks associated with rituximab use: fatal
infusion reactions, tumor lysis syndrome, severe skin and mouth reactions,
hepatitis B virus reactivation, and progressive multifocal leukoencephalopathy
(2). Throughout the policy, rituximab refers to rituximab and biosimilar as
appropriate.

The FDA initially approved rituximab on November 26, 1997. An alert was issued
on September 25, 2013, by the FDA to highlight additional Boxed Warning
information about Rituximab regarding patients with prior Hepatitis B virus
(HBV) infection; HBV reactivation may occur when the body's immune system is
impaired. HBV cases and patient deaths continued to occur. In response, the
FDA recommends screening and monitoring prior to and throughout rituximab's
duration in patients with prior HBV infection (3).

_**This policy addresses the off-labeled,** **non-compendia** **use of
rituximab for non-anti-neoplastic conditions. The use of rituximab for labeled
indications is covered and not addressed in this policy. Off-label use for
anti-neoplastic therapy is not addressed in this policy.**_

**_Definitions:_**

**First-line therapy** \- an agent used in the initial treatment of a
condition.

**Adverse event** \- a documented event that contraindicates further use of
the medication or side effects that are not likely to be transient and resolve
with further treatment or impair functional capacity and/or daily living
activities.

**Lack of efficacy** \- the lack of an expected or desired effect related to
therapy when the dosage and duration of therapy meet published standards.

**Refractory disease** \- when the patient fails to respond to all first-line
therapies that are standard of care for the condition.

**Relapse disease** \- a recurrence of the disease condition that does not
respond to first-line treatments and/or standard of care therapies.

**Indications of Coverage:**

**Hemophilia (acquired)**

Rituximab may be considered in patients with acquired or refractory hemophilia
as first-line combination therapy of corticosteroids and Rituximab.

Rituximab may also be considered as a second-line agent and for use in
refractory disease.

**Thrombotic thrombocytopenic purpura (TTP)**

Rituximab may be considered in patients with severe, refractory, or relapsed
thrombotic thrombocytopenic purpura (acquired) who have failed first-line
therapy (plasma exchange and glucocorticoids).  
  
The use of rituximab for initial therapy and relapse prevention is
investigational.

**Multiple sclerosis**

Rituximab may be considered a second-line option in patients with refractory
or remitting multiple sclerosis who failed first-line therapy.

**Idiopathic inflammatory myopathy**

Idiopathic inflammatory myopathies (IIMs) encompass a heterogeneous group of
rare autoimmune diseases characterized by muscle weakness and inflammation,
but in anti-synthetase syndrome, arthritis and interstitial lung disease are
more frequent and often inaugurate the disease.

Clinical practice guidelines recommend Rituximab as a treatment option for
IIMs with extra muscular (lung) involvement from a large multi-disciplinary
workgroup.(23) However, this is based on expert opinion, without supporting
evidence.(24)

**Immune-mediated myopathies**

(Dermatomyositis (DM), Polymyositis (PM), Antisynthetase syndrome, Immune-
mediated necrotizing myopathy (IMNM), Inclusion body myositis (IBM),
Nonspecific myositis)

Rituximab may be considered in refractory cases of immune-mediated myopathies
that have failed all first-line therapies.

For all other uses, rituximab is considered investigational for immune-
mediated myopathies.

**Immunoglobulin G4-related disease (IgG4-RD)**

Rituximab may be considered a second-line therapy in refractory or relapsed
cases of IgG4-RD that have failed all first-line therapies, or there is an
absolute contraindication to glucocorticoid use.

For all other uses, rituximab is considered investigational for IgG4-RD.

**Minimal change disease**

Rituximab may be considered for children with steroid-dependent, steroid-
sensitive nephrotic syndrome who have continuing frequent relapses despite
optimal combinations of prednisone and corticosteroid-sparing agents or who
have serious adverse effects of therapy.

Rituximab may be considered in adult patients with frequently relapsing or
glucocorticoid-dependent minimal change disease who have also failed to attain
a durable remission with cyclophosphamide or calcineurin inhibitors.

Rituximab in adults with glucocorticoid-resistant MCD is investigational.

Rituximab for first- or second-line therapy for minimal change disease is
investigational.

**Antibody-mediated rejection (AMR)** _**  
**_  
Rituximab may be considered as second-line treatment or as part of a
combination treatment for AMR in kidney, lung, and cardiac transplant
patients.

Rituximab may be considered in highly sensitized patients as part of
desensitization protocols awaiting donor transplants.

All other uses of rituximab for AMR prevention or treatment are considered
investigational.

**Immune thrombocytopenic purpura (ITP)**

Rituximab will be covered when all of the following criteria are met:

  1. Documented lack of response of at least one first line therapy
  2. Documented risk for bleeding (at least one of the following)
    1. Severe ITP (bleeding symptoms)
    2. Risk factors for bleeding are present
    3. In preparation for procedures or surgery with risk of bleeding
    4. Professional or lifestyle risk for trauma
  3. Persistent or chronic disease (>6 months)

**Chronic inflammatory demyelinating polyneuropathy (CIDP)**

Rituximab may be considered in patients who have failed intravenous
immunoglobulin (IVIG), glucocorticoids, and plasma exchange.

Rituximab is considered investigational for CIDP as a first line therapy

**Sj ogren's and systemic sclerosis** __

Rituximab may be considered when corticosteroids and other immunosuppressive
agents were ineffective

Rituximab is considered investigational for _Sj ogren's_ syndrome as a first
line therapy

**Limitations of Coverage:**

**Behcet 's syndrome**

Rituximab is considered investigational for Behcet's syndrome.

**Cerebral ataxia** _ **  
**_  
Rituximab is considered investigational for cerebral ataxia.

**Polyarteritis nodosa**

Rituximab is considered investigational for polyarteritis nodosa. Use in
refractory cases may be considered on a case to case basis.

