**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. Labeled uses for Rituximab
include chronic lymphocytic leukemia, non-Hodgkin lymphomas, pemphigus
vulgaris, rheumatoid arthritis, Antineutrophilic cytoplasmic antibody
(ANCA)-associated vasculitis (which includes microscopic polyangiitis,
granulomatosis with polyangiitis (GPA) (formerly Wegener's Granulomatosis) and
eosinophilic GPA (formally Churg-Strauss syndrome). It is thought to act
primarily by depleting CD20-positive cells. 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 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 (see A58113 Off-Label Use of Anti-Cancer Drugs
and Biologicals)._**

**Coverage**

**For this policy:**

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

An adverse event is 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 is the lack of an expected or desired effect related to
therapy when the dosage and duration of therapy meet published standards.

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

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

If a patient is treated with Rituximab, they are expected to be treated with
the standard doses per medical literature for the condition. After the initial
treatment, re-treatment requires a positive response to Rituximab documented
in the medical record.



**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.

**Immune thrombocytopenic purpura**

  
This is addressed in LCD [L38268 Immune Thrombocytopenia (ITP)
Therapy.](https://www.cms.gov/medicare-coverage-database/indexes/lcd-
contractor-index.aspx?bc=AIAAgAAAAAAA&)

**Thrombotic thrombocytopenic purpura (acquired)**

  
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.

**Autoimmune hemolytic anemia (AIHA)**

  
Rituximab may be covered as first-line treatment in patients with symptomatic,
severe cold AIHA.

Rituximab may be covered as second-line therapy for refractory warm AIHA after
failed first-line treatment.

**Evans Syndrome**

  
Rituximab may be considered as a second-line treatment for Evans syndrome
after failed response to first-line therapies.

**Multiple Sclerosis**

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

**Bullous pemphigoid**

Rituximab may be considered in cases of refractory bullous pemphigoid, which
has failed first-line therapy.

**Membranous nephropathy**

Rituximab may be considered in cases of refractory or resistant membranous
nephropathy.

Rituximab may be considered for patients with membranous nephropathy with
proteinuria of at least 5 grams per 24 hours in quantified creatinine
clearance of at least 40 ml per minute per 1.73 m2 of the body surface area
and had been receiving angiotensin-system blockade for at least three months
to receive intravenous Rituximab (two infusions, 1000 mg each, administered 14
days apart).

Rituximab is otherwise considered investigational for first-line use.

**Immunotherapy-related Encephalitis**

Rituximab may be considered in immunotherapy related to encephalitis with
positive autoimmune encephalopathy antibodies and limited or no improvement
with first-line therapy.

For other uses, Rituximab is considered investigational for encephalitis.

**_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. __

**Myasthenia Gravis**

Rituximab may be considered for patients with MuSK-positive myasthenia gravis
who have an unsatisfactory response to initial immunotherapy.

Rituximab may be considered in refractory AChR-Ab+ MG in patients who fail or
do not tolerate other immunosuppressive agents.

Rituximab is considered investigational for other uses in myasthenia gravis,
including initial treatment.

**Neuromyelitis Optica**

Rituximab may be considered in refractory cases of neuromyelitis optica that
have failed first-line therapies.

Rituximab is considered investigational as first-line therapy for
neuromyelitis optica.

**Lupus nephritis**

Rituximab is considered investigational for lupus nephritis for initial or
first-line treatment.

Rituximab may be considered for lupus nephritis in patients refractory defined
by at least six months of conventional therapy and has failed cyclophosphamide
(CYC) or mycophenolate mofetil (MMF) treatments or is worsening despite three
months of treatment with glucocorticoids plus CYC or MMF.

**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.

**Hematopoietic Stem Cell Transplant**  
Rituximab may be considered as part of combination treatment for preparative
regimens and post-transplantation maintenance.

**Graft vs. Host Disease**

Rituximab may be considered in cases of chronic graft-versus-host disease.

Rituximab is considered investigational as a first-line agent for graft-
versus-host disease.

