RITUXIMAB:

TREATMENT OF AUTOIMMUNE
NEUROLOGICAL DISORDERS

HEALTH TECHNOLOGY ASSESSMENT SECTION

MEDICAL DEVELOPMENT DIVISION
MINISTRY OF HEALTH MALAYSIA
i
001/2012
DISCLAIMER
Technology review is a brief report, prepared on an urgent basis, which draws on
restricted reviews from analysis of pertinent literature, on expert opinion and / or
regulatory status where appropriate. It has been subjected to an external review
process. While effort has been made to do so, this document may not fully
reflect all scientific research available. Additionally, other relevant scientific
findings may have been reported since completion of this review.

Please contact: htamalaysia@moh.gov.my, if you would like further information.

Health Technology Assessment Section (MaHTAS),

Medical Development Division
Ministry of Health Malaysia
Level 4, Block E1, Precinct 1
Government Office Complex
62590 Putrajaya

Tel: 603 88831246

Fax: 603 8883 1230

Available at the following website: http://www.moh.gov.my

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Prepared by:
Maharita Binti Ab Rahman
Assistant Director (Pharmacist)
Health Technology Assessment Section (MaHTAS)
Ministry of Health Malaysia

Reviewed by:
Datin Dr Rugayah Bakri
Deputy Director
Health Technology Assessment Section (MaHTAS)
Ministry of Health Malaysia

External reviewer

Dato Dr. Md. Hanip bin Rafia

Senior Consultant Physician and Neurologist
Head of Department
Neurology Department
Hospital Kuala Lumpur

Dr. Hussain Imam Haji Mohammad Ismail

Senior Consultant Physician and Paediatrician
Head of Department
Paediatric Department
Hospital Kuala Lumpur

DISCLOSURE

The author of this report has no competing interest in this subject and the
preparation of this report is totally funded by the Ministry of Health, Malaysia.

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EXECUTIVE SUMMARY

Introduction
Rituximab (Rituxan or MabThera) is a chimeric monoclonal antibody against
the protein CD20, which is primarily found on B cells surfaces. Rituximab is
approved for use as a single agent to treat patients with relapsed or refractory
low-grade or follicular B-cell non-Hodgkins lymphoma (NHL). In 2006, rituximab
was approved to be used in combination with chemotherapy to treat certain
conditions. It is also widely used as off-label to treat difficult cases of multiple
sclerosis (MS) and other autoimmune disorders including systemic lupus
erythematosus (SLE). However, USFDA did not approve the safety and the
efficacy of rituximab in treatment of SLE. This technology review will further
discuss about Rituximab for treatment of autoimmune neurological disorders
based on a request from Consultant Paediatric Neurologist of Paediatric
Department in Hospital Kuala Lumpur.

Objective/Aim
To assess the efficacy / effectiveness, safety and cost-effectiveness of rituximab
for treatment of autoimmune neurological disorders such as myasthenia gravis
(MG), neuromyelitis optica (NMO), multiple sclerosis (MS) and opsoclonus-
myoclonus syndrome (OMS).

Results and conclusions

There was limited fair level of evidence retrieved to show that rituximab was
effective and safe in treatment of autoimmune neurological disorders (MG, NMO,
MS and OMS). However there were adverse events reported. No cost-
effectiveness study on rituximab in treatment of autoimmune neurological
disorder was retrieved.

Methods
Electronic databases were searched through the MEDLINE(R) In-process and
other Non-Indexed Citations and Ovid MEDLINE(R) 1948 to present, EBM
Reviews - Cochrane Central Register of Controlled Trials-4th Quarter 2010 and
EBM Reviews - Health Technology Assessment - 4th Quarter 2010. Other
database was PubMed, National Horizon Scanning and FDA website. Besides
that, additional articles from bibliographies of retrieved articles and requestor lists
were also included. There was no limit in the search. Relevant articles were
critically appraised using Critical Appraisal Skills Programme (CASP) and the
studies were graded according to US/Canadian Preventive Services Task Force
(Harris 2001).

iv
1. INTRODUCTION

Rituximab (Rituxan or MabThera) is a chimeric monoclonal antibody

against the protein CD20, which is primarily found on B cells surfaces.
Rituximab received United State of Food and Drug Administration
marketing approval on November 26, 1997, for use as a single agent to
treat patients with relapsed or refractory low-grade or follicular B-cell non-
Hodgkins lymphoma (NHL).1