**Hemophilia**

Acquired Hemophilia A (AHA) is a rare bleeding disorder that stems from
neutralizing autoantibodies against coagulation factor VIII (4). In 2020,
Tiede and colleagues published an international recommendations guideline that
proposed three suggestions for using rituximab to treat acquired hemophilia
conditions (5).

One recommendation suggested combining corticosteroids with rituximab or a
cytotoxic agent for first-line therapy in patients with FVIII <1 IU/dL or
inhibitor titer >20 BU with a grade of 2B. This recommendation was based on
the GTH-AH study, a prospective observational study with 102 patients included
for analyses and a two-year UKHCDO observational study of 172 patients
conducted by the United Kingdom Haemophilia Centre Doctors' Organization to
identify and characterize the presenting features and outcome of patients with
acquired hemophilia A (6). The GTH-AH study established the primary endpoint
as the time to achieve a partial remission (PR), defined as FVIII activity
restored to .50 IU/dL and no active bleeding after stopping any hemostatic
drug for 24 hours. Secondary endpoints were time to complete remission (CR),
defined as PR plus negative inhibitor test, prednisolone tapered to 15 mg/day,
and any other immunosuppressive treatment stopped. Overall survival, adverse
events, and causes of death were also considered. Partial remission was
achieved by 83% of patients after a median of 31 days (range 7-362). Patients
with baseline FVIII <1 IU/dL achieved PR less often and later (77%, 43 days)
than patients with 1 IU/dL (89%, 24 days). After adjusting other baseline
characteristics, low FVIII remained associated with a lower rate of PR (hazard
ratio 0.52, 95% confidence interval 0.33-0.81, P < .01). In contrast, PR
achieved on steroids alone within 21 days was associated with patients with
FVIII 1 IU/dL and inhibitor concentration <20 BU/mL (odds ratio 11.2, P <
.0001). Low FVIII was also associated with a lower rate of complete remission
and decreased survival (7).

Tiede and associates' second recommendation included a second-line therapy
with rituximab or a cytotoxic agent, whichever was not used during first-line
therapy with a grade of 1B, also based on the GTH-AH study.

A third recommendation of rituximab at a dose of 375 mg/m2 weekly for a
maximum of four cycles with a grade of 2B, which was based on one literature
review, four case reports, a multicenter phase II trial, and a randomized
phase III trial. A source was also referenced from the European Medicines
Agency, which was no longer available for review.

In a 2017 review, the authors recommended a first line immunosuppression
combination of corticosteroids and rituximab (8) derived from observations
made in the UKHCDO surveillance study (n=40), (6) the EACH2 registry (n=142),
(9) and the GTH-AH registry (n=102) (7).

A 2018 review of the evidence recommended rituximab as a second line
treatment. The authors report that the first-line of treatment remains
corticosteroids alone or in combination with cyclophosphamide (10).

For refractory disease, a 2014 systematic literature review comprised of 46
case reports and case series identified cyclophosphamide and rituximab as the
most frequently used agent for the treatment of inhibitory antibodies seen in
hemophilia. In all cases exposed to cyclophosphamide, rituximab, and other
immunosuppressive agents, a success rate defined as a complete response was
40-44%, 40-63%, and 33-56%, respectively. The authors expressed the need for
randomized trials and acknowledged the study's limitations and inconsistency
among the reports (11).

**Thrombotic thrombocytopenic purpura (TTP)**

Primary or acquired TTP is a potentially life-threatening condition. There is
a familial link, and it also has been associated with the development of
autoantibodies to the ADAMTS13 enzyme. The primary treatment is plasma
exchange therapy and glucocorticoids. Rituximab has been explored in the
treatment of TTP, but there are no randomized trials.

A systematic review evaluating rituximab's efficacy for treating acute
refractory or chronic relapsing nonfamilial acquired TTP identified individual
data of 100 patients from 15 case series and 16 case reports. Rituximab
induced complete remission (platelet recovery lasting more than 30 days) in
98% of patients, with a 9% relapse rate. For patients with complete remission,
the median follow-up was 13 months. Median platelet recovery from the first
dose of Rituximab was 14 days in ADAMTS13 deficiency, and autoantibody
positivity were both highly predictive of response to rituximab; each had a
positive predictive value of 99% for predicting complete response, implying
that these can be useful markers in predicting response to Rituximab in acute
refractory or chronic relapsing idiopathic TTP (12,13). A phase 2, non-
randomized, multicenter trial with forty patients to evaluate safety and
efficacy of Rituximab with plasma exchange therapy and glucocorticoids did not
show a difference between the rituximab and control groups for the median
number of plasma exchange treatments until remission (16.5 vs. 18; _P_ =
0.5)., but on subgroup analysis, there was a trend for white patients to
achieve higher remission rate with Rituximab than non-white (14).

Investigation of rituximab for TTP's initial management is limited to small
observational studies and suggests a reduced relapse rate when used as initial
TTP therapy. The STAR trial was stopped early for accrual futility after the
third and final enrolled patient's death following the initial Rituximab
infusion (15).

**Multiple sclerosis (MS)**

Multiple sclerosis is the most common immune-mediated inflammatory
demyelinating disease of the central nervous system. First-line treatment is
typically initiated with ocrelizumab, which is FDA approved to treat primary
progressive multiple sclerosis (16). Rituximab has been used as an alternative
for the relapsing or remitting disease.

A 2009 phase II double-blinded trial randomized 104 patients with relapsing or
remitting multiple sclerosis, with 69 receiving rituximab and thirty-five
receiving placebo. They determined a single course of rituximab reduced
inflammatory brain lesions and clinical relapse for forty-eight weeks (17). In
a 2009 trial called the OLYMPUS trial, 429 PPMS patients were randomized to
two 1,000mg intravenous rituximab or placebo infusions every twenty-four weeks
for a total of ninety-six weeks. They evaluated the time to confirmed disease
progression and did not find a statistical difference between the rituximab
versus placebo (18).

