Coverage Policy Manual
Policy #: 2021034
Category: Pharmacy
Initiated: November 2021
Last Review: October 2022
  Rituximab (e.g., Rituxan) and Biosimilars – Non-Oncologic Indications

Description:
Rituximab, an anti-CD20 monoclonal antibody, was originally approved by the FDA in November 1997 for the treatment of relapsed or refractory low grade or follicular CD20+ B-cell non-Hodgkin’s lymphoma (NHL).  Since its introduction there have been expanded FDA approved indications, and a number of off-label conditions for which the drug has been investigated.  
 
Rituximab has shown impressive benefit for some conditions, and in addition the drug has been found to have some serious adverse effects for which the FDA has issued "Black Box Warnings."  Fatal infusion reactions may occur within 24 hours of rituximab infusion; approximately 80% of fatal reactions occurred with first infusion. Monitor individuals and discontinue rituximab infusion for severe reactions. Acute renal failure requiring dialysis with instances of fatal outcome can occur in the setting of Tumor Lysis Syndrome (TLS) following treatment of rituximab in individuals with non-Hodgkin's lymphoma (NHL). Severe and potentially fatal mucocutaneous reactions can occur in individuals receiving rituximab. JC virus infection resulting in Progressive Multifocal Leukoencephalopathy (PML) and death can also occur in individuals receiving rituximab.
 
Regulatory Status
Rituximab and Hyaluronidase (e.g., Rituxan Hycela), is a combination of rituximab and hyaluronidase human, an endoglycosidase.  The FDA approved the rituximab and hyaluronidase, subcutaneous injection, in June 2017.  It is for the treatment of adult individuals with FL, CLL and DLBCL.  
 
On 11/28/2018, the FDA approved Rituximab abbs (e.g., Truxima) for the treatment of adult individuals with:
        • Non-Hodgkin’s lymphoma (NHL)
        • Relapsed or refractory, low grade or follicular, CD20-positive B-cell NHL as a single agent.
        • Previously untreated follicular, CD20-positive, B-cell NHL in combination with first line chemotherapy and, in individuals achieving a complete or partial response to a rituximab product in combination with chemotherapy, as single-agent maintenance therapy.
        • Non-progressing (including stable disease), low-grade, CD20 positive, B-cell NHL as a single agent after first-line cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy.
 
On 5/23/19 the FDA approved biosimilar, Rituximab-abbs (e.g., Truxima), for the adult individuals with:
        • previously untreated diffuse Large B-cell, CD20-positive non-Hodgkin’s lymphoma (NHL) in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or other anthracycline-based chemotherapy regimens.
        • previously untreated and previously treated CD20-positive chronic lymphocytic leukemia (CLL) in combination with fludarabine and cyclophosphamide (FC).
 
On July 25, 2019, the Food and Drug Administration approved rituximab-pvvr (e.g., Ruxience), a biosimilar to Rituximab (e.g., Rituxan) for the treatment of adult individuals with non-Hodgkin’s lymphoma (NHL), chronic lymphocytic leukemia (CLL), and granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA).
 
On 12/18/2019 the FDA approved, biosimilar, Rituximab-abbs (e.g., Truxima) for the adult individuals with:
        • Rheumatoid arthritis (RA) in combination with methotrexate in adult patients with moderately-to severely active RA who have inadequate response to one or more TNF antagonist therapies.
        • Granulomatosis with polyangiitis (GPA) Wegener's granulomatosis) and microscopic polyangiitis (MPA) in adult individuals win combination with glucocorticoids.
 
On December 17, 2020, the Food and Drug Administration approved rituximab-arrx (e.g., Riabni), the third biosimilar version of Rituxan for NHL, CLL, GPA, and MPA.
 
On June 3, 2022, the Food and Drug Administration approve rituximab-arrx (e.g., Riabni) for Rheumatoid Arthritis (RA) in combination with methotrexate in adult individuals with moderately -to-severely active RA who have inadequate response to one or more TNF antagonist therapies.
 
Coding
Effective January 01, 2019, there is a specific HCPCS code for Rituximab 10 mg injection and a specific code for rituxan Hycela (rituximab/hyaluronidase):
 
J9311     Injection, rituximab 10 mg and hyaluronidase
J9312     Injection, rituximab, 10 mg   
J9310     Injection, rituximab, 100mg
Q5115    Injection, rituximab-abbs, biosimilar, (truxima), 10 mg
Q5119    Injection, rituximab-pvvr, biosimilar, (ruxience), 10mg
Q5123    Injection, rituximab-arrx, biosimilar, (riabni), 10mg

Policy/
Coverage:
For coverage prior to November 1, 2021, please refer to policy number 2006016.
 
After November 1, 2021, please refer policy number 2006016 for oncological Rituximab uses.
 
Effective April 01, 2022 Prior Approval is required for rituximab.
 
The Step Therapy Medication Act is applicable to fully-insured (Arkansas Blue Cross, Health Advantage, and Exchange) and specified governmental (ASE/PSE and ASP) health plans. The law is not applicable to FEP or self-insured ERISA groups (including but not limited to Walmart, Tyson or other Blue Advantage groups).   Initial approval for exigent request is 28 days. Otherwise, initial approval for standard review is up to 1 year.
 
Effective October 26, 2022
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
1. RITUXIMAB (e.g., Rituxan®)
The use of Rituximab meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the following indications:
 
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
 
FDA APPROVED INDICATIONS
        1. Rheumatoid Arthritis (RA), For those moderate to severely active, in combination with methotrexate for individuals who have had an inadequate response to one or more TNF antagonist therapies.
        2. Anti-Neutrophil Cytoplasmic Antibody (ANCA) Vasculitides (associated small vessel vasculitis), Granulomatosis with Polyangiitis (GPA) (Wegener’s Granulomatosis) and Microscopic Polyangiitis (MPA) in adult and pediatric individuals 2 years of age and older when initial treatment with azathioprine, methotrexate, and/or mycophenolate has been tried and failed or individual is intolerant.
        3. Pemphigus Vulgaris (PV) and Pemphigus Foliaceus, unresponsive to conventional therapy (e.g., systemic corticosteroids and immunosuppressive agents) or in those individuals in whom these drugs would not be tolerated.
 
CONTINUATION OF THERAPY for 12 months:
        1. Individual meets criteria for initial approval based on indication.
        2. Individual has experienced a positive clinical response to rituximab.
        3. Must be dosed in accordance with the FDA label unless otherwise specified.
 
Dosage and administration
 
Must be dosed in accordance with the FDA label unless otherwise specified.
 
RA
The dose for RA in combination with methotrexate is two-1,000mg IV infusions separated by 2 weeks, (one course) every 24 weeks, or based on clinical evaluation not sooner than every 16 weeks. Methylprednisolone 100 mg IV or equivalent glucocorticoid is recommended 30 min prior to each infusion.
 
ANCA Vasculitides: GPA and MPA
Induction dose for adult individuals with active GPA and MPA in combination with glucocorticoids is 375 mg/m2 once weekly for 4 weeks. Follow-up dose for those who have achieved control with induction treatment, in combination with glucocorticoids is 500 mg/m2 IV separated by 2 weeks followed by 500 mg/m2 infusion every 6 months thereafter based on clinical evaluation.
 
Induction dose for pediatric individuals in combination with glucocorticoids is 375 mg/m2 once weekly for 4 weeks. Follow-up dosing in combination with glucocorticoids is two 250 mg/m2 infusions separated by two weeks, followed by a 250 mg/m2 IV infusions every 6 months thereafter based on clinical evaluation.
 
PV
The dose for PV is two-1,000 mg IV infusion separated by 2 weeks in combination with a tapering course of glucocorticoids, then a 500 mg infusion at month 12 and every 6 months thereafter or based on clinical evaluation. Dose on relapse is a 1,000 mg infusion with considerations to resume or increase the glucocorticoid dose based on clinical evaluation. Subsequent infusion may be no sooner than 16 weeks after the previous infusion.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
2. RITUXIMAB-PVVR (e.g., Ruxience), RITUXIMAB-ARRX (e.g., Riabni), and Rituximab-abbs (e.g., Truxima)
Rituximab-pvvr and Rituximab-arrx meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the following indication:
 
FDA APPROVED INDICATIONS
        1. Anti-Neutrophil Cytoplasmic Antibody Vasculitis (ANCA) associated small vessel vasculitis, Granulomatosis with Polyangiitis (GPA) (Wegener’s Granulomatosis) and Microscopic Polyangiitis (MPA) in adult and pediatric individuals 2 years of age and older when initial treatment with azathioprine, methotrexate, and/or mycophenolate has been tried and failed or individual is intolerant.
        2. Rheumatoid Arthritis (RA) in combination with methotrexate in adult individuals with moderately-to severely active RA who have inadequate response to one or more TNF antagonist therapies.  
CONTINUATION OF THERAPY for 12 months:
        1. Individual meets criteria for initial approval based on indication.
        2. Individual has experienced a positive clinical response to rituximab.
        3. Must be dosed in accordance with FDA label unless otherwise specified.
 
