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Child Health Guideline Identifier

Rheumatology - Rituximab

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Background

Rituximab is a chimeric (murine/human) monoclonal antibody directed against B cells. It binds to CD20 antigen, causing B cell lysis. Rituximab spares B cell progenitors, and B cells usually repopulate 4-12 months after therapy. CD27+ B-cells (memory B-cells) can remain suppressed for 2 years after depletion1.

Treatment is aimed at reducing autoantibody production, and thereby disease activity. It may also be used as a steroid-sparing agent. Rituximab is available via the Hospital Medicines List (HML) - an application must be completed by the relevant subspecialist.

Indications

Rituximab has been reported to be effective against RF+ve polyarticular juvenile idiopathic arthritis (JIA), juvenile dermatomyositis (JDM) and some forms of vasculitis2,3,4,5. Effectiveness has also been reported against treatment resistant systemic lupus erythematosus (SLE)1.

Rituximab may be indicated for the following conditions if standard treatment regimes have failed1:

  • Resistant childhood Systemic Lupus Erythematosus (SLE)6
  • Dermatomyositis and vasculitis (particularly ANCA associated)4,7,8,9
  • Polyarticular/Systemic Juvenile Idiopathic Arthritis (JIA)* - case reports only 2,10
  • Systemic sclerosis/ severe widespread localised scleroderma* 11
  • Childhood Autoimmune Thrombocytopoenia* 12

*needs NPPA completed as not covered in the HML

Regimen

Usual practice is to give rituximab as two single doses of 750mg/m2 (max.1g) two weeks apart1. Further infusions can be given once the B cells have repopulated, usually 4-12 months after infusion. In SLE (and possibly vasculitidies), each rituximab infusion may be followed the next day by 500-1000mg/m2 (Max. 1gram) of IV cyclophosphamide. This needs to be in discussion with a paediatric rheumatologist. This cycle can be repeated twice. In JIA concomitant use of methotrexate is recommended14.

Other regimens, e.g. 375mg/m2 weekly for 4 weeks have been used13.

Re-treatment with rituximab is considered once peripheral B-cell count is >2%. Re-treatment before formal recovery of B-cells may be warranted if clinical features of active disease return before B-cell markers have recovered to >2% (conventional flow cytometry may be insensitive and 'lesional' B cells can be present if peripheral B-cell count is still <2%)14.

Review and follow-up

  • Rheumatology review at each infusion visit with documentation of any side effects.
  • Clinic review at minimum of 6 monthly intervals.
  • Rituximab may take some time to become effective

Contraindications

Absolute contra-indications

  • Untreated chronic infection, such as tuberculosis
  • Any active infection or pyrexia
  • Severe heart failure
  • Known hypersensitivity to any component of the product

Relative contraindications/cautions

  • Chronic hepatitis B carriage
  • Underlying conditions which predispose infection (e.g. Crohn's, diabetes)
  • Pregnancy

Before treatment commences

  1. Consent
    Medical team must fully discuss the treatment with the patient and/or carer and ensure a written patient information leaflet has been provided.
    Responsible consultant to document discussion regarding risks/benefits of treatment (including serious risks) in full.
  1. Before starting Rituximab (or any other biologic), it is important to exclude possible pre-existing infections. Screening prior to immunosuppressive therapy is outlined in the Starship guideline on immunosuppression, infection and immunisation.  Children should have the following:
    1. TB excluded with serum TB quantiferon gold, Mantoux (preferred if ≤5yrs) and CXR
    2. Viral serology - Measles Mumps and Rubella IgG, VZV IgG, Hep A, B, C, HIV. It is recommended that immunisations are up to date before commencing Rituximab if possible depending on degree of urgency and immunosuppression1Where possible any catch up immunizations should be given one month before starting Rituximab.
  2. Blood tests: CD 19&20, immunoglobulins (G,A and M), Rh Factor, ANA is needed annually
  3. It is important that a baseline level of disease activity has been recorded (eg JADAS)
  4. Consider pregnancy testing in females of childbearing age

Before each cycle of Rituximab

  • Ensure tests above have been done and confirmed OK to proceed.
  • Blood and urine tests (preferably done the day before infusion):
Test FBC ESR & CRP U&E LFT & Albumin CK LDH C3 & C4 dsDNA (in last 3 mths) ANCA (in ANCA assoc. vaculitis) Urine Prot/Cr ratio Urine microscopy
JIA tick   tick tick  tick

X 

 X  X  X  X X   X
JDM tick   tick tick   tick tick tick  X  X  X  X  X
SLE tick   tick tick  tick   X  X tick  tick  X tick   tick
Vasculitis tick  tick  tick   tick  X  X  X  X  tick  tick tick 