**Non 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.

**Sjorgren 's syndrome**

Rituximab is considered investigational for Sjorgren's syndrome.

_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 Rituximab8 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



_Immune thrombocytopenia (refractory)_

Addressed in [Immune Thrombocytopenia therapy policy
L38268](https://www.cms.gov/medicare-coverage-database/indexes/lcd-contractor-
index.aspx?bc=AIAAgAAAAAAA&)



_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 Rrituximab'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



_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.16 There are case
reports of ataxia improvement with Rituximab, but most are improvement in
ataxia related to other neurological conditions.17

****



_Autoimmune hemolytic anemia_

Autoimmune hemolytic anemias (AIHAs) are rare, heterogeneous disorders
characterized by the destruction of red blood cells through warm or cold
antibodies. Glucocorticoids are considered the first-line agent for warm
AIHA.18 Investigations into Rituximab have demonstrated a role for this agent
in AIHA.

Multiple retrospective and small observational studies support the use of
Rituximab for the refractory treatment of AIHA. This data is compiled in a
2015 meta-analysis of 21 observational studies with 409 patients supporting
Rituximab's use in AIHA management. This analysis reported that Rituximab
seems to be a safe and effective therapy for AIHA. The authors suggest that it
could be used at an earlier point in therapy, before more toxic
immunosuppressive drugs, or in place of splenectomy in some cases. The meta-
analysis was limited as the existing evidence consisted of observational
studies with data from a small prospective multicenter study support the use
of low-dose Rituximab (in combination with prednisone) in patients with newly
diagnosed or refractory AIHA.19 A 2013 RCT assigned 64 patients with newly
diagnosed patients with warm AIHA to glucocorticoids with or without Rituximab
weekly for four weeks. The authors reported a better response rate at 12
months (36 versus 75%), with responses continuing to occur over the first six
months even after completing therapy. At 36 months, the remission rates
remained higher in the combination group (45 versus 70%) and improved relapse-
free survival in the combined therapy group (hazard ratio [HR] 0.33; 95% CI
0.12-0.88). Adverse events were similar in both groups. A 2017 trial with 32
adults with warm AIHA found similar results with response rates at 12 months
of 31 versus 75 percent and 24 months of 63 versus 19 percent. A small sample
size limits these trials, but larger trials are difficult as the condition is
rare.

Cold AIHA may be treated by avoidance of cold triggers, but cases may be
severe. Cold AIHA is not responsive to glucocorticoids or other treatment
options. Several case reports followed by larger, prospective, but
uncontrolled trials have shown that approximately 60% of patients respond to
Rituximab.20 A retrospective study of 232 patients reported rituximab plus
bendamustine therapy resulted in responses in 35 (78%) of 45 patients; 24
(53%) achieved complete response. In patients responding to Rituximab-
bendamustine estimated 5-year sustained remission was 77%.21

In 2020 the First International Consensus Group met to develop recommendations
and algorithms for AIHA management.18 They reviewed available evidence
acknowledging the lack of clinical trials or consensus on best practices and
recommend the following:

  * Corticosteroids remain first-line therapy for warm-AIHA, while the addition of Rituximab should be considered early in severe cases and if no prompt response to steroids is achieved.
  * Rituximab with or without bendamustine should be used in the first line for patients with cold agglutinin disease requiring therapy.

_Evans Syndrome_

Evans syndrome is a rare autoimmune condition most often in children presents
with two or more cytopenia's, commonly AIHA and ITP with or without
neutropenia. It also may occur as a secondary condition associated with other
underlying diseases. First-line treatment is usually glucocorticoids and, in
some cases, intravenous immunoglobulin. In refractory cases or steroid-
dependent cases, Rituximab has been used.22,23 In combination with steroids,
response rates of up to 76% have been reported in a case series of 17
pediatric cases. Literature is limited to one small prospective study (n=15),
retrospective case series (n=68 adults and n=17 pediatrics), and case
reports.23



_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.24 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.25 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.26