However, in 2006, rituximab (RTX) was approved to be used in

combination with cyclophosphamide, vincristine and prednisolone (CVP)
chemotherapy for the initial treatment of slow-growing (follicular) B-cell
NHL, to be used alone in patients with low-grade, B-cell NHL whose
tumour remain stable or shrink following initial treatment with CVP
chemotherapy, in combination with anthracycline-based combination
chemotherapy for the initial treatment of diffuse large B-cell NHL. It is also
used in combination with methotrexate to treat moderately to severely
active rheumatoid arthritis in adults who have had an inadequate response
to one or more TNF antagonist therapies to reduce signs and symptoms of
arthritis.2 Despite of arthritis and NHL, RTX is also widely used off-label to
treat difficult cases of multiple sclerosis, other autoimmune disorders and
systemic lupus erythematosus (SLE). However, USFDA did not approve
the safety and the efficacy of RTX in treatment of SLE.3

In autoimmune neurological disorders, B-cells have traditionally been

associated with the production of autoantibody (an antibody produced by
the body in reaction to any of its own cells or cell products) from plasma
cells, which are the end products of B-cells differentiation. As a treatment,
the RTX has become an alternative to treat the disease which is believed
to deplete the B cells.4

This technology review will further discuss about RTX for treatment of
autoimmune neurological disorders based on request from Consultant
Paediatric Neurologist of Paediatric Department in Hospital Kuala Lumpur.

2. OBJECTIVE/AIM

To assess the efficacy / effectiveness, safety and cost-effectiveness of

RTX for treatment of autoimmune neurological disorders such as
myasthenia gravis (MG), neuromyelitis optica (NMO), multiple sclerosis
(MS) and opsoclonus-myoclonus syndrome (OMS).

3. TECHNICAL FEATURES

RTX is a chimeric (from mouse/human origin) monoclonal antibody

against protein CD20 which is primarily found on the surface of B cells.

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 RTX destroys both normal and malignant B cells that have CD20 on their
surfaces and is therefore used to treat diseases which are characterized
by having too many B cells, over reactive B cells or dysfunctional B cells.1

Pharmacokinetic analysis data reported by Wood AM (2001) revealed a

steady rise in pre-infusion and post-infusion serum antibody levels with
each RTX dose. The data was based on 166 patients treated with
375mg/m2 once weekly for four doses over 22 days. The detectable
antibody levels were still present one, three, and six months after the end
of treatment. Consistent with these findings, the elimination half-life of
RTX increased from a mean standard deviation of 76.3 31.1 hours
after the first infusion to 205.8 95.0 hours after the fourth and final
infusion. Clearance was 38.2 mL/hr after the first dose and 9.2 mL/hr after
the fourth. Prolongation of RTX's half-life is probably due to the absence of
circulating CD20-positive B cells, which bind antibodies during initial
infusions. It is also likely that prior RTX saturation of involved lymph node
sites would increase antibody availability and decrease the clearance.5

Petereit HF. and Rubert-Roth A. did a cross-sectional study which only

involved 14 paired serum and cerebrospinal fluid (CSF) from three
patients. Those samples were taken before and after treatment with RTX.
The samples were analyzed for RTX level. All the three patients were
administered with 375mg/m2 body surface four times in weekly intervals.
The measurement of B-cell count in CSF was taken four to five weeks
after the first infusion. The results showed that the highest RTX level in
CSF was at week 3 (170ng/mL) and at week four (201ng/mL). Meanwhile
the RTX serum level at week three and four was about 1000-fold higher
than in the CSF. The detection might indicate that the RTX was
biologically active when detected in the CSF and serum samples.8

3.1 Mechanism of Action6

The exact mechanism of RTX is unknown; however, there are 3 proposed

mechanisms to induce B-cell destruction by RTX. They are:

i) Antibody-dependent cell-mediated cytotoxicity (ADCC):

Natural killer cells, T cells and macrophages are involved in
recognizing and killing antibody-labeled target cells, leading to cell
lysis.

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ii) Complement-dependent cytotoxicity (CDC):
Binding of the antibody recruits complement proteins, which punch
holes in the cell membrane, flooding the cell and leading to cell
lysis.

iii) Apoptosis:
Binding of the antibody signals the cell to self-destruct.

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4. METHODS

4.1. Searching

Electronic databases were searched through the MEDLINE(R) In-process

and other Non-Indexed Citations and Ovid MEDLINE(R) 1948 to present,
EBM Reviews - Cochrane Central Register of Controlled Trials-4th Quarter
2010 and EBM Reviews - Health Technology Assessment - 4th Quarter
2010. Other database was PubMed, National Horizon Scanning and FDA
website. Besides that, additional articles from bibliographies of retrieved
articles and requestor lists were also included. The search term used can
be referring to Appendix.