Dosage and administration
 
Must be dosed in accordance with the FDA label unless otherwise specified.
 
ANCA Vasculitides: GPA and MPA
Induction dose for adult individuals with active GPA and MPA in combination with glucocorticoids is 375 mg/m2 once weekly for 4 weeks. Follow-up dose for those who have achieved control with induction treatment, in combination with glucocorticoids is 500 mg/m2 IV separated by 2 weeks followed by 500 mg/m2 infusion every 6 months thereafter based on clinical evaluation.
 
RA
The dose for RA in combination with methotrexate is two-1,000 mg intravenous infusions separated by 2 weeks (one course) every 24 weeks or based on clinical evaluation, but not sooner than every 16 weeks. Methylprednisolone 100 mg intravenous or equivalent.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
OFF-LABEL INDICATIONS for Rituximab (e.g., Rituxan) and Biosimilars, (e.g., Ruxience; Truxima and Riabini)
The use of Rituximab and biosimilars meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for off-label use for treatment of the following conditions:
 
    1. Acquired inhibitors in Hemophilia – (Refractory or intolerant of cyclophosphamides and steroid therapy) [Collins 2009, Rossi 2016]
    2. ANCA associated small vessel vasculitis: Churg-Strauss syndrome
    3. Autoimmune Hemolytic Anemia (AIHA) in individuals that have failed to respond to corticosteroid therapy [Shanafelt 2003, Birgens 2013, Michel 2017]
    4. Autoimmune encephalitis (AE) when the following criteria are met [Graus, 2016]
·    Autoimmune limbic encephalitis - ALL criteria are required:
            • Subacute onset (rapid progression of <3 months) of working memory deficits (short-term memory loss), seizures, or psychiatric symptoms suggesting involvement of the limbic system
            • Bilateral brain abnormalities on T2-weighted FLAIR MRI highly restricted to the medial temporal lobes
            • At least one of the following:
· CSF pleocytosis (>5 white blood cells per mm3)
· EEG with epileptic or slow-wave activity involving the temporal lobes
·    Reasonable exclusion of alternative causes.
·    For continued therapy, diagnosis is confirmed by detection of a specific autoantibody associated with AE including but not limited to:
            • NMDAR, LGI1, Caspr2, AMPAR, GABA-A or GABA-B receptor, IgLON5, DPPX, GlyR, mGluR1, mGluR2, mGluR5, Neurexin 3-alpha, or dopamine-2 receptor (D2R)]; AND
            • individual has had an inadequate response to, is intolerant of, or has a contraindication to first line agent(s) including immunoglobulin therapy or plasma exchange
5. Anti-NMDA receptor encephalitis (Graus, 2016) – ALL criteria below must be met:
·   Rapid onset (<3 months) of at least four of the six following major groups of symptoms:
            • Abnormal (psychiatric) behavior or cognitive dysfunction
            • Speech dysfunction
            • Seizures
            • Movement disorder, dyskinesias, or rigidity/abnormal postures
            • Decreased level of consciousness
            • Autonomic dysfunction or central hypoventilation
·    At least one of the following laboratory results:
            • Abnormal EEG (focal or diffuse slow or disorganized activity, epileptic activity, or extreme delta brush), OR
            • CSF with pleocytosis or oligoclonal bands
·    Reasonable exclusion of other disorders
·    For continuation of therapy,
            • IgG anti-GluN1 antibodies [diagnosis of anti-NMDA receptor encephalitis is confirmed by the detection of IgG antibodies to the GluN1 (also known as NR1) subunit of the NMDA receptor in serum or CSF] in the presence of one or more of the six major groups of symptoms, after reasonable exclusion of other disorders, AND
            • individual has had an inadequate response to, is intolerant of, or has a contraindication to first line agent(s) including immunoglobulin therapy or plasma exchange
6. Catastrophic Antiphospholipid antibody Syndrome (CAPS) [Rao 2009]
7. Cryoglobulinemia associated with Sjogren’s or SLE [Ramos 2009]
8. Cryoglobulinemic vasculitis associated with Hepatitis C virus infection [Petrarca 2010, KDIGO 2018]
9. Ebstein-Barr Virus infection in individuals
10.  with X-linked Immunodeficiency [Milone 2005]
11. Graft vs. Host Disease, Chronic [Cutler 2006]10.
12. Grave’s Ophthalmopathy [El Fassi 2007, Salvi 2007]
13. Immunoglobulin G4 related disease – (Failure or intolerance to steroid therapy.) [Carruthers 2015]
14. ITP, in children with ITP who have significant ongoing bleeding and/or have a need for improved quality of life despite conventional treatment. Also, may be considered as an alternative to splenectomy in children with chronic ITP or as therapy in those who have failed splenectomy. [Oved 2017
15. ITP, in adults at risk of bleeding who have failed one line of therapy such as corticosteroids, IVIg, or splenectomy. [Ghanima 2015]
16. Lupus Erythematosus, Systemic, as second- or third-line therapy [Merrill 2010]
17. Evan’s Syndrome, pediatric and adult, who are unresponsive to, or unable to tolerate corticosteroids [Bader-Meunier 2007, Rucker 2008]
18. Myasthenia Gravis generalized and MuSK positive Myasthenia Gravis. [Narayanaswami 2020, Singh 2019]
19. Membranous Glomerulonephropathy for individuals refractory to, or cannot take alkylating agents or calcineurin inhibitors [Müller-Deile 2015, Anjum 2019]17
20. Membranous Nephropathy (primary MN) In individuals with primary MN, initial therapy is based on an assessment of the individual’s risk of progressive disease [DeVriese, 2017]:
          • In individuals with primary MN regardless of phospholipase A2 receptor (PLA2R) – 2 or more of the following are considered very high risk for progressive disease:
          • Serum creatinine 1.5 mg/dL [133 micromol/L] considered to be due to active MN
          • Progressive decline in kidney function (eg, decrease in estimated glomerular filtration rate [eGFR] 25 percent from baseline over the prior two years) considered to be due to active MN
          • 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) For those individuals with primary MN and normal kidney function and do not have severe or life -threatening nephrotic syndrome, will observe for 3- 6 months (Including renin-angiotensin system inhibition). After 3-6 months of observation
 
High risk – Individuals with 2 or more of the following for progressive disease:
          • Decrease in eGFR of 25 percent, not explained by other causes, at any time during the observation period
          • Proteinuria >8 g/day at the end of the observation period or persistent nephrotic syndrome (proteinuria >3.5 g/day and serum albumin <3.5 g/dL [if measured by bromocresol green methods] or <3.0 g/dL [if measured by bromocresol purple methods])
          • If the individual is anti-PLA2R antibody positive, serial anti-PLA2R antibody titers are high (arbitrarily defined as 150 RU/mL by the ELISA method) and not declining or are increasing to 150 RU/mL
Moderate risk – pts with 2 or more of the following for progressive disease:
          • Normal or stable eGFR (ie, <25 percent decrease) over the three-to-six-month period
          • Proteinuria <4 g/day at the end of the observation period
          • If the patient is anti-PLA2R antibody positive, serial anti-PLA2R antibody titers are low (arbitrarily defined as <50 RU/mL by the ELISA method) or decreasing by 25 percent at three to six months
21. Monoclonal Gammopathy of Unknown Significance with Polyneuropathy (with or without anti-MAG antibodies in individuals refractory to standard therapy [Chaudry 2017, Svahn, 2018]
22. Neuromyelitis Optica for individuals with disease refractory to immunosuppressive drugs and/or plasmapheresis [Nikoo, 2017]
23. Non-ANCA small vessel vasculitis: Henoch-Schönlein purpura and Cryoglobulinemic vasculitis
24. Multiple Sclerosis, Relapsing Remitting [Rae-Grant 2018] Pediatric Nephrotic Syndrome –(Refractory or intolerant to steroid therapy and immunosuppressants.) [KDIGO 2012]
25. Rheumatoid arthritis, as a single agent in individuals who have failed DMARDs, and antitumor necrosis alfa drugs, and who have been shown to be intolerant of methotrexate FDA Approval
26. Sjögren’s Syndrome [Dass 2008]
27. Systemic Sclerosis (SSc)
          • Systemic Sclerosis (SSc)-associated Interstitial Lung Disease (ILD) (Goswami, 2021)
          • Previous trial/failure of standard treatment (i.e., Mycophenolate Mofetil (MMF), cyclophosphamide, or tocilizumab therapy).
          • Baseline pulmonary functional parameters [FVC (% predicted)]
          • Systemic Sclerosis (SSc)-Pulmonary Arterial Hypertension (PAH) (Zamanian, 2021)
          • Screening 6-minute Walking Distance (6MWD) of at least 100 meters
28.  Thrombotic Thrombocytopenic Purpura, Acquired, due to ADAMTS13 deficiency - (refractory or relapsing to plasma exchange treatment and steroid therapy.) [Joly 2017]
29.  Transplant, Heart, Acute Graft Rejection due to Antibody Mediated Disease, in individuals refractory to plasmapheresis/IVIG [Bierl 2006]
30.  Transplant, Kidney, Desensitization of ABO Incompatible individuals on Renal Transplant Waiting List, when used in conjunction with IVIG [Echterdiek 2020, Wongsaroj 2015]
31.  Transplant, Kidney, Desensitization of Panel Reactive Antibodies on Renal Transplant Waiting List [Vo 2010] Transplant, Kidney, Acute Graft Rejection due to Antibody Mediated Disease, when used as second-line therapy [KIDGO 2009]
32.  Transplant, Lung, Acute Humoral Antibody Mediated Disease [Martinu 2010]
33.  Transplant, Heart, Desensitization of Panel Reactive Antibodies in individuals on Cardiac Transplant Waiting List [Colvin, 2019]
 