The National Institute for Health and Care Excellence (NICE): Clinical
guideline on multiple sclerosis in adults - Management (2014, updated 2019)
does not mention rituximab (19).

A 2016 retrospective cohort study in Sweden reported switching from
natalizumab (another alternative agent) to rituximab resulted in a reduced
risk of relapse compared to switching to fingoimod (1.8% vs. 17.6%; HR=0.10,
95% CI: 0.02-0.43) and a lower proportion of participants with contrast-
enhancing lesions (1.4% vs. 24.2%; OR=0.05, 95% CI: 0.0-0.22). The authors
concluded improved effectiveness and tolerability of rituximab when a switch
in medication is indicated (20). The 2018 European Committee of Treatment of
Research in Multiple Sclerosis (ECTRIMS)/European Academy of Neurology (EAN):
Guideline on the pharmacological treatment of people with multiple sclerosis
(2018) rated this evidence with a moderate risk of bias using GRADE
methodology (21).

2018 Practice guideline recommendations summary: Disease-modifying therapies
for adults with multiple sclerosis Report of the Guideline Development,
Dissemination, and Implementation Subcommittee of the American Academy of
Neurology published a systematic review on disease-modifying therapies for
adults with multiple sclerosis (22) reports:

  * They report that rituximab is possibly no more effective than placebo in reducing the risk of disability progression in people with progressive MS (low confidence).
  * Rituximab and teriflunomide are probably more effective than placebo in reducing volume or number of MRI detected T2 lesions (moderate confidence).

A 2020 report evaluating disease-modifying therapies for multiple sclerosis
reported on a nationwide registry- in Sweden followed a cohort of 6421
patients, of which 3260 were taking rituximab over six years, plus a
comparator cohort of 42,645 individuals. They evaluated severe infections
resulting in hospitalization. They reported that patients with MS are
generally at increased risk of infection was most significant in the off-label
use of rituximab group with an incident rate of 19.7 [95% CI, 16.4-23.5] per
1000 person-years and higher than the other therapies evaluated (23). In 2018
American Academy of Neurology recommendations on disease-modifying therapies
for adults with multiple sclerosis recommended a discussion about the risk of
progressive multifocal leukoencephalopathy (PML) reported in case reports in
patients with MS on Rituximab (24).

**Idiopathic inflammatory myopathy**

Idiopathic inflammatory myopathies (IIMs) encompass a heterogeneous group of
rare autoimmune diseases characterized by muscle weakness and inflammation,
but in anti-synthetase syndrome, arthritis and interstitial lung disease are
more frequent and often inaugurate the disease.

Clinical practice guidelines recommend rituximab as a treatment option for
IIMs with extra muscular (lung) involvement from a large multi-disciplinary
workgroup (25). However, this is based on expert opinion, without supporting
evidence (26).

**Immune-mediated myopathies**

Inflammatory myopathies are a group of disorders characterized by the common
feature of immune-mediated muscle injury. Distinctions in clinical and
histopathologic conditions suggest that different pathogenic processes may
cause each of the inflammatory myopathies. The most common of these disorders
include Dermatomyositis (DM), Polymyositis (PM), Antisynthetase syndrome,
Immune-mediated necrotizing myopathy (IMNM), Inclusion body myositis (IBM),
and Nonspecific myositis. Many patients with inflammatory myopathies cannot be
assigned to any category and may be classified as having nonspecific myositis.
In most cases, the precise mechanisms leading to tissue injury in the
inflammatory myopathies are incompletely defined (27).

Zhang and colleagues reported that three out of three elderly patients with
refractory HMGCR-antibody-related immune-mediated necrotizing myositis
achieved complete remission after treatment with rituximab (28). So and
colleagues reported four out of four patients with refractory rapidly
progressive interstitial lung disease related to anti-MDA5 antibody-positive
amyopathic dermatomyositis responded to rituximab. Daily prednisolone dose
usage dropped from 20 to 6.25 mg post-treatment. Two patients developed a
chest infection and one wound infection within six months after the RTX
infusion (29).

Oddis et al. reported results from the RIM trial, with 200 randomized patients
(76 with PM, 76 with DM, and 48 with juvenile DM), 195 showed no difference in
the time to achieve the definition of improvement (DOI) [defined as _>_ 20%
improvement in 3 of any 6 CSMs, with no more than two worsening by _>_ 25%].
Between the rituximab late (n = 102) and rituximab early (n = 93) groups,
there was a median time to achieve a DOI of 20.2 weeks and 20.0 weeks,
respectively. There was no significant difference between the two treatment
groups in terms of the secondary endpoints. However, 83% of the randomized
patients met the DOI, and individual CSMs improved in both groups throughout
the 44-week trial (30).

Levine conducted a pilot study and reported six of six patients with
refractory dermatomyositis responded to rituximab with muscle strength
increasing over baseline by 36-113%. Four patients had symptoms recur in
conjunction with the recurrence of CD19+ B cells. There were no treatment-
related severe or serious adverse events during this study (31). Unger and
colleagues reported a real-life retrospective analysis of refractory myositis
patients treated with rituximab, in which 14 of 19 patients responded as
measured by CK, pulmonary function, and daily prednisone dosage. One patient
died from aspiration pneumonia three weeks after the first RTX infusion (32).
A retrospective cohort study included 43 refractory patients who experienced a
75% clinical response and reduction of average prednisone from 18 to 6 mg in
42% of patients. Five patients were excluded for side effects at the first
rituximab application (33). Barsotti et al. conducted a single center study
with 26 patients with refractory myositis and obtained a favorable P<0.001
response rate (34). Ahn et al. performed a retrospective cohort study that
included 16 patients with refractory immune-mediated myopathy and achieved a
75% response rate (35). Mahler and associates conducted a study to assess the
efficacy of rituximab in patients with inflammatory myopathies refractory to
conventional immunotherapy. The study included 13 patients with refractory
myositis treated with Rituximab. Patients experienced a median reduction in CK
93% (36). Valiyil and colleagues conducted a case series, which resulted in
six of eight patients with refractory SRP antibody (+) myositis responded to
rituximab (37). Fasano and associates conducted a review of all available
trials as of 2015; 48 studies found 458 myositis patients treated with
rituximab, with an overall response rate of 78.3% (38).

