Effectiveness of Rituximab Treatment in Primary Sjogren’s

Syndrome

A Randomized, Double-Blind, Placebo-Controlled Trial

ARTHRITIS & RHEUMATISMARTHRITIS & RHEUMATISM

Vol. 62, No. 4, April 2010Vol. 62, No. 4, April 2010

Study Eligibility• Inclusion criteria:

– >18yr– American-European consensus group criteria for

primary sjogren syndrome– Rate of secretion of stimulated whole saliva

>0.15ml/min– Positive Anti –SSA and or Anti SSB– Positive IgM RF– Positive salivary gland biopsy within last 12 months– Contraception through entire duration– No DMARDS 1-6 months prior to study– Baseline echo and cxr

• Exclusion criteria– Prior failure to Rituximab– Chronic systemic illness, malignancy, immune

dysfunction, chronic or latent infection

Drug AdministrationDrug Administration

• 20 patients in study group and 10 patients in placebo arm

• 1,000mg Rituximab infusion on day 1 and day 15• Pretreatment

– Methylprednisolone 100mg IV, acetaminophen 1000mg orally and clemastine (non selective H1 blocker) 2mg IV

– Prednisone 60mg on days 1,2,3– 30mg on days 3 and 4 – 15mg on days 5

• Artificial eye drop and saliva on same dose

Outcome Meaures

• Primary end point– Significant improvement in the secretion

of stimulated whole saliva flow rate (ml/min)

• Secondary end point– Assessment of salivary gland function– Immunologic parameters– Subjective response parameters

• Assessment scheduled at baseline, 5, 12, 24, 28 weeks

Determination of Salivary and Lacrimal Function

• Quantitative measurement of whole saliva, parotid, submandibular/sublingual saliva

• Tested at same time (1-4pm), unstimulated saliva collected in cups and syringes for 5 minutes

• 10 minutes stimulation with 2% citric solution• Flow rate and composition by standardized

method( not discussed)• Schrimer’s test I, Lissamine green test and 1%

Fluorescien Breakup time( BUT)

Lissamine green test

• Instillation of 1% lissamine green in both eyes

• After 1 or 2 full blinks, the intensity of staining of both medial and lateral bulbar conjunctiva and the cornea was scored

• maximum score of 9 points (up to 3 points for each section)

• 1 sparsely scattered, 2 densely scattered, 3 confluent

Fluorescien Breakup time (BUT)

• Interval between a complete blink and the appearance of the first randomly distributed dry spots

• Assessed by instilling a 1% fluorescein solution in the fornix of both eyes

• The patient was asked to blink a few times, after which the interval in

• seconds between the last blink and the first break in the tear film was measured

Patients with a tear-film breakup time of less than five seconds can be diagnosed with dry eye

Laboratory and subjective assessment

• CBC, Immunoglobulins, IgM-RF• Circulating CD19, CD4, CD8 B cells• Multifunctional Fatigue inventory• Oral and ocular sicca VAS 100mm• Extra glandular manifestations reported as present or

absent• Serum sickness: low complements, Dec PLTS and

arthritis after infusions• Termination if Serum sickness in 2/9 after 1St and

3/29 after 2nd infusion• Compared form baseline from the same cohort and

from other arm

Randomization of patients with primary sjogren syndrome

† P <0.05 versus placebo.

Results: Salivary Gland function

• Primary end point: compared to baseline had statistially significant improvement @5 weeks (P=0.01) and @ 12 weeks (P=0.004)

• These values decreased in placebo arm (progression of disease)• Mean change from baseline in the group was significant (P=0.038)• Submandibular/sublingual flow rate significantly increased ( data

not shown)

Lacrimal Gland function

Changes in Laboratory variables

•Mean change in RF ; P< 0.05)•Same patterns of change for Immunoglobulins•Significant change in the MFI score, and improvement in SF 36 scores

Changes in Subjective measurement

Changes in sicca symptoms

SF36 score for vitality and MFI for fatigue

Extra glandular manifestations

Significant decrease several extra glandular manifestations

• Vasculitis @ 24 week (P=0.03)• Reynaud's (P= 0.057)• Tendomyalgia (P=0.074)• Arthralgia (P = 0.058)• Neuropathy and arthritis improved

Adverse events

Discussion