The National Institute for Health and Care Excellence (NICE): Clinical
guideline on multiple sclerosis in adults - Management (2014, updated 2019)
does not mention Rituximab.27

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.28 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.29

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 sclerosis30 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.31 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.32

****

_Bullous Pemphigoid_

Bullous pemphigoid (BP) is a rare autoimmune disease characterized by
cutaneous blistering at the epithelial basement membrane zone. First-line
therapy may consist of topical or systemic corticosteroids. Additional
immunomodulatory therapies may be added to minimize the adverse effects of
chronic corticosteroid therapy. A case report and two small case series
suggest Rituximab may be effective for refractory bullous pemphigoid to
conventional therapies.33-35 A 2015 study provides a comparison and shows that
first-line combination therapy has similar or even lower rates of infection
and mortality than conventional treatment.36 In 2019 the Japanese
Dermatological Association published a guideline for the management of
pemphigoid. They report in severe cases (including treatment-resistant cases),
steroid pulse therapy, various immunosuppressants as azathioprine, plasma
exchange therapy, and intravenous immunoglobulin (IVIG) therapy used in
combination. The authors report that Rituximab is effective, but future
clinical studies are necessary to confirm this finding.37 A 2019 consensus on
the treatment of autoimmune bullous dermatoses was composed by the Brazilian
Society of Dermatology.38 In cases of treatment resistance, anti-CD20
immunotherapy (rituximab) may be prescribed. New compounds are being proposed
based on the immunopathogenesis of BP.39-41 A guideline on the management of
bullous pemphigoid by the European Dermatology Forum and European Academy of
Dermatology and Venerology (EADV) was constructed and did not mention the use
of Rituximab.42 The 2012 British Association of Dermatologists' guidelines for
managing bullous pemphigoid makes no mention of Rituximab.43



_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.44 However, this is based on expert opinion, without supporting
evidence.45

_Encephalitis_

Encephalitis is a viral infection of the central nervous system resulting in
clinical syndromes of aseptic meningitis or encephalitis. Rituximab, combined
with steroids and IVIG or plasma exchange therapy, is considered an
alternative approach for severe cases. Titulaer and colleges reported that the
use of Rituximab with second-line immunotherapy significantly improved the
outcome of patients who failed to respond to first-line therapy and
experienced decreased frequency of relapses.46 The 2012 Association of British
Neurologists and British Infection Association National Guidelines reports
some success using Rituximab in patients who fail to respond to first-line
therapy.47 The 2007 NICE guideline on Chronic fatigue syndrome/ myalgic
encephalomyelitis (or encephalopathy): diagnosis and management made no
mention of Rituximab.48

_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.49

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.50 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.51

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.52

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.53 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.54 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.55 Barsotti et al. conducted a single center study with
26 patients with refractory myositis and obtained a favorable P<0.001 response
rate.56 Ahn et al. performed a retrospective cohort study that included 16
patients with refractory immune-mediated myopathy and achieved a 75% response
rate.57 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%.58 Valiyil
and colleagues conducted a case series, which resulted in six of eight
patients with refractory SRP antibody (+) myositis responded to Rituximab.59
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%.60

**__**

_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.61

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.62 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.63 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.64
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.65 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.66 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.67 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.68