4.2. Selection

A reviewer screened the titles and abstracts against the inclusion and
exclusion criteria and then evaluated the selected full-text articles for final
article selection. The inclusion and exclusion criteria were:

Inclusion criteria
Population Efficacy & safety: Patient with autoimmune
neurological disorders such as MG, NMO, MS and
OMS and other autoimmune diseases included RA,
arthritis, autoimmune haemolytic anaemia, and SLE.
Interventions Rituximab (RTX)
Comparators Other monoclonal antibodies
Outcomes Efficacy/effectiveness, safety and cost-effectiveness
for autoimmune neurological disorders such as MG,
NMO, MS and OMS and other for autoimmune
disorders included RA, arthritis, autoimmune
haemolytic anaemia, and SLE.
Study design Randomized control trials, systematic reviews, case
control, cohort and descriptive studies.
Type of English Full Text
publication

Exclusion criteria
Study design Abstract, animal study, efficacy: other than autoimmune
neurological disorders
Type of Non-English Full Text
publication

Relevant articles were critically appraised using Critical Appraisal Skills

Programme (CASP) and evidence graded according to the US / Canadian
Preventive Services Task Force (Appendix 2).

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5. RESULTS AND DISCUSSION

Six full text articles were included in this technology review were on
efficacy/effectiveness and safety of RTX in treatment of autoimmune
neurological disorder such as MG, NMO, MS and OMS.

5.1 EEFICACY/ EFFECTIVENESS: RITUXIMAB IN TREATMENT OF

AUTOIMMUNE NEURLOGICAL DISORDERS

Hauser SL et al. conducted a phase 2, randomized double-blind, placebo-

controlled study at 32 centres in United States and Canada. This trial was
supported by Biogen Idec and GlaxoSmithKlien. Hundred and four (104)
patients (18-55 years old) with relapsing-remitting multiple sclerosis (MS)
were randomly assigned in 2:1 ratio to receive either intravascular (IV)
1000mg RTX (69 patients) or placebo (35 patients) and were
hierarchically stratified according to study site; study with respects to
previous treatment and baseline disease severity according to Expanded
Disability Status Scale (EDSS) score. The study was based on intention-
to-treat (ITT) basis. The primary end-point was total count of gadolinium-
enhancing lesions (GEL) detected on magnetic resonance imaging scans
of the brain (at weeks 12, 16, 20, 24) and relapse. The total GEL at weeks
12, 16, 20 and 24 of RTX group was reduced compared with placebo
group (p<0.001). The RTX patients had mean of 0.5 GEL compared with
5.5 GEL in patients received placebo (relative reduction of 91%). At week
24, relapse was reduced in RTX group compared to placebo group with
14.5% versus 34.3% (P=0.02) and at week 48, 20.3% versus 40.0%
(P=0.04) respectively. Then, for new GEL (new lesion which was
considered after compared with reference scan), the RTX reduced the
lesions at weeks 2, 16, 20 and 24 as compared with placebo (P<0.001).
Besides that, reduction in volume of lesions detected on T2-weighted MRI
from baseline to week 24 and from baseline to week 36 was greater in
patients who received RTX than in placebo (P=0.08 and P=0.04). Based
on this trial, the authors suggested that the RTX may be an option to treat
relapsing-remitting MS. However, the efficacy and safety profile should
sustain with larger and longer-term controlled trials.7, Level I Calculated
number need to treat (NNT) for this study showed that, in order to prevent
new GEL at 12, 16, 20 and 24 weeks, the NNT was four. Then to prevent
relapse at 12, 16, 20 and 24 weeks, the NNT was five.