**IgG4 related systemic disease**

Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated
fibroinflammatory condition that can affect multiple organs. The involved
organs share several core pathologic features and striking clinical and
serologic similarities. Elevated serum concentrations of IgG4 are common.
Before its recognition as a unified disease in the early 2000s, the seemingly
dissimilar manifestations had been presumed to be unrelated, single-organ
disorders (39).

In a French retrospective cohort, 29 of 31 (93.5%) patients with IgG4 disease
exhibited a clinical response to rituximab, with 51.5% able to withdraw
steroids (40). Khosroshahi conducted a review resulting in nine of ten
patients treated with rituximab had a favorable clinical response, 10/10 were
able to discontinue steroid, and DMAR (41). Omar and colleagues conducted a
network meta-analysis of IgG4 treatments consisting of 15 studies with 1169
patients and showing rituximab had lowest OR of relapse (0.10) amongst
treatment studied (42). A 2020 Systemic review consisting of 27 articles and
264 patients resulted in 90.7% of patients using rituximab as second-line
therapy responded, 100% of the 10% of patients using it as first-line therapy
responded (43). Carruthers et al. conducted an open-label prospective trial of
30 patients who received RTX, 97% had a clinical response, and 77% met primary
outcome. The primary outcome, measured at six months, was defined as (1)
decline of the IgG4-RD RI >=2 points compared with baseline; (2) no disease
flares before month 6; and (3) no GC use between months 2 and 6. Complete
remission was defined as an IgG4-RD RI score of 0 with no GC use (44).
Wallwork conducted a study resulting in 22 (88%) patients with retroperitoneal
fibrosis (73% of whom were due to IgG4 disease) had a favorable radiologic
response to rituximab. Nineteen of 19 patients had improvement in pain if
present. Three patients (12%) patients experienced severe infections (45). A
2015 International consensus panel guideline for evaluation and management of
IgG4 related disease, which included data supporting the use of rituximab in
some urgent cases, if glucocorticoid treatment is contraindicated (46).

**Minimal change disease**

Glucocorticoid therapy is the treatment of choice in minimal change disease
(MCD), leading to a complete remission of proteinuria in over 85 to 90 percent
of cases. MCD is more common in children than adults and accounts for 10-25
percent of adults' nephrotic syndrome cases. Rituximab has shown in
observational studies to have potential benefit in adults with frequently
relapsing or glucocorticoid dependent MCD. These reports suggest that patients
who have failed to obtain a durable remission with cyclophosphamide or
calcineurin inhibitors may benefit from rituximab. However, it does not appear
to be effective in adults with glucocorticoid resistant MCD (47).

KDOQI US commentary on the 2012 KDIGO Clinical Practice Guidelines for
Idiopathic Membranous Nephropathy (2013) reports that rituximab should be
reserved for patients with frequent relapses despite optimal combinations of
prednisone and corticosteroid-sparing therapy or intolerance to therapy. They
also state that randomized control trials are needed to evaluate secondary
agents' comparative effectiveness, including rituximab, and recommend use in
clinical trials. Optimal dosing regimen, safety, and efficacy have not been
clearly established as existing data consists of case series, small trials,
and retrospective analysis with 25 patients or fewer in the reports (48).

In children, the Kidney Disease Improving Global Outcomes (KDIGO) Clinical
Practice Guidelines for Idiopathic Membranous Nephropathy suggest that
Rituximab be considered only in children with steroid dependent, steroid-
sensitive nephrotic syndrome who have continuing frequent relapses despite
optimal combinations of prednisone and corticosteroid-sparing agents, and/or
who have serious adverse effects of therapy with a grade of 2C. There is very
low-quality evidence to support the efficacy of rituximab (48). A small RCT
with 54 children with idiopathic nephrotic syndrome dependent on prednisone
and calcineurin inhibitors for >12 months were randomized. Three-month
proteinuria was 70% lower in the rituximab arm (95% confidence interval 35% to
86%) than the standard therapy arm (intention-to-treat). Additional relapse
rates were 18.5% (intervention) and 48.1% (standard arm) (P = 0.029) and
probabilities of being drug-free at 3 months were 62.9% and 3.7%, respectively
(P < 0.001). 50% of rituximab cases were in stable remission without drugs
after nine months (49).

**Antibody-mediated rejection (AMR)**

Antibody-mediated rejection is caused by human leukocyte antigen (HLA)
antibodies resulting in an immune attack on the transplant organ. Immune
suppression to prevent this response and early graft rejection is an ongoing
aspect of transplanted research. Rituximab has been used to treat AMR in lung,
kidney, liver, and heart transplant patients. It has been explored as both a
desensitization strategy before transplant in high-risk individuals and AMR
treatment. There is a lack of high of high-quality evidence from randomized
controlled trials regarding optimal therapy for AMR.

Some of the evidence's challenges were highlighted in a 2011 report from an
international consensus conference on antibody-mediated rejection in heart
transplantation. The panel concluded it is difficult to recommend evidence-
based guidelines for AMR treatment because the criteria for diagnosis have not
been well established and have been used variably in different clinical
series, and the use of a multiplicity of therapeutic agents hampering the
ability to evaluate the efficacy of the single agent. They stated rituximab is
beginning to be used for desensitization in highly sensitized patients
awaiting heart transplantation. They recommend it as a secondary therapy for
the treatment of AMR when first-line agents failed. Evidence is limited to
case reports and series (50). In a 2015 scientific statement from the American
Heart Association and endorsed by the International Society for Heart and Lung
Transplantation, they state:

  * It is reasonable for primary therapy for AMR to include IVIg, plasmapheresis, anti-lymphocyte antibodies, and  
High-dose corticosteroids ( _Class IIa; Level of Evidence B_ ).