Day of Rituximab Infusion

  1. Medical review and admission note prior to infusion - particularly to identify FEVER, active or suspected infection or recent exposure to infectious diseases (eg gastroenteritis/measles/chickenpox).
    1. Baseline temperature, pulse rate, blood pressure and respiratory rate
    2. Height and weight
  2. Safety
    1. Check a rheumatologist is available on call during infusion - must be available onsite for the first infusion at Starship.  Where rituximab is given elsewhere, a consultant paediatrician and resuscitation facilities should be available.
    2. Review prescribed dose of rituximab and check pre-medication and adrenaline charted.
    3. Review results of blood testing from day prior/ obtain required tests and review if not already done.

Delay infusion and discuss with Consultant

  • If absolute neutrophil count <1
  • If platelets <50 (delay until count >100)
  • If ALT>3x upper limit normal (delay until <3x normal)
  • Active/suspected infection or recent exposure to viral infection (delay at least 7/7)

Rituximab dosage and administration

This is a hazardous medicine. Please ensure you follow your local policy with regards to protection when preparing and administering it

Dosage

Rituximab for use in rheumatology: 2 single doses of 750mg/m2 to nearest 100mg (max 1 gram), two weeks apart.

  • Consider using dry weight/ideal body weight for drug calculations if patient is overweight due to steroid toxicity/obesity. Any variation from standard dosage should be under advice from the responsible Consultant.
  • Other regimens, such as use of rituximab with cyclophosphamide (375mg/m2 with maximum of 1g), have been described. Any variation to the standard prescription must be made by the responsible specialist consultant.

Adrenaline for anaphylaxis - chart adrenaline in case of reaction (see Anaphylaxis Guideline for dose)

Pre-Medication (give 30-60mins before infusion)

  1. Loratadine or cetirizine (oral):
      1-2 years <30kg  > 30kg
    Loratidine (daily)  2.5mg  5mg  10mg
     Cetirizine (twice daily)  <2 years  2-6 years 6-12 years   >12 years
     0.25mg/kg  2.5mg 5mg  10mg
  2. Paracetamol 15mg/kg/dose PO (max dose 60mg/kg/day to maximum of 1gram)
  3. Hydrocortisone (IV) 4mg/kg IV, 15-30 minutes prior to infusion, if previous reaction.

Preparation

Rituximab is ordered from Pharmacy, at least 24 hours before the infusion. Rituximab is available in 100mg/10ml or 500mg/50ml vials.

  • Rituximab should be diluted with 0.9% saline to a concentration of 1-4mg/ml
  • The prepared solution can be stored for up to 30 days prior to infusion in the refrigerator (2-8 oC).

Standard Infusion Protocol

  • Infuse using intravenous giving set, filter not required
  • Initial infusion rate is 25mg/hour (NB not mls/hr)
  • Increase by 25mg/hour every 30 minutes as tolerated to maximum rate of 200mg/hour
  • If tolerated during first infusion, subsequent doses may be given slightly faster by starting at 50mg/hr, increasing every 30 minutes in increments of 50mg/hr as tolerated, to a maximum of 200mg/hr.
  • Flush line with 0.9% sodium chloride to complete infusion

Observations during infusion

  1. Pulse and BP every 15 minutes for the first hour and then every 30 minutes thereafter
  2. Temperature every hour
  3. The patient should remain in unit/ward for 1 hour post infusion as delayed reactions can occur

Observe for signs of adverse drug reaction

Adverse effects

Allergic reactions have been reported in about 10% of patients given Rituximab infusions.

Serious symptoms include:

  • Hypotension
  • Loss of consciousness/collapse
  • Shortness of breath/wheezing, persistent cough
  • Swelling of the tongue
  • Difficulty talking or hoarse voice
  • Chest/abdominal pain
  • Fevers/chills
  • Headache/dizziness
  • Itching, rash (usually 24-48 hours after second or third infusion, and can last for several days)

Mild/moderate reactions (occur most frequently with first or second infusions) can include:

  • Flushing
  • Nausea
  • Fatigue

If reaction occurs, STOP the infusion until medical review.

Anaphylaxis (see Anaphylaxis guideline)

If an anaphylactic reaction occurs (ie significant respiratory or haemodynamic instability), stop infusion and call 777. Follow anaphylaxis flow chart in the anaphylaxis guideline.

