Table 1 Eligibility criteria for randomisation into the TRACTISS trial

1

Aged between 18 and 80 years of age.

2

A confirmed diagnosis of primary Sjögren’s Syndrome by AECG criteria.

3

Positive for anti-Ro auto-antibodies.

4

Patients with a diagnosis of primary Sjögren’s Syndrome (by AECG criteria) with more than 10 years disease duration must have at least one systemic feature of:

  • Hypergammaglobulinaemia (IgG over 16)*, or

  • Low complement C4*, or

  • Cryoglobulinaemia

OR

  • Active/past history since diagnosis of the following (ascribed to Sjögren’s Syndrome):

    ○ Purpura/cutaneous vasculitis,

    ○ Lymphadenopathy,

    ○ Persistent parotid salivary gland swelling not due to infection,

    ○ Peripheral neuropathy (previously documented by nerve conduction tests),

    ○ Interstitial lung disease confirmed by HRCT,

    ○ Renal tubular acidosis requiring treatment,

    ○ CNS disease ascribed to Sjögren’s syndrome (confirmed by MRI),

    ○ Myositis (CPK>2N and EMG or biopsy evidence of myositis),

    ○ Inflammatory arthritis

5

An unstimulated salivary flow rate greater than 0 ml in 15 minutes.

6

Symptomatic oral dryness (≥ 5/10 on patient-completed Likert**).

7

Symptomatic fatigue (≥ 5/10 on patient-completed Likert**).

8

Patients on corticosteroids, NSAIDS, antidepressants, DMARDs (e.g. methotrexate, hydroxychloroquine, azathioprine, MMF, leflunomide, ciclosporin etc.), or pilocarpine*** must have been on a stable dose for 4 weeks prior to receiving the first infusion of study medication and expected to remain on this dose throughout the study. If they have stopped any of these drugs they should have been off it for at least 4 weeks prior to receiving study medication.

9

Given their written informed consent to participate in the trial and expected to be able to adhere to the study visit schedule and other protocol requirements.

*Anti-Ro antibody test, IgG, RF and C4 assays performed within 6 months of screening may be used to confirm eligibility. If greater than 6 months repeats should be performed locally at screening to confirm eligibility.

**LIKERT range 0-10 with 10 corresponding to worst severity.

***Pilocarpine or drugs with similar pharmacological action should not be used within 12 hours of the assessment visits at screening, baseline, week 16, week 24, week 36 and week 48 (end of study).

Exclusion criteria

Patients will be excluded from the trial for the following reasons:

1

Diagnosis of secondary Sjögren’s Syndrome.

2

Pregnancy, lactation or women of child-bearing potential (WCBP) unwilling to use medically approved contraception whilst receiving treatment and for 12 months after treatment has finished.

3

Men whose partners are of child-bearing potential but who are unwilling to use appropriate medically approved contraception whilst receiving treatment and for 12 months after treatment has finished.

4

Patient has active or prior hepatitis B or C, known HIV positivity or known history of tuberculosis.

5

Immunodeficiency or neutropaenia <1.5 × 10⁹/l (unless a diagnosis of benign ethnic neutropaenia has been confirmed in which case the neutrophil count must be > 0.9 × 109/l at screening for Jamaican and Afro-Caribbean populations [16]).

6

Any AECG exclusion criteria not covered elsewhere (graft versus host disease, primary lymphoma excluding PSS, sarcoidosis).

7

Any malignancies that would normally preclude the use of rituximab within the past 5 years, including solid tumours, haematological malignancies and carcinoma in situ (except basal cell or squamous cell carcinoma of the skin that has been excised and cured).

8

Participation in a clinical study involving administration of an investigational drug within the past 4 weeks prior to the first infusion.

9

A history of major surgery within 3 months prior to first infusion or planned surgery during the study.

10

Receipt of live/attenuated vaccine within 4 weeks prior to the first infusion.

11

Previous exposure to rituximab or any other monoclonal antibody within the past 5 years.

12

History of recurring or chronic infections or underlying conditions which may further predispose patients to serious infection.

13

History of moderate to severe congestive heart failure according to the New York Heart Association (NYHA) functional classification system or other uncontrolled heart disease, or who have a clinically significant abnormal ECG at the time of screening.

14

History of receiving human/murine recombinant products or known allergy or anaphylactic reaction to a biologic agent or any component of the active substance or any of its excipients or murine components.

15

Patients with fibromyalgia or a diagnosis of significant depression or anxiety that in the opinion of the clinician would confound the interpretation of the study results.

16

Current or a history of severe, progressive or uncontrolled renal, hepatic, hematologic, gastrointestinal, endocrine, pulmonary, cardiac, neurologic, or cerebral disease (including demyelinating diseases such as multiple sclerosis).

17

Any history of organ transplant (with the exception of a corneal transplant >3 months prior to study entry).

18

Presence of a clinically significant illness or mental disorder within 4 weeks of the start of the trial where the safety of the individual might be at risk by entry into the trial, or where the individual does not have the capacity to consent or where the outcome of the therapy cannot be assessed by virtue of the illness or disorder. Each patient will be assessed individually and no person who wishes to participate will be unreasonably excluded by virtue of the illness or disorder.