_Myasthenia Gravis_

Myasthenia gravis (MG) is an autoimmune disorder of the postsynaptic
neuromuscular junction characterized by fluctuating weakness involving
variable combinations of ocular, bulbar, limb, and respiratory muscles. First-
line treatment includes acetylcholinesterase inhibition, immunosuppressive
agents, immunomodulating agents, and thymectomy. Approximately 10-15% of
patients with generalized MG have difficulty controlling the disease referred
to as treatment-refractory MG. Drug resistance has been defined as a failure
of at least three second-line agents. In these refractory or resistant
patients, treatment is individualized, and Rituximab is a proposed treatment
option.69,70 Rituximab's potential benefits have been investigated and
reported in several case reports and small (<20 patients) retrospective series
in refractory MG with favorable results. A phase II randomized trial of
Rituximab with generalized MG did not show a significant steroid-sparing
effect at one year than placebo; however, the results were presented but then
never followed with full-text publication.71 A 2017 systematic review
including a total of 169 patients with myasthenia gravis treated with
Rituximab and 57 patients who were Mu-Sk positive found that the Mu-SK-
positive patients were more likely to achieve minimal disease manifestations
(72 versus 30%) and improved rates of pharmacological or complete sustained
remission (47 versus 16 percent).72 A 2020 systematic review of the literature
on Rituximab's use for autoantibody against acetylcholine receptor (AChR)
subtype of MG reported heterogeneous data and lack of RCTs. They found that
treatment with rituximab appears to work in some. However, not all patients
with the AChR subtype of MG were reported, and additional research to
determine the subtype of patients who may benefit is needed.73 There is an
active RCT trial to investigate further rituximab's role in refractory MG.70
Preliminary retrospective data suggest rituximab's potential role in first-
line treatment for myasthenia gravis; however, data is limited.74

2020 International Consensus guidance on the management of myasthenia gravis
(updated from 2016 guidelines) provides the following recommendations:

  * Rituximab should be considered as an early therapeutic option in patients with MuSKAb+ MG who have an unsatisfactory response to initial immunotherapy. (Median 9, range 4-9) with 7-9 being considered appropriate.
  * The efficacy of Rituximab in refractory AChR-Ab+ MG is uncertain. It is an option if patients fail or do not tolerate other IS agents. (Median 8, range 4-9)75

_Neuromyelitis Optica_

Neuromyelitis Optica spectrum disorders (NMOSD, previously known as Devic
disease or neuromyelitis optica [NMO]) are inflammatory disorders of the
central nervous system characterized by severe, immune-mediated demyelination
and axonal damage predominantly targeting optic nerves and spinal cord.76,77
Rituximab has been proposed as a potential agent for attack prevention. An
open-label RCT 68 patients with NMODS with or without AQP4 antibodies were
randomized to Rituximab (n=33) or azathioprine(AZA) (n=35). They found a
decrease in relapse rate in both groups, but more significant in the Rituximab
group with AZA group decreased from 1 (0.38) to 0.51 (0.55) ( _P-_ value
<0.001) and in the RIT group decreased from 1.30 __ (0.68) to 0.21 (0.42) (
_P-_ value <0.001). Nineteen patients (54.3%) in AZA group and 26 patients
(78.8%) in RIT group became relapse-free after intervention ( _P-_ value =
0.033).78 A 2016 systematic review reported on forty-six studies that reported
Rituximab's use in the treatment of NMOSD. This included small case series and
case reports with a total of 438 patients. they reported a mean reduction in
the annualized relapse rate ratio of 0.79 (0.15) (95%CI, 1.08 to 0.49) And a
reduction in the mean expanded disability status scale score of 0.64 (0.27)
(95%CI, 1.18 to 0.10). However, adverse effects were reported in 26% of
patients treated with Rituximab, including infusion-related adverse effects,
infection, leukopenia, and two patients with posterior reversible
encephalography and seven deaths. They conclude that Rituximab therapy reduces
the frequency of NMOSD relapses and neurological disability but cautions use
as first-line therapy due to safety concerns.79



A 2020 multi-center, double-blinded RCT reported on 38 participants randomized
to Rituximab or placebo for NMOSD. Rituximab was administered every week for
four weeks, and then every six months, and patients were monitored for signs
of relapse. Seven (37%) relapses occurred in patients allocated placebo **,**
**** and none were recorded in patients assigned Rituximab (group difference
36*8%, 95% CI 12*3-65*5; log-rank p=0*0058). This study demonstrates the
potential that rituximab may prevent relapsing disease; however, there was a
16% drop out rate and was limited by a small sample size.80