If reaction is suspected or any of the above signs and symptoms are observed during the infusion and the patient remains haemodynamically stable:

  • The infusion should be stopped.
  • Notify and discuss with consultant
  • The infusion may be restarted after 30mins at a halved rate if symptoms resolved
  • If the patient continues to display signs and symptoms of hypersensitivity, an IM or IV dose of antihistamine must be administered.

Other potential side effects15,16

  • Severe skin/lip/mouth reactions - sores, ulcers, blisters, peeling skin, rash, pustules
  • Hepatitis B reactivation
  • Rarely, serious bacterial, fungal or viral infections can occur
  • Progressive multifocal leukencephalopathy (PML)
  • Angina pectora, cardiac arrhythmia, heart failure, myocardial infarction
  • Rarely, there have been reports of pulmonary symptoms due to interstitial lung disease16

Discharge planning/follow up

Confirm second infusion date if relevant. Alternatively ensure outpatient follow up arranged for 3 months after infusion. Families should be aware of the necessary precautions relating to immune suppression and review the information in the written patient information leaflets verbally prior to discharge.

As a minimum, the following monitoring is recommended after infusion:

  • Day 7-10 post first dose of Rituximab: FBC, immunoglobulins, CD19 and CD20*
  • Consider immunoglobulins, CD19 and CD20 every 3 months from 1st dose. In some patients, disease activity may be associated with repopulation of B cells.
  • Measures of disease activity as appropriate for underlying disease

*B cells express CD19 and CD20. Rarely (normally in the context of malignancy) B cells may not express CD20 and will not therefore be eliminated by rituximab. If there is a concern that B cells are not eradicated after 7-10 days, routine B cell measurement should be repeated and discuss with immunology laboratory whether direct measurement of CD20 would be helpful. B Cells will occasionally repopulate earlier than 4 months post rituximab.

Consider cotrimoxazole prophylaxis for 6 months if additional immunosuppression of steroids (would definitely use if also on cyclophosphamide)

Information for Families

Rituximab (Arthritis Australia)

References

  1. McErlane, F Pain, C and McCann L. bspar guideance for rituximab. rheumatology.org.uk. [Online] 2016. [Cited: 10 April 2017.] http://www.rheumatology.org.uk/includes/documents/cm_docs/2016/b/bspar_guidance_for_rituximab.pdf.
  2. Efficacy and safety of repeat courses of rituximab treatment in patients with severe refractory juvenile idiopathic arthritis. Alexeeva, EI, Valieva SI, Bzarova TM et al. 1163, s.l. : Clin Rheumatology, 2011, Vol. 30. 10.1007/s10067-011-1720-7.
  3. Safety and efficacy of Rituximab in SLE: results from 136 patients from the French Autoimmunity and Rituximab registry. Terrier, B et al. 2010, Arthritis Rheum, pp. 2458-2466.
  4. Rituximab in the treatment of dermatomyositis. An open label pilot study. Levine, T. 2, s.l. : Arthritis Rheum, 2005, Vol. 52.
  5. Rituximab for remission induction in severe ANCA-associated vasculitis: report of a prospective open-label pilot trial in 10 patients. al., Keogh KA et. s.l. : Arthritis Rheum, 2004, Vol. 50.
  6. B lymphocyte depletion therapy in children with refractory SLE. al, Marks SD et. 10, s.l. : Arthritis Rheum, 2005, Vol. 52.
  7. safety and efficacy of rituximab in severe juvenile dermatomyositis: results from 9 patients from the French autoimmunity and rituximab registry. al, Bader-Meunier B et. 7, s.l. : Journal of Rheumatology, 2011, Vol. 38.
  8. Rituximab treatment in patients with refractory inflammatory myopathies. Elien AM, et al. 12, Oxford : Rheumatology, 2011, Vol. 50. 10.1093/rheumatology/ker088.
  9. Rituximab in the treatment of refractory adult and juvenile dermatomyositis and adult polymyositis: a randomised, placebo-phase trial. al, Oddis CV et. s.l. : Arthritis and Rheumatism, 2013, Vol. 65. 10.1002/art.37754.
  10. 10. A successful treatment of juvenile idiopathic arthritis with rituximab: A report of two cases. al, Berrada et. 4, s.l. : Eurpoean Journal Rheumatology, 2014, Vol. 1.
  11. 11. Experience with rituximab in scleroderma: results from a 1-year, proof-of-principle study. al, Daoussis D et. 2, s.l. : Rheumatology, 2010, Vol. 49.
  12. 12. Successful use of anti-CD20 (Rituximab) in the treatment of severe thrombocytopenia associated with juvenile systemic autoimmune disease. al, Russo RA et. s.l. : Arthritis Rheum, 2004, Vol. 50.
  13. 13. (eds), Foster H and Brogan PA.Paediatric Rheumatology. Oxford : Oxford University Press, 2012. 978-0-19-959263-0.
  14. 14. Clinical Effects and Safety of Rituximab for Treatment of Refractory Pediatric Autoimmune Diseases. al, El-Hallak M et. s.l. : J Pediatrics, 2007, Vol. 150.
  15. 15. Medsafe NZ. Medsafe. Medsafe Datasheets. [Online] 14 October 2014. [Cited: 20 October 2016.] http://www.medsafe.govt.nz/profs/datasheet/a/Actemrainf.pdf.