  * It is reasonable for secondary therapy for AMR to include rituximab, bortezomib, and anti-complement antibodies  
( _Class IIa; Level of Evidence C_ ) (51).

A systematic review of five RCTs and seven non-randomized controlled trials
evaluating the effects of different treatments on graph survival in kidney
transplant recipients suggested a potential benefit from treatment with
rituximab, plasmapheresis, and bortezomib; however, because some studies used
a combination of therapies, the personal effects could not be distinguished
(52). A phase III, multicenter randomized placebo-controlled trial evaluating
rituximab's effects in 38 kidney transplant recipients with biopsy-proven AMR
also showed a trend in favor of rituximab without a clinically significant
difference between the groups (53). An observational study evaluating the
combination of plasmapheresis, IVIG, and rituximab versus high dose IVIG alone
in the AMR treatment showed graph survival at 36 months with 92% in the
combination group compared to 50% in the IVIG alone (54,55).

AMR is rare in lung transplant patients. Case series of acute lung transplant
patients with AMR suggests a benefit of Rituximab in treatment (56).

Rituximab has also been explored in the prevention of AMR. HLA desensitization
protocols are aimed at reducing the risk of progression to AMR. Rituximab has
been investigated as an agent in these protocols. There is no high-quality
data in the form of randomized controlled trials comparing the existing
desensitization protocols. Approaches and optimal therapy have not been
defined. The use of these desensitization protocols has allowed patients in
need of a transplant to shorten the time to transplantation and permit
transplant in approximately 75 to 80% of patients. Most of these protocols
include a high dose of IVIG and rituximab (57).

A case series of twenty highly sensitized patients were enrolled and received
treatment with intravenous immune globulin and rituximab and followed for
evidence of rejection. This combination was effective for desensitization for
patients awaiting a transplant (58). A subsequent study included seventy-six
HLA sensitized patients who met strict sensitization criteria who underwent
this IVIG and rituximab protocol. They reported significant reductions in time
on the waitlist, which for deceased donor recipients was reduced from 95+/-46
months to 4.2+/-4.5 months after desensitization treatment (59). In another
series of 108 patients treated with the IVIG and rituximab protocol, 74% of
the highly sensitive patients could undergo transplant after treatment (60).

**Immune thrombocytopenic purpura (ITP)**

Rituximab is a chimeric monoclonal antibody directed against the B cell
surface protein CD20 and has been used off-label for the treatment of ITP. The
initial response to rituximab is approximately 60%, and a long term remission
is reported in 15-30% of patients in prospective and retrospective cohort
studies, systematic reviews and meta-analysis in both splenectomized and non-
splenectomized patients (Grade 2C) (61-64). There are multiple systematic
reviews and meta-analysis in the literature; however, most studies were not
randomized control trails and did not offer a control arm limiting the data
sets. A systematic review of patients who failed first-line therapies (19
studies, 313 adult patients half who had splenectomy) reported a complete
response in 44% and a response in 63% with a median duration of 11 months
(65). A meta-analysis of non-splenectomized patients (5 RT/463 patients)
reported a complete response in 47% and response in 58%, which was comparable
to a prior meta-analysis that also included observational studies (62,63). A
multi-centered, randomized, double-blinded, placebo controlled trial with the
longest duration comparing rituximab or placebo after initial corticosteroids
demonstrated only a modest response at 1.5 years (66), however also reported a
small benefit with rituximab could not be ruled out based on longer duration
of response, numerically higher responses, and late responders (65). Factors
predictive of a response have not been clearly established, but older age and
longer disease duration (>10 years) seem to reduced response (67,68). There is
a lack of long term safety data with reports of rare risk of progressive
multifocal leucoencephalopathy and hypogammaglobulinaemia (62,69). There is an
FDA black box warning for the potential to cause reactivation of hepatitis B
necessitating testing for hepatitis B before use. Rituximab is included as
second-line therapy in the 2018 ASH guidelines as it offers the potential for
a treatment-free remission without surgical intervention (70).

**Chronic inflammatory demyelinating polyneuropathy (CIDP)**

Tracy and Dyck (2010) examined the data for treatment of inflammatory
demyelinating peripheral neuropathies, particularly chronic inflammatory
demyelinating polyneuropathy (CIDP). A large clinical trial showed short and
long-term efficacy of IVIG for the treatment of CIDP and the U.S. Food and
Drug Administration approved the use of IVIG (Gamunex) as a treatment for
CIDP. Recent trials for other agents for CIDP treatment have not proved as
promising, with a large study of methotrexate failing to show significant
benefit. There are recent cases of monoclonal antibodies (e.g., rituximab,
alemtuzumab) showing benefit in patients with CIDP, but the side effect
profiles can be worrisome. Clinical history, neurological examination, spinal
fluid examination, and electrophysiological evaluation remain mainstays for
the diagnosis of demyelinating inflammatory polyradiculoneuropathy. Genetic
testing and nerve biopsy are important diagnostic tools in some patients.
Potential treatments for immune-mediated demyelinating
polyradiculoneuropathies are varied, with the authors generally favoring IVIG
and/or corticosteroids as first-line agents. Plasma exchange can be helpful in
selected patients. Data for efficacy of other oral immunomodulatory agents are
based primarily on case reports and case series, and have not been uniformly
positive. The use of monoclonal antibodies (particularly rituximab) may have
promise, but further research needs to be done, and the risks need to be
carefully considered (71).