CONTINUATION OF THERAPY for 12 months:
        1. Individual meets criteria for initial approval based on indication.
        2. Individual has experienced a positive clinical response to rituximab.
        3. Must be dosed in accordance with FDA label unless otherwise specified.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of Rituximab and biosimilars do not meet member benefit Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes for any other indications including the following conditions:
 
    1. Atopic Eczema
    2. Autoimmune Neutropenia
    3. Autoimmune Retinopathy
    4. Chronic Fatigue Syndrome
    5. Chronic Inflammatory Demyelinating Polyneuropathy
    6. Cryoglobulinemia for any indication except the use described under covered conditions.
    7. Desensitization of HLA Incompatible individuals on liver transplant waiting list.
    8. Desensitization of HLA Incompatible individuals on renal transplant waiting list when used as a single agent.
    9. Ebstein-Barr Virus infection in any condition other than X-linked immunodeficiency
    10. Glomerulosclerosis, Focal Segmental
    11. Graft-Versus-Host Disease, Acute for treatment of active disease
    12. Graft-Versus-Host Disease, Acute, as a preventative agent
    13. Graft-Versus-Host Disease, Acute, for steroid-refractory disease
    14. Graft-Versus-Host Disease, Chronic, as initial, (first line) therapy
    15. Graft-Versus-Host Disease, Chronic, as preventative therapy
    16. Fibrillary Glomerulonephritis· Hemophilia A, treatment to eradicate or suppress autoimmune anti-factor VIII antibodies.
    17. IgA Nephropathy
    18. Multiple Myeloma, for Primary, Recurrent, Relapsed, or Refractory Disease in individuals with absence of CD20+ antigen plasma cells
    19. Multiple Sclerosis, Primary Progressive
    20. Polymyositis
    21. Pemphigus Vulgaris and Pemphigus Foliaceous, when administered concomitantly (or sequentially) with immune globulin.
    22. Primary Biliary Cirrhosis
    23. Red Cell Aplasia or Diamond Blackfan Anemia
    24. Rheumatoid arthritis, when administered concomitantly (or within the same month) with anti-tumor necrosis alpha drugs.
    25. Transplant, Heart, Desensitization of ABO Incompatible individuals on Transplant Waiting List
    26. Transplant, Kidney, Desensitization of HLA Panel Reactive Antibodies developing in kidney transplant recipients to prevent potential rejection.
    27. Transplant, Kidney, as Induction Given Prior to Transplant
    28. Transplant, Liver, Desensitization of ABO Incompatible individuals on Transplant Waiting List
    29. Transplant, Liver, Rejection
    30. Transplant, Lung, Acute Rejection due to Cellular Vascular Rejection
    31. Transplant, Lung, Desensitization of ABO Incompatible individuals on Transplant Waiting List
    32. Urticaria, Chronic
 
Requests for coverage of any of the conditions on the non-Covered list, or for any condition not listed in the policy will require submission of data on effectiveness which will be reviewed to determine if the proposed indication meets member certificate of benefit coverage criteria.
 
For off-label use for non-malignant conditions, rituximab does not meet member certificate of benefit primary coverage criteria if:
 
    1. The use is being studied in phase I, II, or III clinical trials or otherwise under study to determine effectiveness.
    2.  If there is lack of scientific evidence of effectiveness; or
    3.  The effectiveness of the particular use is in conflict or the subject of debate amongst experts.
 
For contracts without primary coverage criteria, any other use of rituximab that is not listed as a covered indication is investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective October 19, 2022 to October 25, 2022
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
1. RITUXIMAB (e.g., Rituxan®)
The use of Rituximab meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the following indications:
 
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
 
FDA APPROVED INDICATIONS
    1. Rheumatoid Arthritis (RA), For those moderate to severely active, in combination with methotrexate for individuals who have had an inadequate response to one or more TNF antagonist therapies.
    2. Granulomatosis with Polyangiitis (GPA) (Wegener’s Granulomatosis) and Microscopic Polyangiitis (MPA) (Anti-Neutrophil Cytoplasmic Antibody Vasculitis) in combination with Glucocorticoids in adult and pediatric individuals 2 years of age and older in combination with glucocorticoids.
    3. Pemphigus Vulgaris (PV) and Pemphigus Foliaceus, unresponsive to conventional therapy (e.g., systemic corticosteroids and immunosuppressive agents) or in those individuals in whom these drugs would not be tolerated.
 
CONTINUATION OF THERAPY for 12 months:
1. Individual meets criteria for initial approval based on indication.
2. Individual  has experienced a positive clinical response to rituximab.
3. Must be dosed in accordance with the FDA label unless otherwise specified.
 
Dosage and administration
 
Must be  dosed in accordance with the FDA label unless otherwise specified.
 
RA
The dose for RA in combination with methotrexate is two-1,000mg IV infusions separated by 2 weeks, (one course) every 24 weeks, or based on clinical evaluation not sooner than every 16 weeks. Methylprednisolone 100 mg IV or equivalent glucocorticoid is recommended 30 min prior to each infusion.
 
GPA and MPA
Induction dose for adult individuals with active GPA and MPA in combination with glucocorticoids is 375 mg/m2 once weekly for 4 weeks. Follow-up dose for those who have achieved control with induction treatment, in combination with glucocorticoids is 500 mg/m2 IV separated by 2 weeks followed by 500 mg/m2 infusion every 6 months thereafter based on clinical evaluation.
 
Induction dose for pediatric individuals in combination with glucocorticoids is 375 mg/m2 once weekly for 4 weeks. Follow-up dosing in combination with glucocorticoids is two 250 mg/m2 infusions separated by two weeks, followed by a 250 mg/m2 IV infusions every 6 months thereafter based on clinical evaluation.
 
PV
The dose for PV is two-1,000 mg IV infusion separated by 2 weeks in combination with a tapering course of glucocorticoids, then a 500 mg infusion at month 12 and every 6 months thereafter or based on clinical evaluation. Dose on relapse is a 1,000 mg infusion with considerations to resume or increase the glucocorticoid dose based on clinical evaluation. Subsequent infusion may be no sooner than 16 weeks after the previous infusion.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
2. RITUXIMAB-PVVR (e.g., Ruxience), RITUXIMAB-ARRX (e.g., Riabni), and Rituximab-abbs (e.g., Truxima)
Rituximab-pvvr, Rituximab-arrx, and Rituximab-abbs meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the following indication:
 
FDA APPROVED INDICATIONS
    1. Granulomatosis with Polyangiitis (GPA) (Wegener’s Granulomatosis) and Microsopic Polyangiitis (MPA) in adult Individuals  in combination with glucocorticoids.
    2. Rheumatoid Arthritis (RA) in combination with methotrexate in adult individiuals with moderately to severely active RA who have inadequate response to one or more TNF antagoinist therapies.
 
CONTINUATION OF THERAPY for 12 months:
1. Individual meets criteria for initial approval based on indication.
2. Individual has experienced a positive clinical response to rituximab.
3. Must be dosed in accordance with FDA label unless otherwise specified.
 
Dosage and administration
 
Must be dosed in accordance with the FDA label unless otherwise specified.
 