__

_Lupus nephritis_

Patients with the autoimmune condition systemic lupus erythematosus may
develop diffuse or focal proliferative lupus nephritis. The definition of a
complete response to initial immunosuppressive therapy is variable; however, a
patient who fails to achieve a complete or partial response to initial
treatment has a worse overall prognosis, so investigations on therapy for
resistant or refractory lupus nephritis is ongoing. Typically, patients need
to be treated for a minimum of six to twelve months before a complete response
may be seen with initial therapy.81 Patients who fail to respond after six
months of treatment with glucocorticoids plus cyclophosphamide (CYC) or
mycophenolate mofetil (MMF).82 This is based on data from cohort studies,
including 43 patients with both membranous and proliferative lupus nephritis
treated with Rituximab with positive results.83 A prospective study of 136
patients with lupus nephritis reported improvement in patients receiving
Rituximab and reporting a response in 91% of relapse patients after re-
treatment with Rituximab, an acceptable safety profile.84 This contrasted with
two randomized control trials evaluating Rituximab's potential benefit that
does not show benefit compared to placebo.85 A 2019 meta-analysis evaluated 24
studies with a total of 940 patients with lupus nephritis investigating the
benefit of Rituximab in patients with lupus nephritis. This meta-analysis did
not include a systematic review or assessment of the risk of bias, so
interpretation is limited. The authors reported that complete and total
remission rates were higher in patients who received Rituximab in the case
series trials. In the randomized control trials, they reported that the
complete response was higher in the rituximab group. However, there was no
statistically significant difference between the two groups (OR =1.98, 95% CI:
0.90-4.39, _P_ =0.05). The authors report promising results for Rituximab
treatment in this population and call for further studies. Long term efficacy
and toxicity of rituximab have not been fully defined.81



_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.86

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.87

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.87 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.88

_Membranous Nephropathy (IMN)_

Nephropathy membranous nephropathy is a form of nephrotic syndrome in diabetic
adults. The histological changes include golem annular basement membrane
thickening with little or no cellular proliferation or infiltration. 75 to 80%
of cases are caused by circulating autoantibodies against podocyte antigens,
while the remaining 20 to 25% are associated with various disorders.89  Their
risk classifies patients for progressive disease due to MN as high risk being
two or more of the following:89

  * Serum creatinine 1.5 mg/dL [133 micromol/L] 
  * Progressive decline in kidney function (e.g., decrease in estimated glomerular filtration rate [eGFR] 25 percent from baseline over the prior two years) 
  * Severe, disabling, or life-threatening nephrotic syndrome (defined by the presence of a serum albumin <2.5 g/dL [if measured by bromocresol green methods] or <2.0 g/dL [if measured by bromocresol purple methods] and refractory edema, or a thromboembolic event)

Immunotherapy is recommended for high risk patients or patients who have shown
signs of rapid disease progression. Glucocorticoids are not effective in high
risk patients. In the membranous nephropathy trial of Rituximab (MENTOR), 130
patients with proton area  5g/day and 24- creatinine clearance 40
mL/min/1.73 m2 were randomized to receive two infusions of 1 gram administered
14 days apart of Rituximab or six months of oral cyclosporin. They found
Rituximab was more effective than cyclosporin in maintaining complete or
partial remission of proteinuria at 24 months. At 12 months, rates of complete
or partial remission were similar between the groups, but at 24 months,
Rituximab had a higher rate of complete or partial remission as compared to
the cyclosporin group. Creatinine clearance was higher, anti-PLA2 antibody
levels or decreased, and serious adverse events were lower in the Rituximab
group as compared to cyclosporin. They concluded Rituximab was more effective
at preventing further loss of kidney function and end stage renal disease than
cyclosporin with supportive therapy. They did find patients with high anti
-PLA2R antibody titers at baseline may be less responsive to Rituximab.90 This
contrasts with the idiopathic membranous nephropathy trial (GEMRITUX), where
75 patients were assigned Rituximab or no Rituximab and did not show
improvements in proteinuria at six months.91 However, this may be attributed
to the short duration of follow-up as the improvement was not seen until
greater than 12 months. UpToDate recommends patients classified as high risk
or very high risk with stable kidney function being treated with Rituximab
rather than cytotoxic therapy with a grade 2C recommendation.92 Rituximab has
been shown to have potential in relapsing and remitting disease where using an
immunosuppressive agent that they have not seen previously is recommended
Based on observation and retrospective studies.