Nobile-Orazio et al (2010) stated that chronic inflammatory demyelinating
polyneuropathy (CIDP) and multifocal motor neuropathy (MMN) usually respond to
immune therapies including steroids and plasma exchange for CIDP and high-dose
IVIGs for both diseases. Other immune therapies have been used to reduce the
costs or the side-effects of these therapies, but their efficacy was only
recently assessed in randomized controlled trials (RCTs). The prolonged
efficacy of IVIG in CIDP has been confirmed in a 48-week RCT. Two other RCTs
showed that oral methotrexate or intramuscular interferon beta were not more
effective than placebo in improving the efficacy or reducing the dose of IVIG
or steroids. In MMN, a RCT showed that oral mycophenolate mofetil was not more
effective than placebo in increasing the efficacy or reducing the dose of
IVIG. Other immune therapies were assessed in open trials in both diseases,
but their efficacy remains unclear, even if in some patients a possible
efficacy of rituximab was reported. Some preliminary studies suggest that
subcutaneous immunoglobulin may be as effective as IVIG in the maintenance
therapy of CIDP and MMN. The authors concluded that after several years of
anecdotal reports, a number of RCT have now appeared in CIDP and MMN, but
their results are still insufficient to support the use of new therapies in
these diseases (72).

In a retrospective, observational and multi-center study, Benedetti et al
(2011) analyzed the efficacy of rituximab in a large chronic inflammatory
demyelinating polyneuropathy (CIDP) cohort. Thirteen CIDP patients were
treated with rituximab after the partial or complete lack of efficacy of
conventional therapies. Eight patients had co-occurring hematological
diseases. Patients who improved by at least 2 points in standard clinical
scales, or who reduced or discontinued the pre-rituximab therapies, were
considered as responders. Nine patients (7 with hematological diseases)
responded to rituximab: 6 of them, who were non-responders to conventional
therapies, improved clinically, and the other 3 maintained the improvement
that they usually achieved with IVIG or plasma exchange. Significantly
associated with shorter disease duration, rituximab responses started after a
median period of 2.0 months (range of 1 to 6) and lasted for a median period
of 1 year (range of 1 to 5). The authors concluded that rituximab seems to be
a promising therapeutic choice when it targets both CIDP and co-occurring
hematological diseases (74).

In a Cochrane review, Mahdi-Rogers (2010) systematically reviewed the evidence
from RCTs of cytotoxic drugs and interferons other than corticosteroids,
immunoglobulin and plasma exchange for chronic inflammatory demyelinating
polyneuropathy (CIDP). These researchers sought RCTs and quasi-randomized
trials of all immunosuppressive agents such as azathioprine, cyclophosphamide,
methotrexate, cyclosporin A, mycophenolate mofetil, and rituximab and all
immunomodulatory agents such as interferon alfa and interferon beta in
participants fulfilling standard diagnostic criteria for CIDP. Two authors
independently selected trials, judged their methodological quality and
extracted data. They wanted to measure the change in disability after 1 year
as the primary outcome. Secondary outcomes were change in disability after 4
or more weeks (from randomization), change in impairment after at least 1
year, change in maximum motor nerve conduction velocity and compound muscle
action potential amplitude after 1 year and for those participants who were
receiving corticosteroids or IVIG, the amount of this medication given during
at least 1 year after randomization. Participants with one or more serious
adverse events during the first year was also a secondary outcome. Four trials
fulfilled the selection criteria, one of azathioprine (27 participants), two
of interferon beta-1a (77 participants in total) and 1 of methotrexate (60
participants). None of these trials showed significant benefit in the primary
outcome or secondary outcomes selected for this review. The evidence from RCTs
does not show significant benefit from azathioprine, interferon beta-1a or
methotrexate but none of the trials was large enough to rule out small or
moderate benefit. The evidence from observational studies is insufficient to
avoid the need for RCTs to discover whether these drugs are beneficial. Future
trials should have improved designs, more sensitive outcome measures and
longer durations (73).

**Sj ogren's and systemic sclerosis**

Primary Sjogren's syndrome (pSS) is an autoimmune disorder affecting exocrine
glands; however, a subgroup of pSS patients experience systemic extra-
glandular involvement leading to a worsening of disease prognosis (Carubbi, et
al., 2013). Current therapeutic options are mainly empiric and often
translated by other autoimmune diseases. In the last few years growing
evidence suggests that B-cell depletion by rituximab (RTX) is effective also
in pSS. Patients with early active disease appear to be those who could
benefit the most from RTX (75).

A systematic evidence review concluded that further clinical trials are
necessary to establish the efficacy of rituximab in primary Sjogren syndrome.
Ramos-Casals, et al (2010) searched MEDLINE and EMBASE for articles on drug
therapy for primary Sjogren syndrome published between January 1, 1986, and
April 30, 2010. Controlled trials of topical and systemic drugs including
adult patients with primary Sjogren syndrome were selected as the primary
information source. The search strategy yielded 37 trials. The authors
reported that a placebo-controlled trial found significant improvement in the
Schirmer and corneal staining scores, blurred vision, and artificial tear use
in patients treated with topical ocular 0.05% cyclosporine. Three placebo-
controlled trials found that pilocarpine was associated with improvements in
dry mouth (61%-70% vs 24%-31% in the placebo group) and dry eye (42%-53% vs
26%). Two placebo-controlled trials found that cevimeline was associated with
improvement in dry mouth (66%-76% vs 35%-37% in the placebo group) and dry eye
(39%-72% vs 24%-30%). Small trials (<20 patients) found no significant
improvement in sicca outcomes for oral prednisone or hydroxychloroquine and
limited benefits for immunosuppressive agents (azathioprine and cyclosporine).
A large trial found limited benefits for oral interferon alfa-2a. Two placebo-
controlled trials of infliximab and etanercept did not achieve the primary
outcome (a composite visual analog scale measuring joint pain, fatigue, and
dryness); neither did two small trials (<30 patients) testing rituximab,
although significant results were observed in some secondary outcomes and
improvement compared with baseline. The authors concluded that, in primary
Sjogren syndrome, evidence from controlled trials suggests benefits for
pilocarpine and cevimeline for sicca features and topical cyclosporine for
moderate or severe dry eye. Anti-tumor necrosis factor agents have not shown
clinical efficacy, and larger controlled trials are needed to establish the
efficacy of rituximab (76). An accompanying editorial by Vissink, et al.
(2010) stated that "larger trials are needed before the role of rituximab in
the treatment of primary Sjogren syndrome can be settled, not only with
respect to its effect on salivary flow rate and xerostomia but also with
regard to the effect of rituximab treatment on general symptoms,
extraglandular involvement, and life-threatening situations in primary Sjogren
syndrome (77).