GPA and MPA
Induction dose for adult individuals with active GPA and MPA in combination with glucocorticoids is 375 mg/m2 once weekly for 4 weeks. Follow-up dose for those who have achieved control with induction treatment, in combination with glucocorticoids is 500 mg/m2 IV separated by 2 weeks followed by 500 mg/m2 infusion every 6 months thereafter based on clinical evaluation.
 
RA
The dose for RA in combination with methotrexate is two-1,000 mg intravenous infusions separated by 2 weeks (one course) every 24 weeeks or based on clinical evaluation, but not sooner than every 16 weeks. Methylprednisolone 100 mg intravenous or equivalent.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
OFF-LABEL INDICATIONS for Rituximab (e.g., Rituxan) and Biosimilars, (e.g., Ruxience; Truxima and Riabini)
The use of Rituximab and biosimilars meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for off-label use for treatment of the following conditions:
 
1. Acquired inhibitors in Hemophilia – (Refractory or intolerant of cyclophosphamides and steroid therapy) [Collins 2009, Rossi 2016]
2. Autoimmune Hemolytic Anemia (AIHA) in individuals that have failed to respond to corticosteroid therapy [Shanafelt 2003, Birgens 2013, Michel 2017]
3. Autoimmune encephalitis (AE) when the following criteria are met [Graus, 2016]
· Autoimmune limbic encephalitis - ALL criteria is required:
o Subacute onset (rapid progression of <3 months) of working memory deficits (short-term memory loss), seizures, or psychiatric symptoms suggesting involvement of the limbic system
o Bilateral brain abnormalities on T2-weighted FLAIR MRI highly restricted to the medial temporal lobes
o At least one of the following:
· CSF pleocytosis (>5 white blood cells per mm3)
· EEG with epileptic or slow-wave activity involving the temporal lobes
· Reasonable exclusion of alternative causes.
· For continued therapy, diagnosis is confirmed by detection of a specific autoantibody associated with AE [including but not limited to:
o NMDAR, LGI1, Caspr2, AMPAR, GABA-A or GABA-B receptor, IgLON5, DPPX, GlyR, mGluR1, mGluR2, mGluR5, Neurexin 3-alpha, or dopamine-2 receptor (D2R)]; AND
o individual has had an inadequate response to, is intolerant of, or has a contraindication to first line agent(s) including immunoglobulin therapy or plasma exchange
4. Anti-NMDA receptor encephalitis (Graus, 2016) – ALL criteria below must be met:
· Rapid onset (<3 months) of at least four of the six following major groups of symptoms:
o Abnormal (psychiatric) behavior or cognitive dysfunction
o Speech dysfunction
o Seizures
o Movement disorder, dyskinesias, or rigidity/abnormal postures
o Decreased level of consciousness
o Autonomic dysfunction or central hypoventilation
· At least one of the following laboratory results:
o Abnormal EEG (focal or diffuse slow or disorganized activity, epileptic activity, or extreme delta brush), OR
o CSF with pleocytosis or oligoclonal bands
· Reasonable exclusion of other disorders
· For continuation of therapy,
o IgG anti-GluN1 antibodies [diagnosis of anti-NMDA receptor encephalitis is confirmed by the detection of IgG antibodies to the GluN1 (also known as NR1) subunit of the NMDA receptor in serum or CSF] in the presence of one or more of the six major groups of symptoms, after reasonable exclusion of other disorders, AND
o individual has had an inadequate response to, is intolerant of, or has a contraindication to first line agent(s) including immunoglobulin therapy or plasma exchange
5. Catastrophic Antiphospholipid antibody Syndrome (CAPS) [Rao 2009]
6. Cryoglobulinemia associated with Sjogren’s or SLE [Ramos 2009]
7. Cryoglobulinemic vasculitis associated with Hepatitis C virus infection [Petrarca 2010, KDIGO 2018]
8. Ebstein-Barr Virus infection in individuals with X-linked Immunodeficiency [Milone 2005]
9. Graft vs. Host Disease, Chronic [Cutler 2006]10.
10. Grave’s Ophthalmopathy [El Fassi 2007, Salvi 2007]
11. Immunoglobulin G4 related disease – (Failure or intolerance to steroid therapy.) [Carruthers 2015]
12. ITP, in children with ITP who have significant ongoing bleeding and/or have a need for improved quality of life despite conventional treatment. Also, may be considered as an alternative to splenectomy in children with chronic ITP or as therapy in those who have failed splenectomy. [Oved 2017
13. ITP, in adults at risk of bleeding who have failed one line of therapy such as corticosteroids, IVIg, or splenectomy. [Ghanima 2015]
14. Lupus Erythematosus, Systemic, as second- or third-line therapy [Merrill 2010]
15. Evan’s Syndrome, pediatric and adult, who are unresponsive to, or unable to tolerate corticosteroids [Bader-Meunier 2007, Rucker 2008]
16. Myasthenia Gravis generalized and MuSK positive Myasthenia Gravis. [Narayanaswami 2020, Singh 2019]
17. Membranous Glomerulonephropathy for patients refractory to, or cannot take alkylating agents or calcineurin inhibitors [Müller-Deile 2015, Anjum 2019]17
18. Membranous Nephropathy (primary MN) In individuals  with primary MN, initial therapy is based on an assessment of the individual's risk of progressive disease [DeVriese, 2017]:
· In individuals  with primary MN regardless of phospholipase A2 receptor (PLA2R) – 2 or more of the following are considered very high risk for progressive disease:
o Serum creatinine 1.5 mg/dL [133 micromol/L] considered to be due to active MN
o Progressive decline in kidney function (eg, decrease in estimated glomerular filtration rate [eGFR] 25 percent from baseline over the prior two years) considered to be due to active MN
o 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) For those individuals with primary MN and normal kidney function and do not have severe or life -threatening nephrotic syndrome, will observe for 3- 6 months (Including renin-angiotensin system inhibition). After 3-6 months of observation
 
High risk – Individuals  with 2 or more of the following for progressive disease:
· Decrease in eGFR of 25 percent, not explained by other causes, at any time during the observation period
· Proteinuria >8 g/day at the end of the observation period or persistent nephrotic syndrome (proteinuria >3.5 g/day and serum albumin <3.5 g/dL [if measured by bromocresol green methods] or <3.0 g/dL [if measured by bromocresol purple methods])
· If the individual is anti-PLA2R antibody positive, serial anti-PLA2R antibody titers are high (arbitrarily defined as 150 RU/mL by the ELISA method) and not declining or are increasing to 150 RU/mL
Moderate risk – pts with 2 or more of the following for progressive disease:
· Normal or stable eGFR (ie, <25 percent decrease) over the three-to-six-month period
· Proteinuria <4 g/day at the end of the observation period
· If the patient is anti-PLA2R antibody positive, serial anti-PLA2R antibody titers are low (arbitrarily defined as <50 RU/mL by the ELISA method) or decreasing by 25 percent at three to six months
19. Monoclonal Gammopathy of Unknown Significance with Polyneuropathy (with or without anti-MAG antibodies in individuals refractory to standard therapy [Chaudry 2017, Svahn, 2018]
20. Neuromyelitis Optica for individuals with disease refractory to immunosuppressive drugs and/or plasmapheresis [Nikoo]  
21. Multiple Sclerosis, Relapsing Remitting [Rae-Grant 2018]
22. Pediatric Nephrotic Syndrome –(Refractory or intolerant to steroid therapy and immunosuppressants.) [KDIGO 2012]
23. Rheumatoid arthritis, as a single agent in individuals who have failed DMARDs, and antitumor necrosis alfa drugs, and who have been shown to be intolerant of methotrexate FDA Approval
24. Sjögren’s Syndrome [Dass 2008]
25. Systemic Sclerosis (SSc)
      • Systemic Sclerosis (SSc)-associated Interstitial Lung Disease (ILD) (Goswami, 2021)
          • Previous trial/failure of standard treatment (i.e., Mycophenolate Mofetil (MMF), cyclophosphamide, or tocilizumab therapy).
          • Baseline pulmonary functional parameters [FVC (% predicted)]
      • Systemic Sclerosis (SSc)-Pulmonary Arterial Hypertension (PAH) (Zamanian, 2021)
        • Screening 6-minute Walking Distance (6MWD) of at least 100 meters
26. Thrombotic Thrombocytopenic Purpura, Acquired, due to ADAMTS13 deficiency - (refractory or relapsing to plasma exchange treatment and steroid therapy.) [Joly 2017]
27. Transplant, Heart, Acute Graft Rejection due to Antibody Mediated Disease, in individuals refractory to plasmapheresis/IVIG [Bierl 2006]
28. Transplant, Kidney, Desensitization of ABO Incompatible Patients on Renal Transplant Waiting List, when used in conjunction with IVIG [Echterdiek 2020, Wongsaroj 2015]
29. Transplant, Kidney, Desensitization of Panel Reactive Antibodies on Renal Transplant Waiting List [Vo 2010]Transplant, Kidney, Acute Graft Rejection due to Antibody Mediated Disease, when used as second-line therapy [KIDGO 2009]
30. Transplant, Lung, Acute Humoral Antibody Mediated Disease [Martinu 2010]
31. Transplant, Heart, Desensitization of Panel Reactive Antibodies in Patients on Cardiac Transplant Waiting List [Colvin, 2019]
 