Bibliography

  1. McErlane, F Pain, C and McCann L. bspar guideance for rituximab. rheumatology.org.uk. [Online] 2016. [Cited: April 10, 2017.] http://www.rheumatology.org.uk/includes/documents/cm_docs/2016/b/bspar_guidance_for_rituximab.pdf.
  2. Efficacy and safety of repeat courses of rituximab treatment in patients with severe refractory juvenile idiopathic arthritis. Alexeeva, EI, Valieva SI, Bzarova TM et al. 1163, s.l. : Clin Rheumatology, 2011, Vol. 30. 10.1007/s10067-011-1720-7.
  3. Safety and efficacy of Rituximab in SLE: results from 136 patients from the French Autoimmunity and Rituximab registry. Terrier, B et al. 2010, Arthritis Rheum, pp. 2458-2466.
  4. Rituximab in the treatment of dermatomyositis. An open label pilot study. Levine, T. 2, s.l. : Arthritis Rheum, 2005, Vol. 52.
  5. Rituximab for remission induction in severe ANCA-associated vasculitis: report of a prospective open-label pilot trial in 10 patients. al., Keogh KA et. s.l. : Arthritis Rheum, 2004, Vol. 50.
  6. B lymphocyte depletion therapy in children with refractory SLE. al, Marks SD et. 10, s.l. : Arthritis Rheum, 2005, Vol. 52.
  7. safety and efficacy of rituximab in severe juvenile dermatomyositis: results from 9 patients from the French autoimmunity and rituximab registry. al, Bader-Meunier B et. 7, s.l. : Journal of Rheumatology, 2011, Vol. 38.
  8. Rituximab treatment in patients with refractory inflammatory myopathies. Elien AM, et al. 12, Oxford : Rheumatology, 2011, Vol. 50. 10.1093/rheumatology/ker088.
  9. Rituximab in the treatment of refractory adult and juvenile dermatomyositis and adult polymyositis: a randomised, placebo-phase trial. al, Oddis CV et. s.l. : Arthritis and Rheumatism, 2013, Vol. 65. 10.1002/art.37754.
  10. A successful treatment of juvenile idiopathic arthritis with rituximab: A report of two cases. al, Berrada et. 4, s.l. : Eurpoean Journal Rheumatology, 2014, Vol. 1.
  11. Experience with rituximab in scleroderma: results from a 1-year, proof-of-principle study. al, Daoussis D et. 2, s.l. : Rheumatology, 2010, Vol. 49.
  12. Successful use of anti-CD20 (Rituximab) in the treatment of severe thrombocytopenia associated with juvenile systemic autoimmune disease. al, Russo RA et. s.l. : Arthritis Rheum, 2004, Vol. 50.
  13. (eds), Foster H and Brogan PA.Paediatric Rheumatology. Oxford : Oxford University Press, 2012. 978-0-19-959263-0.
  14. Clinical Effects and Safety of Rituximab for Treatment of Refractory Pediatric Autoimmune Diseases. al, El-Hallak M et. s.l. : J Pediatrics, 2007, Vol. 150.
  15. Medsafe NZ. Medsafe. Medsafe Datasheets. [Online] October 14, 2014. [Cited: October 20, 2016.] http://www.medsafe.govt.nz/profs/datasheet/a/Actemrainf.pdf.
  16. Long term safety of rituximab: final report of the rheumatoid arthritis global clinical trial program over 11 years. Van Vollenhoven, RF et al. 10, s.l. : journal of rheumatology, 2015, Vol. 42. https://doi.org/10.3899/jrheum.150051 .
  17. non-infectious pulmonary toxicity of rituximab: a systematic review. hadjinicolaou, AV et al. 4, s.l. : Rheumatology, 2012, Vol. 51.

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Document Control

  • Date last published: 22 February 2018
  • Document type: Clinical Guideline
  • Services responsible: Paediatric Rheumatology
  • Owner: Jackie Yan
  • Editor: Greg Williams
  • Review frequency: 2 years

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