Carubbi et al (2013) conducted a study to investigate the efficacy and safety
of RTX in comparison to disease modifying anti-rheumatic drugs (DMARDs) in
early active pSS patients. Forty-one patients with early pSS and active
disease (EULAR Sjogren's syndrome disease activity index, ESSDAI  6) were
enrolled in the study. Patients were treated with either RTX or DMARDs in two
different rheumatology centers and followed up for 120 weeks. Clinical
assessment was performed by ESSDAI every 12 weeks up to week 120 and by self-
reported global disease activity pain, sicca symptoms and fatigue on visual
analogic scales, unstimulated saliva flow and Schirmer's I test at week 12,
24, 48, 72, 96, and 120. Laboratory assessment was performed every 12 weeks to
week 120. Two labial minor salivary gland (MSG) biopsies were obtained from
all patients at the time of inclusion in the study and at week 120. The
investigators concluded that their study demonstrated that RTX treatment
results in a faster and more pronounced decrease of ESSDAI and other clinical
parameters compared to DMARDs treatment. No adverse events were reported in
the two groups. The investigators also observed that RTX is able to reduce
glandular infiltrate, interfere with B/T compartmentalization and consequently
with the formation of ectopic lymphoid structures and germinal center-like
structures in pSS-MSGs. The investigators reported that this is the first
study performed in a large cohort of early active pSS patients for a period of
120 weeks. The investigators stated that the study showed that RTX is a safe
and effective agent to be employed in pSS patients with systemic, extra-
glandular involvement. Furthermore, they noted that their data on pSS-MSGs
provide additional biological basis to employ RTX in this disease (78).

In a double-blind, randomized, placebo-controlled trial, Meijer et al (2010)
examined the safety and effectiveness of rituximab in patients with primary
Sjogren's syndrome (pSS). Patients with active pSS, as determined by the
revised American-European Consensus Group criteria, and a rate of stimulated
whole saliva secretion of greater than or equal to 0.15 ml/min were treated
with either rituximab (1,000 mg) or placebo infusions on days 1 and 15.
Patients were assigned randomly to a treatment group in a ratio of 2:1
(rituximab:placebo). Follow-up was conducted at 5, 12, 24, 36, and 48 weeks.
The primary end point was the stimulated whole saliva flow rate, while
secondary end points included functional, laboratory, and subjective
variables. A total of 30 patients with pSS (29 females) were randomly
allocated to a treatment group. The mean +/- SD age of the patients receiving
rituximab was 43 +/- 11 years and the disease duration was 63 +/- 50 months,
while patients in the placebo group were age 43 +/- 17 years and had a disease
duration of 67 +/- 63 months. In the rituximab group, significant
improvements, in terms of the mean change from baseline compared with that in
the placebo group, were found for the primary end point of the stimulated
whole saliva flow rate (p = 0.038 versus placebo) and also for various
laboratory parameters (B cell and rheumatoid factor [RF] levels), subjective
parameters (Multidimensional Fatigue Inventory [MFI] scores and visual analog
scale [VAS] scores for sicca symptoms), and extra-glandular manifestations.
Moreover, in comparison with baseline values, rituximab treatment
significantly improved the stimulated whole saliva flow rate (p = 0.004) and
several other variables (e.g., B cell and RF levels, unstimulated whole saliva
flow rate, lacrimal gland function on the lissamine green test, MFI scores,
Short-Form 36 health survey scores, and VAS scores for sicca symptoms). One
patient in the rituximab group developed mild serum sickness-like disease. The
authors concluded that these results indicated that rituximab is an effective
and safe treatment strategy for patients with pSS (79).

Mekinian et al (2012) evaluated RTX in pSS with peripheral nervous system
(PNS) involvement. Patients with pSS and PNS involvement who were included in
the French AIR registry were analyzed. A total of 17 patients (aged 60 years
(44 to 78 years); 14 were female) were included in this analysis. Neurological
improvement was noted in 11 patients (65 %) at 3 months. Rankin scale
decreased from 3 (1 to 5) to 2 (1 to 5), 2 (1 to 5) and 2 (1 to 6) after 3, 6
and 9 months (p = 0.02). European Sjogren's Syndrome Disease Activity Index
(ESSDAI) decreased from 18 (10 to 44) to 11 (5 to 20), 11 (5 to 29) and 12 (5
to 30) after 3, 6 and 9 months (p < 0.05). Rituximab was effective in
neurological involvement in 9/10 patients with vasculitis or cryoglobulinemia
(90 %) (group 1) at 3 months and in 2/7 cases (29 %) without cryoglobulinemia
and vasculitis (p = 0.03). Rankin and European Sjogren's Syndrome Disease
Activity Index scales decreased significantly in group 1. The authors
concluded that RTX seems effective in cryoglobulinemia or vasculitis-related
PNS involvement in pSS (80).