Pellfoker HL et al. conducted a prospective long-term cohort study on 10

patients with NMO who failed to respond at least to one standard
immunotherapy. Two courses of RTX treatment were prepared. First
course was intravascular (IV) 2g RTX, divided into two biweekly infusions,
preceded by premedication (100mg prednisolone, 1g acetaminophen, and
4mg dimethidene). The second course RTX was infused after appearance
of B cells at fixed time intervals (every six to nine months). Clinical

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 examinations and level of B-cells count were measured every three
months to observe body response towards RTX. Monotherapy with RTX
resulted in a reduction of relapse rate in eight of ten patients and one
patient required combined RTX with methotrexate to experience moderate
relapse rate. The B-cells counts became undetectable in nine patients
fourteen days after the first dose.2, Level II-2

Jacob A et al. conducted a pre and post intervention study involving 25

patients at age of 7 to 65 years old with NMO at 20 centres. Two RTX
regimens were used; 375mg/m2 which was infused once weekly for four
weeks and 1000mg twice a week with two weeks interval between the
infusions. The assessment on efficacy was on relapse rate. For all 25
patients, the median annualized pre-treatment relapse rate was 1.7
relapse (range 0.5-5.0 relapses). Meanwhile the median annualized post-
treatment rate was 0 relapses (range 0.0-3.2 relapse).10, Level II-3

Pranzatelli MR et al. followed up a 30 months old child who was

diagnosed with OMS for about 23 months. The analysis was using
videotape scoring method and flow cytometry analysis. Previously, the
child was treated with IV 1g/kg immunoglobulin (Ig) which was
discontinued later on. Essentially, the child required for immunotherapy
however the parent refused to take corticotropin and it was replaced with
RTX as the other alternative treatment once a week for four consecutive
weeks along with acetaminophen and diphenhydramine. The assessment
looked into the clinical response towards RTX monotherapy and B-cells
response to the RTX. One week after initial RTX treatment the child
showed some improvement and after the fourth infusion the child seemed
much happier, less tremulous, calmer, more focused and more stable.
According to child motor performance on OMS evaluation scale, the child
improved in station and gait with fewer fine-motor difficulties and
elimination of opsoclonus with total score decreased by 42% which
represented almost one severity. With regards to B-cells response to RTX,
after three months, the CSF CD19+ and CD5+ B-cells count were depleted
as well as B-cells count in the blood. At nine months the CSF CD19 +
returned to approximately one third (1/3) of the pre-treatment value within
the normal range (<2%) and the CD5+ B-cells subset was still absent.
Then, by nine to 12 months the B-cells percentage in peripheral blood had
returned to the baseline value.9, Level II-3

5.2.1 SAFETY

Tony HP et al. conducted a cross-sectional study involving 370

autoimmune patients (299 pts-yrs of observation) from 42 German
centres. The centres included university, large hospitals, and private
practices. Those patients suffered various autoimmune diseases which
included arthritis, autoimmune haemolytic anaemia, autoimmune

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neurological disorders and systemic lupus erythematosus. Out of the 370
patients, about 70 were autoimmune neurological disorders patients such
as MS/NMO (n=56), MG (n=5), chronic inflammatory demyelinating
polyneuropathy (n=3) and autoimmune neuropathy (n=1). These patients
received RTX on or before 31 August 2008 with the last follow up before
20 December 2008. The outcome measures were clinically adverse
events, where the intensity of AEs was graded using National Cancer
Institute Common Terminology Criteria for Adverse Events (CTCAE). The
overall rate of infection during treatment with RTX was 18.1 per 100 pt-yrs.
By looking at autoimmune neurological disorder only, the high rate of
infections and serious infections occur in MG. Eleven deaths also reported
in overall study however, only two deaths involved autoimmune
neurological disorders patients. One death was assessed as related to
infection and the other one was due to unspecified cause.11, Level II-3

Brown BA and Torabi M conducted a cross-sectional study to assess the

incidence of infusion-associated reactions in MS patients who received
RTX infusions. Medical charts from 70 patients were retrospectively
reviewed from Partners Multiple Sclerosis Centre, Brookline, MA, USA.
Those patients were treated with RTX for MS between 20 November 2007
and 24 November 2009. The authors further classified the infusion-
associated reactions on a grading scale. Based on the scale, all the
reactions were graded with grade 1 (mild) and grade 2 (moderate),
consisting most commonly of generalized pruritis, itchy throat,
erythematous rash and hives. Most treatments for the reactions included
stopping the infusion and administration of H1 receptor antagonist
(intravenous famotidine). Based on this, the authors suggested that
premedication for RTX infusions in MS patients should include
corticosteroids (methyprednisolone 100mg intravenously).12, Level II-3

In the randomized controlled trial conducted by Hauser SL et al., 78.3%

patients in RTX group experienced infusion associated AEs within 24
hours compared to only 40% in the placebo group. Infections mostly
occurred in placebo group (71.4%) compared to RTX group (about
69.6%). One death also occurred in RTX group but due to homicide case.7