CONTINUATION OF THERAPY for 12 months:
1. Individual meets criteria for initial approval based on indication.
2. Individual has experienced a positive clinical response to rituximab.
3. Must be dosed in accordance with FDA label unless otherwise specified.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of Rituximab and biosimilars do not meet member benefit Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes for any other indications including the following conditions:
 
1. Atopic Eczema
2. Autoimmune Neutropenia
3. Autoimmune Retinopathy
4. Chronic Fatigue Syndrome
5. Chronic Inflammatory Demyelinating Polyneuropathy
6. Cryoglobulinemia for any indication except the use described under covered conditions.
7. Desensitization of HLA Incompatible individuals on liver transplant waiting list.
8. Desensitization of HLA Incompatible individuals on renal transplant waiting list when used as a single agent.
9. Ebstein-Barr Virus infection in any condition other than X-linked immunodeficiency
10. Glomerulosclerosis, Focal Segmental
11. Graft-Versus-Host Disease, Acute for treatment of active disease
12. Graft-Versus-Host Disease, Acute, as a preventative agent
13. Graft-Versus-Host Disease, Acute, for steroid-refractory disease
14. Graft-Versus-Host Disease, Chronic, as initial, (first line) therapy
15. Graft-Versus-Host Disease, Chronic, as preventative therapy
16. Fibrillary Glomerulonephritis· Hemophilia A, treatment to eradicate or suppress autoimmune anti-factor VIII antibodies.
17. IgA Nephropathy
18. Multiple Myeloma, for Primary, Recurrent, Relapsed, or Refractory Disease in individuals with absence of CD20+ antigen plasma cells
19. Multiple Sclerosis, Primary Progressive
20. Polymyositis
21. Pemphigus Vulgaris and Pemphigus Foliaceous, when administered concomitantly (or sequentially) with immune globulin.
22. Primary Biliary Cirrhosis
23. Red Cell Aplasia or Diamond Blackfan Anemia
24. Rheumatoid arthritis, when administered concomitantly (or within the same month) with anti-tumor necrosis alpha drugs.
25. Transplant, Heart, Desensitization of ABO Incompatible individuals on Transplant Waiting List
26. Transplant, Kidney, Desensitization of HLA Panel Reactive Antibodies developing in kidney transplant recipients to prevent potential rejection.
27. Transplant, Kidney, as Induction Given Prior to Transplant
28. Transplant, Liver, Desensitization of ABO Incompatible individuals on Transplant Waiting List
29. Transplant, Liver, Rejection
30. Transplant, Lung, Acute Rejection due to Cellular Vascular Rejection
31. Transplant, Lung, Desensitization of ABO Incompatible individuals on Transplant Waiting List
32. Urticaria, Chronic
 
Requests for coverage of any of the conditions on the non-Covered list, or for any condition not listed in the policy will require submission of data on effectiveness which will be reviewed to determine if the proposed indication meets member certificate of benefit coverage criteria.
 
For off-label use for non-malignant conditions, rituximab does not meet member certificate of benefit primary coverage criteria if:
 
      1.  The use is being studied in phase I, II, or III clinical trials or otherwise under study to determine effectiveness.
      2.  If there is lack of scientific evidence of effectiveness; or
      3.  The effectiveness of the particular use is in conflict or the subject of debate amongst experts.
 
For contracts without primary coverage criteria, any other use of rituximab that is not listed as a covered indication is investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage
 
Due to the detail of the policy statement, the document containing the coverage statements for dates prior to October 19, 2022 are not online. If you would like a hardcopy print, please email: codespecificinquiry@arkbluecross.com .
 
For coverage prior to November 1, 2021, please refer to policy number 2006016.

Rationale:
Due to the detail of the rationale, it is not online. If you would like a hardcopy print, please email : codespecificinquiry@arkbluecross.com
 
Update August 2019
Granulomatosis with polyangiitis (formerly called Wegener’s granulomatosis), microscopic polyangiitis, and renal-limited antineutrophil cytoplasm antibody (ANCA)–associated vasculitides are the main ANCA-associated vasculitis variants.  The combination of cyclophosphamide and glucocorticoids leads to remission in most patients with antineutrophil cytoplasm antibody (ANCA)-associated vasculitides. However, even when patients receive maintenance treatment with azathioprine or methotrexate, the relapse rate remains high. Rituximab may help to maintain remission.
 
In this study, patients with newly diagnosed or relapsing granulomatosis with polyangiitis, microscopic polyangiitis, or renal-limited ANCA-associated vasculitis in complete remission after a cyclophosphamide-glucocorticoid regimen were randomly assigned to receive either 500 mg of rituximab on days 0 and 14 and at months 6, 12, and 18 after study entry or daily azathioprine until month 22. The primary end point at month 28 was the rate of major relapse (the reappearance of disease activity or worsening, with a Birmingham Vasculitis Activity Score>0, and involvement of one or more major organs, disease-related life-threatening events, or both).
 
115 enrolled patients (87 with granulomatosis with polyangiitis, 23 with microscopic polyangiitis, and 5 with renal-limited ANCA-associated vasculitis) received azathioprine (58 patients) or rituximab (57 patients). At month 28, major relapse had occurred in 17 patients in the azathioprine group (29%) and in 3 patients in the rituximab group (5%) (hazard ratio for relapse, 6.61; 95% confidence interval, 1.56 to 27.96; P=0.002). The frequencies of severe adverse events were similar in the two groups. Twenty-five patients in each group (P=0.92) had severe adverse events; there were 44 events in the azathioprine group and 45 in the rituximab group. Eight patients in the azathioprine group and 11 in the rituximab group had severe infections, and cancer developed in 2 patients in the azathioprine group and 1 in the rituximab group. Two patients in the azathioprine group died (1 from sepsis and 1 from pancreatic cancer) (Guillevin L, et al 2014).
In conclusion, the between-group differences in relapse rate observed at month 28 in this trial showed that 500-mg rituximab infusions administered every 6 months were superior to azathioprine as maintenance therapy for ANCA-associated vasculitides, at least for patients positive for anti–proteinase 3 ANCA. Rituximab use for maintenance in those patients was found to have a clear clinical benefit in our study. Further studies are warranted for patients with antimyeloperoxidase ANCA–positive vasculitis. (Funded by the French Ministry of Health; MAINRITSAN ClinicalTrials.gov number, NCT00748644; EudraCT number, 2008-002846-51.).
 
Granulomatosis with polyangiitis (GPA) is a systemic necrotizing vasculitis, typically engaging the upper airways, kidneys and lungs and often associated with circulating anti-neutrophil cytoplasmic antibodies (ANCA) directed against proteinase 3 (PR3). The well-established standard treatment for remission induction in GPA has been cyclophosphamide (CY), in combination with corticosteroids (CS) [Hoffman GS, et al. 1992 and Mukhtyar C, et al. 2009]. This treatment regimen, introduced in the 1970s, has dramatically improved the outcome for GPA patients but with a risk of considerable side effects, including infections, sterility and bladder cancer [Knight A, et al. 2004]. Maintenance treatment is usually given with methotrexate (MTX), azathioprine (AZA) or mycophenolate mofetil (MMF), but as at least 50 % of patients have one or several relapses, repeated induction treatment is often necessary with the risk of high cumulative doses of CY [Jayne D et al 2003 and Pagnoux C, et al. 2008].
 
Recently, rituximab (RTX) has been approved by the FDA and the European Medicines Agency (EMA) for induction treatment of GPA and microscopic polyangiitis (MPA) in combination with CS, using the lymphoma protocol of 375 mg/m2 once weekly for 4 weeks. However, the efficacy and safety of repeated RTX courses as maintenance treatment has not yet been established.
 
The study includes 12 patients (seven females, five males) with relapsing GPA treated with repeated cycles of RTX from January 2003 through February 2013. Of the 12 included patients, all with a positive proteinase 3–anti-neutrophil cytoplasmic antibodies, generalised disease and a median disease duration of 35 months (21–270), 92% (11/12) achieved sustainable remission during a median follow-up time of 32 months (range 21–111) from first RTX treatment. Concomitant immunosuppressants were reduced. Infections were the most common adverse events, but infections were an issue also before the start of RTX. RTX administered every 6 months seems to be an effective maintenance treatment in a population with severe, relapsing long-standing GPA. Granulomatous as well as vasculitic manifestations responded equally well. Infections are a problem in this patient group but no new safety problems were identified [Knight A, et al. 2014].
 