Gottenberg et al (2013) evaluated the safety and effectiveness of rituximab in
patients with progressive systemic sclerosis (pSS). The AutoImmune and
Rituximab registry has included 86 patients with pSS treated with rituximab,
prospectively followed-up every 6 months for 5 years. A total of 78 patients
with pSS (11 men, 67 women), who already had at least 1 follow-up visit, were
analyzed. Median age was 59.8 years (29 to 83), median duration of disease was
11.9 years (3 to 32). Indications for treatment were systemic involvement for
74 patients and only severe glandular involvement in 4 patients. The median
ESSDAI was 11 (2 to 31); 17 patients were concomitantly treated with another
immunosuppressant agent. Median follow-up was 34.9 months (6 to 81.4) (226
patient-years). Overall efficacy according to the treating physician was
observed in 47 patients (60 %) after the first cycle of rituximab. Median
ESSDAI decreased from 11 (2 to 31) to 7.5 (0 to 26) (p < 0.0001). Median
dosage of corticosteroid decreased from 17.6 mg/day (3 to 60) to 10.8 mg/day
(p = 0.1). A total of 41 patients were retreated with rituximab; 4 infusion
reactions and 1 delayed serum sickness-like disease resulted in rituximab
discontinuation. Three serious infections (1.3/100 patient-years) and 2
cancer-related deaths occurred. The authors concluded that in common practice,
the use of rituximab in pSS is mostly restricted to patients with systemic
involvement. This prospective study showed good efficacy and tolerance of
rituximab in patients with pSS and systemic involvement (81).

**Behcet 's syndrome**

Behcet's syndrome is an auto-inflammatory disorder in which ulceration of
mucous membranes and inflammation of the skin, eyes, and nervous system
occurs. There are case reports on the use of rituximab for Bechet's treatment.
The European League Against Rheumatism (EULAR) Standing Committee for Clinical
Affairs multi-disciplinary task force, the Consensus Conference on Treatment
of Skin and Mucosal Lesions Committee of Guideline for the Diagnosis and
Treatment of Mucocutaneous Lesions of Behcet's disease, and the evidence-based
diagnosis and clinical practice guidelines for intestinal Behcet's disease
2020 edited by Intractable Diseases, the Health and Labour Sciences Research
Grants do not mention rituximab in their guidelines (82,83).

**Cerebral Ataxia**

Cerebral ataxia is an acquired or genetic degenerative disease of the nervous
system that causes cerebellar degeneration. In some cases, a treatable cause
can be identified, but there are no effective therapies in many cases.
Rituximab has been proposed as a possible therapy due to clinical improvements
seen in antibody-depleting treats such as plasma exchange and rituximab
response in other similar conditions. A cohort study of 118 adult patients
with ataxia compared outcomes of various treatments did not report an
improvement on the three patients who received rituximab (84). There are case
reports of ataxia improvement with rituximab, but most are improvement in
ataxia related to other neurological conditions (85).

**Polyarteritis nodosa**

Polyarteritis nodosa (PAN) is a systemic necrotizing vasculitis that
predominantly affects medium-sized muscular arteries and often involves small
muscular arteries. Rituximab has been used as an alternative agent for a
resistant disease, defined as patients with a persistent severe or worsening
disease that does respond adequately to glucocorticoids or cyclophosphamide
treatment within two to three months. Evidence for the use of rituximab in
this setting is limited to case reports (86). The 2009 European League Against
Rheumatism (EULAR) recommendations for the management of primary small and
medium vessel vasculitis recommends patients who do not achieve remission or
relapse on a maximal dose of standard therapy be referred to an expert Center
for further management enrolled in clinical trials (level of evidence 3, great
of recommendation C) (87).

Rituximab's properties to deplete B-cells have proven useful in many
autoimmune conditions. There is growing interest in the use of rituximab off-
label for multiple conditions.

It can be challenging to obtain high-quality evidence from well-designed
randomized controlled trials for rare and life-threatening medical conditions.
In many cases, the literature is limited to case reports or case series or
small observational studies, demonstrating potential promise. However, low
quality literature cannot provide firm evidence of the drug's efficacy or
safety for off-label use. In many of the conditions within this policy, there
is a paucity of high-quality evidence and limited literature to support the
use. Due to these conditions' unique nature, NGS has determined to cover many
off-label use cases refractory to first-line treatment or not improving with
first-line treatment where alternative treatment options are limited or
nonexistent. If additional peer-reviewed literature that provides more robust
clinical evidence emerges, further coverage can be considered. In cases for
which the policy determines rituximab's use is investigational, NGS is
cognitive that there may be exceptional cases where there are minimal or no
alternative treatment options, and a trial of rituximab may be clinically
indicated. In these cases, consideration on a case to case basis may be made.

For off-label use, there is an interest in using these agents as the initial
therapy. In most of these cases, there was not enough evidence to support
first-line use. Multiple sclerosis is a condition where there is interest in
the use of rituximab as initial therapy. There was a promising phase two
double-blinded randomized trial that showed rituximab's promise in initial
therapy. However, this study was limited by the small number of participants,
short follow-up, and was not adequate to address long-term safety. There is
also a lack of quality studies to compare Rituximab to standard treatments to
understand if this therapy is equivalent or superior to current treatments. In
addition, there is some concern regarding the increased risk of serious
infection associated with the long-term use of Rituximab. Therefore, rituximab
will not be considered the initial agent for multiple sclerosis treatment but
will be considered for refractory or failed first-line cases. For antibody-
mediated rejection, pre-transplant desensitization protocols have been shown
to improve the recipients' potential to undergo successful transplants and,
therefore, be covered when the patient is highly sensitized and at risk while
awaiting further studies on desensitization protocols.

**Immune thrombocytopenic purpura (ITP)**

Rituximab has been studied in multiple trials with conflicting results but
overall favorable with durable response rate similar to TPO-RA of
approximately 40% (Grade 2C). The potential advantage of rituximab is the
possibility for durable remission (69). Rituximab is administered
intravenously weekly for four consecutive weeks, and if there is a response,
it may reduce the need for chronic maintenance therapy (69). The use of
rituximab is off-label, and high quality evidence is lacking. It is included
in the ASH Guidelines as if offers the potential for treatment-free remission.
The guidelines include the trial of rituximab may be desirable before
splenectomy as it has the potential to be splenectomy sparing. If there is the
rational for the decision not to perform splenectomy the literature and
guidelines support rituximab as a second-line option and evidence-based
reviews (other than the ASH Guidelines) rank the quality of evidence as Grade
2B (69,70).