_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 ARM.

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.93 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_ ).94

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.95
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.96 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.97,98

AMR is rare in lung transplant patients. Case series of acute lung transplant
patients with AMR suggests a benefit of Rituximab in treatment.99

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.100

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.101 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.102 In another
series of 108 patients treated with the IVIG and Rituximab protocol, 74% of
the highly sensitive patients could undergo transplant after treatment.103



_Graft vs. Host Disease (chronic, steroid-refractory)_

Chronic graft-versus-host disease (GVHD) is a common complication of
allogeneic hematopoietic cell transplant (HCT). GVHD occurs when immune cells
transplanted from a non-identical donor (the graft) recognize the transplant
recipient (the host) as foreign, thereby initiating an immune reaction that
causes disease in the transplant recipient.104

GVHD has divided into acute and chronic variants based on the time of onset,
traditionally using 100 days as a cutoff. Signs of acute and chronic GVHD have
challenged the division between acute and chronic variants outside of the
selected periods. The National Institutes of Health (NIH) consensus criteria
for GVHD's diagnosis and standardized features of chronic GVHD and acute GVHD
appear together and are widely accepted.105 Reports of Rituximab's use in
patients with chronic refractory GVHD suggests the potential use of agents
directed at B cells. Rituximab is currently being evaluated for chronic GVHD
prophylaxis, in which Rituximab 375 mg/m2 is administered weekly for a total
of four weeks. If a partial response is reported, up to two more four-week
courses may be administered.

Five studies have suggested favorable response rates among patients with skin
or musculoskeletal involvement. In a phase II trial consisting of thirty-seven
patients with steroid-refractory chronic GVHD, clinical responses were seen in
thirty-two patients (86%)106, and responses were maintained at one year. This
resulted in corticosteroid dose reductions in twenty-one patients. Clinical
responses were positively produced in the skin, oral cavity, and
musculoskeletal system. In another study of twenty-one patients with steroid-
refractory chronic GVHD, positive responses were seen in 70% of
participants.107 Responses were seen in cutaneous and musculoskeletal cases
for one year of therapy. A retrospective analysis consisted of eighteen
patients with steroid-refractory chronic GVHD. Favorable clinical responses
were seen in eleven patients (55%). One patient achieved a complete response
while ten successfully reduced or discontinued corticosteroid therapy.108 A
phase II randomized study evaluated agents for sclerotic chronic GVHD.
Successful clinical improvements were seen in skin sclerosis or joint range of
motion in ten of thirty-seven (27%) of those treated with rituximab and nine
of thirty-five (36%) of patients randomized to imatinib.104,109 NCCN suggested
Rituximab as a systemic agent for chronic steroid-refractory GVHD.110

**__**

**_Non Coverage_**

_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).111,112

__

_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.113 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).114



_Sj ogren's syndrome (pSS) _

Rituximab has been evaluated for its use in pSS. The cohort studies and early
small RCTs show significant improvement compared to baseline. a 2014
randomized control trial randomized 122 pSS patients to receive Rituximab
(n=63) or placebo (n-57). They found no significant improvement.115 Another
randomized control trial of 133 pSS patients was randomized to rituximab
(n=67) or placebo (n=66) and also found no significant results in the primary
outcome.116 Two recent meta-analyses, including the four randomized controlled
trials, confirmed the lack of significance between group differences in mean
improvement between baseline and week 24 values for fatigue, oral dryness,
salivary flow rate, and Schirmer test.117,118 2019 European League Against
Rheumatism recommendations concluded low quality evidence using GRADE
methodology supporting the efficacy and safety Is low level evidence from
therapeutic studies and underscores the need for larger trials to determine
safety and efficacy. They report limited data from prospective studies
suggesting a lack of efficacy in systemic disease, especially in
cryoglobulinemic vasculitis.119

**__**



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, CGS 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, CGS 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,Rrituximab
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.