Update October 2019
 The study design consisted of an initial 6-month remission induction phase, and a minimum 12month follow-up phase up to a maximum of 54 months (4.5 years) in pediatric patients 2 years to 17 years of age with GPA and MPA. Patients were to receive a minimum of 3 doses of intravenous methylprednisolone (30 mg/kg/day, not exceeding 1g/day) prior to the first RITUXAN or non-U.S.licensed rituximab intravenous infusion. The remission induction regimen consisted of four once weekly intravenous infusions of RITUXAN or non-U.S.-licensed rituximab at a dose of 375 mg/m2 BSA, on study days 1, 8, 15 and 22 in combination with oral prednisolone or prednisone at 1 mg/kg/day (max 60 mg/day) tapered to 0.2 mg/kg/day minimum (max 10 mg/day) by Month 6. After the remission induction phase, patients could receive subsequent RITUXAN or non-U.S.licensed rituximab intravenous infusions on or after Month 6 to maintain remission and control disease activity. The primary objectives of this study were to evaluate safety and PK parameters in pediatric GPA and MPA patients (2 years to 17 years of age). The efficacy objectives of the study were exploratory and principally assessed using the Pediatric Vasculitis Activity Score (PVAS).
A total of 25 pediatric patients 6 years to 17 years of age with active GPA and MPA were treated with RITUXAN or non-U.S.-licensed rituximab in a multicenter, open-label, single-arm, uncontrolled study (NCT01750697). The median age of patients in the study was 14 years and the majority of patients (20/25 [80%]) were female.
 
All 25 patients completed all four once weekly intravenous infusions for the 6-month remission induction phase. A total of 24 out of 25 patients completed at least 18 months from Day 1 (baseline). After the 6-month remission induction phase, patients who had not achieved remission or who had progressive disease or flare that could not be controlled by glucocorticoids alone received additional treatment for GPA and MPA, that could include RITUXAN or non-U.S.-licensed rituximab and/or other therapies, at the discretion of the investigator. Planned follow-up was until Month 18 (from Day 1).
Fourteen out of 25 patients (56%) received additional RITUXAN or non-U.S.-licensed rituximab treatment at or post Month 6, up to Month 18. Five of these patients received four once weekly doses of intravenous RITUXAN or non-U.S.-licensed rituximab approximately every 6 months; 5 of these patients received a single dose of RITUXAN or non-U.S.licensed rituximab every 6 months, and 4 of these patients received various other RITUXAN or non-U.S.-licensed rituximab doses/regimens according to investigator. Of the 14 patients who received follow-up treatment between Month 6 and Month 18, 4 patients first achieved remission between Months 6 and 12 and 1 patient first achieved remission between Months 12 and 18. Nine of these 14 patients achieved PVAS remission by Month 6 but required additional follow-up treatment after Month 6.
 
December 2019 Update
A study was conducted to retrospectively evaluate the efficacy and safety of rituximab (Rtx) treatment in patients with anti-synthetase syndrome (ASS) and severe interstitial lung disease (ILD).
Patients with severe ILD and>12 months follow-up post-Rtx were identified from the Oslo University Hospital ASS cohort (n = 112). Clinical data, including pulmonary function tests (PFTs), were retrospectively collected from medical reports. Extent of ILD pre-, and post-Rtx was scored on thin-section high-resolution CT (HRCT) images and expressed as a percentage of total lung volume. Muscle strength was evaluated by manual muscle testing of eight muscle groups (MMT8).
 
Altogether, 34/112 ASS patients had received Rtx; 24/34 had severe ILD and>12 months follow-up post-Rtx (median 52 months). In these 24 patients, the median percentage of predicted forced vital capacity, forced expiratory volume in 1 s (FEV1) and diffusing capacity of the lungs for carbon monoxide (DLCO) increased by 24%, 22% and 17%, respectively, post-Rtx. Seven patients (allwith disease duration<12 months and/or acute onset/exacerbation of ILD) had>30% improvement in all three PFTs. HRCT analysis showed a median 34% reduction in ILD extent post-Rtx. MMT8 score increased post-Rtx. During follow-up, 7/34 (21%) Rtx-treated ASS patients died; 6/7 deaths were related to infections. The mortality rate in the Rtx-treated group was comparable to that of the remaining ASS cohort (25/78 deceased; 32%).
 
In conclusion, this study, which included 24 Rtx-treated ASS patients with severe ILD, reports improved PFTs after a median 52 months follow-up post-Rtx. The best outcome was observed in patients with a disease duration<12 months and/or acute onset/exacerbation of ILD. The study indicates that Rtx could be a treatment option for selected ASS patients, but infections should be given attention.
 
A study was conducted to assess the efficacy of rituximab (RTX) in SSc.
Fourteen patients with SSc were evaluated. Eight patients were randomized to receive two cycles of RTX at baseline and 24 weeks [each cycle consisted of four weekly RTX infusions (375 mg/m(2))]in addition to standard treatment, whereas six patients (control group) received standard treatment alone. Lung involvement was assessed by pulmonary function tests (PFTs) and chest high-resolution CT (HRCT). Skin involvement was assessed both clinically and histologically.
 
There was a significant increase of forced vital capacity (FVC) in the RTX group compared with baseline (mean +/- s.d.: 68.13 +/- 19.69 vs 75.63 +/- 19.73, at baseline vs 1-year, respectively, P = 0.0018). The median percentage of improvement of FVC in the RTX group was 10.25%, whereas that of deterioration in the controls was 5.04% (P = 0.002). Similarly, diffusing capacity of carbon monoxide (DL(CO)) increased significantly in the RTX group compared with baseline (mean +/- s.d.: 52.25 +/- 20.71 vs 62 +/- 23.21, at baseline vs 1-year respectively, P = 0.017). The median percentage of improvement of DL(CO) in the RTX group was 19.46%, whereas that of deterioration in the control group was 7.5% (P = 0.023). Skin thickening, assessed with the Modified Rodnan Skin Score (MRSS), improved significantly in the RTX group compared with the baseline score (mean +/- s.d.: 13.5 +/- 6.84 vs 8.37 +/- 6.45 at baseline vs 1-year, respectively, P<0.001).
 
In conclusion, results indicate that RTX may improve lung function in patients with SSc. To confirm the results, a proposal of a larger scale, multi-center study with longer evaluation periods is needed. Patients’ with refractory interstitial lung disease, which had previously failed to respond to prednisone and/or other cytotoxic drugs, experiences using rituximab as therapy for refractory antisynthetase syndrome (ASS)-associated interstitial lung disease were assessed retrospectively.
 
All patients (7) received rituximab therapy. Data on pulmonary symptoms, pulmonary function tests and high resolution computed tomography (HRCT) scan of the lungs were collected: (1) before rituximab initiation; and (2) at 6-month and one-year follow-up after the first infusion of rituximab.
 
At one-year follow-up, ASS patients had resolution or improvement of pulmonary clinical manifestations. Patients also exhibited significant improvement of interstitial lung disease parameters: 1) on pulmonary function tests: FVC (p = 0.03) and DLCO (p = 2×10(-5)); 2) and HRCT-scan of the lungs. Due to clinical resolution/improvement of interstitial lung disease, the median daily dose of oral prednisone could be reduced in these 7 ASS patients at one-year follow-up, compared with baseline.
 
These findings suggest that rituximab may be a helpful therapy for refractory interstitial lung disease in patients with ASS.
 
Patients’ with refractory interstitial lung disease, which had previously failed to respond to prednisone and/or other cytotoxic drugs, experiences using rituximab as therapy for refractory antisynthetase syndrome (ASS)-associated interstitial lung disease were assessed retrospectively.
All patients (7) received rituximab therapy. Data on pulmonary symptoms, pulmonary function tests and high resolution computed tomography (HRCT) scan of the lungs were collected: (1) before rituximab initiation; and (2) at 6-month and one-year follow-up after the first infusion of rituximab.
At one-year follow-up, ASS patients had resolution or improvement of pulmonary clinical manifestations. Patients also exhibited significant improvement of interstitial lung disease parameters: 1) on pulmonary function tests: FVC (p = 0.03) and DLCO (p = 2×10(-5)); 2) and HRCT-scan of the lungs. Due to clinical resolution/improvement of interstitial lung disease, the median daily dose of oral prednisone could be reduced in these 7 ASS patients at one-year follow-up, compared with baseline.
 