In the previous pre and post intervention study by Jacob A. et al, the
authors found transient infusion-related AEs in 7 patients (28%), new and
reactivated infections in 5 patients (20%) such as herpes simplex, positive
tuberculin skin test, herpes zoster, recurrent Clostridium difficile colitis,
and fungal infection. Death also occurred in two patients; one patient was
dead nine months after the last dose following a severe relapse and the
other died six months after the last dose of RTX.10

Since 1997, RTX received the approval from United State Food and Drug
Administration (USFDA) under brand Rituxan. Based on USFDA approval,

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 the RTX can be used in the treatment of NHL, chronic lymphocytic
leukaemia (CLL) and RA. However, the RTX is yet to get approval from
USFDA for the treatment of SLE.3

However, in June 2011, a safety summary report obtained was prepared

for RTX, with regards to several fatal infusion-related reactions in patients
receiving RTX treatment. It was a compilation of the safety summary
report from United State, United Kingdom, Venezuela and Algeria. The
report stated that the infusion-related reactions include fever, chills, and
difficulties in breathing, tightness of chest and/or throat, upset stomach,
rash and headache. USFDA warned that RTX administration can result in
serious, including fatal infusion reactions such as deaths within 24 hours
of RTX infusion could occur. The European Medicines Agency (EMA) is
also aware of infusion-related reactions by RTX infusion.13

5.2.2 Safety Data from National Adverse Drug Monitoring Centre, National
Pharmaceutical Control Bureau (NPCB), Ministry of Health, Malaysia

In Malaysia, there are three strengths of RTX products registered in

Malaysia by Roche (Malaysia) Sdn Bhd. They are 100mg/10mL,
500mg/50mL, and 10mg/mL concentrate for solution for infusion. Since
registered in Malaysia until August 2011, the National Adverse Drug
Monitoring Centre received 33 reports on RTX with 58 adverse events.
Some of the adverse events included erythema, itching, rash, urticaria,
giddiness, abdominal pain, hepatic enzymes increased, bronchospasm,
wheezes, acute renal failure, chest discomfort, and oedema periorbital.
Two deaths were also reported to the National Centre of ADR where the
onset of the reactions was 5 minutes and the onset of the other case was
unknown.13

5.3 COST/COST-EFFECTIVENESS

No cost-effectiveness study was found on use of RTX in treatment of

autoimmune neurological disorders. However, the price is about RM4000
to RM4500 per vial depending on the strength of vial.

5.4 LIMITATIONS

This technology review has several limitations. The selection of studies

was done by one reviewer. Although there was no restriction in language
during the search but only English full text articles were included in this
report. Any abstracts without a full text articles were also excluded. Some
of the studies were conducted retrospective instead of prospective.
Besides that, most of the studies included involved patient with small
sample size.

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6. CONCLUSION

There was limited fair level of evidence retrieved to show that rituximab
was effective and safe in treatment of autoimmune neurological disorders
(MG, NMO, MS and OMS). However there were adverse events reported.
No cost-effectiveness study on rituximab in treatment of autoimmune
neurological disorder was retrieved.

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8. REFERENCES

1. Rituximab. http://en.wikipedia.org/wiki/Rituximab Accessed on 18 January

2012.
2. Pellkofer HL, Krumbholz M, Berthele A et al. Long-term Follow-up of
Patients with Neuromyelitis Optica After Repeated Therapy with
Rituximab.
3. Postmarket Drug Safety Information for Patients and Providers.
www.fda.gov Accessed on 23 August 2011.
4. Dalakas MC. B Cells As Therapeutic Targets In Autoimmune Neurological
Disorders. Nature Clinical Practice Neurology. 2008;4(10):557-567.
5. Wood AM. Rituximab. American Society of Health-System Pharmacists.
2001; 58(3) Available at www.medscape.com Accessed on 30 April 2012.
6. http://www.rituxan.com/hem/hcp/mechanism-action/index.html Accessd on
19 January 2012
7. Hauser SL, Waubant E, Arnold DL et al. B-cell Depletion with rituximab in
Relapsing Remitting Multiple Sclerosis. The New England Journal of
Medicine. 2008; 358:7.
8. Petereit HF and Rubert-Roth A. Rituximab Levels in Cerebrospinal Fluid of
Patients with Neurological Autoimmune Disorders. Multiple Sclerosis.
2009;15:189-192.
9. Pranzatelli MR, Tate ED, Travelstead AL. et al. Immunologic and Clinical
Responses to Rituximab in a Child with Opsoclonus-Myoclonus
Syndrome. Pediatrics. 2005;115:e115-e119.
10. Jacob A, Weinshenker BG, Violich I. et al. Treatment of Neuromyelitis
Optica with Rituximab: Retrospective of 25 Patients. Arch Neurol. 2008;
65(11):1443-1448.
11. Tony HP, Burmester G, Schulze-Koops H et al. Safety and Clinical
Outcomes of Rituximab Therapy In Patients with Different Autoimmune
Disease: Experience From a National Registry (GRAID). Arthritis
Research & Therapy. 2011;13:R75.
12. Brown BA and Torabi M. Incidence of Infusion-Associated Reactions with
Rituximab for Treating Multiple Sclerosis: A Retrospective Analysis of
Patients Treated at a US Centre. Drug Saf. 2011; 34(2):117-123.
13. Safety Profile of Rituximab. National Pharmaceutical Control Bureau,
Malaysia. Ruj. Kami: Bil(28)dlmBPFK/FV/1-14. 31 Januari 2012
14. Autoimmune Disease. http://en.wikipedia.org/wiki/Autoimmune_disease
Accessed on 18 January 2012
15. Rituximab. http://en.wikipedia.org/wiki/Rituximab Accessed on 18 January
2012.