These findings suggest that rituximab may be a helpful therapy for refractory interstitial lung disease in patients with ASS.
  
March 2021 Update
B-cell anomalies play a role in the pathogenesis of membranous nephropathy. B-cell depletion with rituximab may therefore be noninferior to treatment with cyclosporine for inducing and maintaining a complete or partial remission of proteinuria in patients with this condition.
 
Patients were randomly assigned who had membranous nephropathy, proteinuria of at least 5 g per 24 hours, and a quantified creatinine clearance of at least 40 ml per minute per 1.73 m2 of body-surface area and had been receiving angiotensin-system blockade for at least 3 months to receive intravenous rituximab (two infusions, 1000 mg each, administered 14 days apart; repeated at 6 months in case of partial response) or oral cyclosporine (starting at a dose of 3.5 mg per kilogram of body weight per day for 12 months). Patients were followed for 24 months. The primary outcome was a composite of complete or partial remission of proteinuria at 24 months. Laboratory variables and safety were also assessed.
 
A total of 130 patients underwent randomization. At 12 months, 39 of 65 patients (60%) in the rituximab group and 34 of 65 (52%) in the cyclosporine group had a complete or partial remission (risk difference, 8 percentage points; 95% confidence interval [CI], -9 to 25; P = 0.004 for noninferiority). At 24 months, 39 patients (60%) in the rituximab group and 13 (20%) in the cyclosporine group had a complete or partial remission (risk difference, 40 percentage points; 95% CI, 25 to 55; P<0.001 for both noninferiority and superiority). Among patients in remission who tested positive for anti-phospholipase A2 receptor (PLA2R) antibodies, the decline in autoantibodies to anti-PLA2R was faster and of greater magnitude and duration in the rituximab group than in the cyclosporine group. Serious adverse events occurred in 11 patients (17%) in the rituximab group and in 20 (31%) in the cyclosporine group (P = 0.06).
 
Rituximab was noninferior to cyclosporine in inducing complete or partial remission of proteinuria at 12 months and was superior in maintaining proteinuria remission up to 24 months. (Fervenza FC, Appel GB, Barbour SJ, et.al., 2019)
 
July 2022 Update
Tanaka Y, Takeuchi T, Miyasaka N, et.al. (2015) evaluated the efficacy and safety of rituximab in Japanese patients with systemic lupus erythematosus (SLE) and lupus nephritis (LN) who are refractory to conventional immunosuppressive therapy.
 
Eligible patients received rituximab at a dose of 1,000 mg at days 1, 15, 169, and 183, and were followed for 53 weeks after the first dose of rituximab. Overall disease activity was assessed monthly using a British Isles Lupus Assessment Group activity index. Patients with LN (Upr/Ucr ≥ 1.0 at study entry) were identified and their renal responses were evaluated according to the criteria proposed by the American College of Rheumatology (ACR) and the Lupus Nephritis Assessment with Rituximab (LUNAR) study.
 
A total of 34 patients were enrolled and received at least one dose of rituximab. Decrease in disease activity was achieved in 16 (76.5%) out of 34 patients. In 17 patients with LN, response rates of 58.8% and 52.9% by ACR and LUNAR criteria, respectively, were seen. Successful steroid tapering was achieved in association with disease remission. Rituximab was well tolerated, and most adverse drug reactions were grade 1–2 in severity.
 
Rituximab is effective for treatment of Japanese patients with SLE and LN refractory to conventional therapy.
 
Iaccarino L, Bartoloni E, Carli L., et.al. (2015), evaluated the efficacy and safety of rituximab (RTX) in patients with systemic lupus erythematosus (SLE) refractory to standard therapy in the clinical practice setting.
 
145 SLE patients (ACR criteria) were treated with RTX in 11 Italian Centres: 118 with two infusions (1 g), two weeks apart; 27 with 4 infusions (375 mg/m2), one week apart, followed in 10 cases by two further doses, after 1 and 2 months. Systemic complete response (CR) was defined as European Consensus Lupus Activity Measurement (ECLAM) score ≤1 and partial response (PR) as 1< ECLAM ≤3. Renal CR (RCR) and renal PR (RPR) were defined according to EULAR recommendations for management of lupus nephritis.
 
Data from 134 (92.4%) patients were available. The mean±SD follow-up was 27.3±18.5 months. After the first course of RTX, CR or PR were observed in 85.8% and CR in 45.5% of cases; RCR or RPR in 94.1% and RCR in 30.9% of patients after 12-month follow-up. Disease flares occurred in 35.1% and renal flares in 31.2% of patients during observational period. Among patients retreated, CR or PR were observed in 84.4% and CR in 57.8% of cases. Adverse events, infections, and infusion reactions occurred after first RTX course in 23.8%, 16.4%, and 3.8% of patients and after retreatment in 33.3%, 22.2% and 11.1%, respectively. No severe infusion reactions or deaths occurred.
 
Data from Italian multicentre RTX Registry confirmed the efficacy and safety of RTX in SLE patients refractory to standard treatment in clinical practice setting.
 
July 2022 Update
 Systemic sclerosis (SSc)-pulmonary arterial hypertension (PAH) is one of the most prevalent and deadly forms of PAH. B cells may contribute to SSc pathogenesis. The safety and efficacy of B-cell depletion for SSc-PAH was investigated. In an NIH-sponsored, multicenter, double-blinded, randomized, placebo-controlled, proof-of-concept trial, 57 patients with SSc-PAH on stable-dose standard medical therapy received two infusions of 1,000 mg rituximab or placebo administered 2 weeks apart. The primary outcome measure was the change in 6-minute-walk distance (6MWD) at 24 weeks. Secondary endpoints included safety and invasive hemodynamics. A machine learning approach was applied to predict drug responsiveness.  57 subjects from 2010 to 2018 were randomized. In the primary analysis, using data through Week 24, the adjusted mean change in 6MWD at 24 weeks favored the treatment arm but did not reach statistical significance (23.6 ± 11.1 m vs. 0.5 ± 9.7 m; P = 0.12). Although a negative study, when data through Week 48 were also considered, the estimated change in 6MWD at Week 24 was 25.5 ± 8.8 m for rituximab and 0.4 ± 7.4 m for placebo (P = 0.03). Rituximab treatment appeared to be safe and well tolerated. Low levels of RF (rheumatoid factor), IL-12, and IL-17 were sensitive and specific as favorable predictors of a rituximab response as measured by an improved 6MWD (receiver operating characteristic area under the curve, 0.88-0.95). B-cell depletion therapy is a potentially effective and safe adjuvant treatment for SSc-PAH. Clinical trial registered with www.clinicaltrails.gov (NCT01086540). (Zamanian RT, Badesch D, Chung L, et.al., 2021)
 
Experts from the Scleroderma Clinical Trials Consortium and the Canadian Scleroderma Research group (n = 170) were asked whether they agreed with SSc algorithms from 2012. Two consensus rounds refined agreement; 62, 54, and 48 experts (36%, 32%, and 28%, respectively) completed the first, second, and third surveys, respectively.
 
For treatment of scleroderma renal crisis, 81% of experts agreed (first-, second-, and third-line treatments were angiotensin-converting enzyme inhibitors, then adding calcium-channel blockers [CCBs], then adding angiotensin receptor blockers [ARBs], respectively). For pulmonary arterial hypertension (PAH), 81% of experts agreed (for mild PAH, treatments were phosphodiesterase 5 [PDE5] inhibitors, then endothelin receptor antagonists plus PDE5 inhibitors, then prostanoids, respectively; for severe PAH, prostanoids were first-line treatment). For mild Raynaud's phenomenon (RP), 79% of experts agreed (treatments were CCBs, then adding PDE5 inhibitors, then ARBs or switching to another CCB, respectively; after the third line of treatment, mild RP was deemed severe). For severe RP, the first- through fourth-line treatments were CCBs, then adding PDE5 inhibitors or prostanoids, then adding PDE5 inhibitors (if not added as second-line treatment) or prostanoids (if not added as second-line treatment), then switching to another CCB, respectively. For active treatment of digital ulcers, 66% of experts agreed (first- and second-line treatments were CCBs and PDE5 inhibitors, respectively). For interstitial lung disease, 69% of experts agreed (for induction therapy, treatments were mycophenolate mofetil [MMF], intravenous cyclophosphamide [IV CYC], and rituximab, respectively; for maintenance, first-line treatment was MMF). For skin involvement, 71% of experts agreed (for a modified Rodnan skin thickness score [MRSS] of 24, first- and second-line treatments were methotrexate [MTX] and MMF, respectively; for an MRSS of 32, first- through fourth-line treatments were MMF, MTX, IV CYC, and hematopoietic stem cell transplantation, respectively). For inflammatory arthritis, 79% of experts agreed (first- through fourth-line treatments were MTX, low-dose glucocorticoids, hydroxychloroquine, and rituximab or tocilizumab, respectively). Algorithms for cardiac and gastrointestinal involvement had 75% agreement.
 