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9. APPENDIX

9.1. Appendix 1: LITERATURE SEARCH STRATEGY

Ovid MEDLINE In-process & other Non-Indexed citations and

OvidMEDLINE 1948 to present

1. Antibodies, Monoclonal/
2. monoclonal antibod$.tw.
3. antibod$ monoclonal.tw.
4. Antibodies, Monoclonal, Murine-Derived/
5. monoclonal antibod$ murine-deriv$.tw.
6. murine-deriv$ monoclonal antibod$.tw.
7. antibod$ murine-deriv$ monoclonal.tw.
8. antibod$ monoclonal murine-deriv$.tw.
9. murine deriv$ monoclonal antibod$.tw.
10. Nervous System Diseases/
11. (nervous system adj (diseas$ or disorder$)).tw.
12. (disorder$ adj (neurologic$ or nervous system)).tw.
13. diseas$ nervous system.tw.
14. (neurologic$ adj (disorder$ or diseas$)).tw.
15. "Autoimmune Diseases of the Nervous System"/
16. (neurologic autoimmune adj (diseas$ or disorder$)).tw.
17. diseas$ neurologic$ autoimmune.tw.
18. ((immune diseas$ or autoimmune disorder$ or immune disorder$) adj2
(neurologic or nervous system)).tw.
19. autoimmune nervous system diseas$.tw.
20. (nervous system adj (autoimmune or immune) adj2 (diseas$ or
disorder$)).tw.
21. autoimmune diseas$ neurologic$.tw.
22. Central Nervous System Diseases/
23. (central nervous system adj (diseas$ or disorder$)).tw.
24. cns diseas$.tw.
25. 1 or 2 or 3
26. 4 or 5 or 6 or 7 or 8 or 9
27. 10 or 11 or 12 or 13 or 14
28. 15 or 16 or 17 or 18 or 19 or 20 or 21
29. 22 or 23 or 24
30. 25 and 27
31. 25 and 28
32. 25 and 29
33. 26 and 27
34. 26 and 28
35. 26 and 29

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OTHER DATABASES
EBM Reviews - Cochrane Central Same as above
Register of Controlled Trials
EBM Reviews - Cochrane database Same as above
of systematic reviews
EBM Reviews - HTA Same as above
PubMed Rituximab
INAHTA Rituximab
FDA Rituximab, rituximab for autoimmune
neurological disorder, rituximab for
autoimmune disorders

9.2. Appendix 2

HIERARCHY OF EVIDENCE FOR EFFECTIVENESS STUDIES

DESIGNATION OF LEVELS OF EVIDENCE

I Evidence obtained from at least one properly designed randomized

controlled trial.

II-I Evidence obtained from well-designed controlled trials without

randomization.

II-2 Evidence obtained from well-designed cohort or case-control analytic

studies, preferably from more than one centre or research group.

II-3 Evidence obtained from multiple time series with or without the
intervention. Dramatic results in uncontrolled experiments (such as the
results of the introduction of penicillin treatment in the 1940s) could also
be regarded as this type of evidence.

III Opinions or respected authorities, based on clinical experience;

descriptive studies and case reports; or reports of expert committees.

SOURCE: US/CANADIAN PREVENTIVE SERVICES TASK FORCE (Harris

2001)

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