Total agreement for SSc algorithms was considerable. These algorithms may guide treatment. (Fernández-Codina A, Walker KM, Pope JE; Scleroderma Algorithm Group., 2018)
 
PubMed and Embase were searched to identify studies on SSc-ILD treated with RTX, confined to a predefined inclusion and exclusion criteria. A systematic review and meta-analysis were performed on the included studies on changes in forced vital capacity (FVC) and diffusion capacity of carbon monoxide (DLCO) from baseline to 6 and 12 months of follow-up.
A total of 20 studies (2 randomized controlled trials, 6 prospective studies, 5 retrospective studies and 7 conference abstracts) were included (n = 575). RTX improved FVC from baseline by 4.49% (95% CI 0.25, 8.73) at 6 months and by 7.03% (95% CI 4.37, 9.7) at 12 months. Similarly, RTX improved DLCO by 3.47% (95% CI 0.99, 5.96) at 6 months and 4.08% (95% CI 1.51, 6.65) at 12 months. In the two studies comparing RTX with other immunosuppressants, improvement of FVC by 6 months in the RTX group was 1.03% (95% CI 0.11, 1.94) greater than controls. At the 12-month follow-up, RTX treatment was similar to controls in terms of both FVC and DLCO. Patients treated with RTX had a lower chance of developing infections compared with controls [odds ratio 0.256 (95% CI 0.104, 0.626), I2 = 0%, P = 0.47).
 
Treatment with RTX in SSc-ILD was associated with a significant improvement of both FVC and DLCO during the first year of treatment. RTX use was associated with lower infectious adverse events. (Goswami RP, Ray A, Chatterjee M,et.al., 2021)
 
A total of 51 patients with SSc-associated interstitial lung disease were recruited and treated with RTX (n = 33) or conventional treatment (n = 18). Median follow-up was 4 years (range: 1-7). Conventional treatment consisted of azathioprine (n = 2), methotrexate (n = 6), and mycophenolate mofetil (n = 10).
 
Patients in the RTX group showed an increase in FVC at 2 years (mean ± SD of FVC: 80.60 ± 21.21 vs 86.90 ± 20.56 at baseline vs 2 years, respectively, p = 0.041 compared to baseline). In sharp contrast, patients in the control group had no change in FVC during the first 2 years of follow-up. At the 7-year time point the remaining patients in the RTX group (n = 5) had higher FVC compared to baseline (mean ± SD of FVC: 91.60 ± 14.81, p = 0.158 compared to baseline) in contrast to patients in the control group (n = 9) where FVC deteriorated (p < 0.01, compared to baseline). Direct comparison between the 2 groups showed a significant benefit for the RTX group in FVC (p = 0.013). Improvement of skin thickening was found in both the RTX and the standard treatment group; however, direct comparison between groups strongly favored RTX at all-time points. Adverse events were comparable between groups.
 
Data indicate that RTX has a beneficial effect on lung function and skin fibrosis in patients with SSc. (Daoussis D, Melissaropoulos K, Sakellaropoulos G, et.al., 2017)
 
SSc is characterized by fibrotic changes in the skin and lung, and the mainstay of treatment has been CYC. B cell involvement suggests that rituximab (RTX) may also be of therapeutic benefit. The aim of the study was to compare the efficacy and safety of RTX compared with CYC in retarding the progression of interstitial lung disease and skin manifestations of primary SSc.
 
60 patients of dcSSc, age 18–60 years with skin and lung involvement, were randomly assigned to monthly pulses of CYC 500 mg/m2 or RTX 1000 mg × 2 doses at 0, 15 days. Primary outcomes were forced vital capacity (FVC) percent predicted at 6 months. Secondary outcomes were absolute change in litres (FVC-l) at 6 months; modified Rodnan skin scores at 6 months, 6-min walk test, Medsgers score and new onset or worsening of existing pulmonary hypertension by echocardiographic criteria.
 
The FVC [%mean (S.D.)] in the RTX group improved from 61.30 (11.28) to 67.52 (13.59), while in the CYC group it declined from 59.25 (12.96) to 58.06 (11.23) at 6 months (P = 0.003). The change of FVC was 1.51 (0.45) l to 1.65 (0.47) l in the RTX group, compared with 1.42 (0.49) to 1.42 (0.46) l in the CYC group. The mRSS changed from 21.77 (9.86) to 12.10 (10.14) in the RTX group and 23.83 (9.28) to 18.33 (7.69) in the CYC group after 6 months. Serious adverse events were more common in the CYC group.
 
RTX is a safe and effective alternative to CYC in the primary therapy of skin and lung manifestations of scleroderma. (Sircar G, Goswami RP, Sircar D, 2018)
 
October 2022 Update
In a study group comprised 1,008 RA patients from 2 independent randomized placebo-controlled phase III clinical trials (REFLEX [Randomized Evaluation of Long-Term Efficacy of Rituximab in Rheumatoid Arthritis] and SERENE [Study Evaluating Rituximab's Efficacy in Methotrexate Inadequate Responders]). A novel threshold selection method was used to identify baseline candidate biomarkers present in at least 20% of patients that enriched for placebo-corrected American College of Rheumatology 50% improvement (ACR50 response; a high clinical efficacy bar) at week 24 after the first course of rituximab.
 
The presence of IgM rheumatoid factor (IgM-RF), IgG-RF, IgA-RF, and IgG anti-cyclic citrullinated peptide (anti-CCP) antibodies together with an elevated C-reactive protein (CRP) level were associated with enhanced placebo-corrected ACR50 response rates in the REFLEX patients with RA who had an inadequate response to anti-tumor necrosis factor therapies. These findings were independently replicated using samples from patients in SERENE who had an inadequate response to disease-modifying antirheumatic drug treatment. The combination of an elevated baseline CRP level together with an elevated level of any RF isotype and/or IgG anti-CCP antibodies was further associated with an enhanced benefit to rituximab.
 
The presence of any RF isotype and/or IgG anti-CCP autoantibodies together with an elevated CRP level identifies a subgroup of patients with RA in whom the benefit of rituximab treatment may be enhanced. Although the clinical benefit of rituximab was greater in the biomarker-positive population compared with the biomarker-negative population, the clinical benefit of rituximab compared with placebo was also clinically meaningful in the biomarker-negative population. (Lal P, Su Z, Holweg CT, et.al., 2011)
 
A phase III study evaluated the efficacy and safety of rituximab plus methotrexate (MTX) in patients with active rheumatoid arthritis (RA) who had an inadequate response to MTX and who were naïve to prior biological treatment.
 
 Patients with active disease on stable MTX (10-25 mg/week) were randomized to rituximab 2 x 500 mg (n=168), rituximab 2 x 1000 mg (n=172), or placebo (n=172). From week 24, patients not in remission (Disease Activity Score (28 joints) > or =2.6) received a second course of rituximab; patients initially assigned to placebo switched to rituximab 2 x 500 mg. The primary end point was American College of Rheumatology 20 (ACR20) response at week 24. All patients were followed until week 48.
 
At week 24, both doses of rituximab showed statistically superior efficacy (p<0.0001) to placebo (ACR20: 54%, 51% and 23%; rituximab (2 x 500 mg) + MTX, rituximab (2 x 1000 mg) + MTX and placebo + MTX, respectively). Secondary end points were also significantly improved for both rituximab groups compared with placebo. Further improvements in both rituximab arms were observed from week 24 to week 48. Rituximab + MTX was well tolerated, demonstrating comparable safety to placebo + MTX through to week 24, and between rituximab doses through to week 48.
 
Rituximab (at 2 x 500 mg and 2 x 1000 mg) plus MTX significantly improved clinical outcomes at week 24, which were further improved by week 48. No significant differences in either clinical or safety outcomes were apparent between the rituximab doses. (Emery P, Deodhar A, Rigby WF, et.al., 2011)

CPT/HCPCS:
C9399Unclassified drugs or biologicals
J3490Unclassified drugs
J9311Injection, rituximab 10 mg and hyaluronidase
J9312Injection, rituximab, 10 mg
J9999Not otherwise classified, antineoplastic drugs
Q5115Injection, rituximab abbs, biosimilar, (truxima), 10 mg
Q5119Injection, rituximab pvvr, biosimilar, (ruxience), 10 mg
Q5123Injection, rituximab-arrx, biosimilar, (riabni), 10 mg

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