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Randomized trial of methotrexate versus hydroxychloroquine to reduce systemic disease activity in adults with moderate‑to‑severe primary Sjögren’s disease

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What is this trial about?

A plain-language summary of the goals, design and what participants do

The trial examines primary Sjögren’s disease, a condition where the body’s moisture‑producing glands become less active, causing dry eyes and mouth. The study compares two medicines: methotrexate, given by injection under the skin, and hydroxychloroquine, taken as tablets. The purpose is to find out which medicine better lowers overall disease activity.

Adults with moderate‑to‑severe disease are assigned randomly to one of the two groups and receive the assigned medication for about a year and a half, with regular clinic visits to check health and safety. The main way effectiveness is measured is a score called ESSDAI, which rates how many parts of the body are affected. Additional assessments include a questionnaire called ESSPRI that asks about symptoms such as pain and fatigue, measurement of how much saliva is produced, and a score called DAS28‑CRP that looks at joint inflammation using a blood test for C‑reactive protein. Participants continue the assigned treatment unless a doctor decides it must be stopped.

The research process

The trial runs in 7 steps – from screening to follow-up. Each step says what happens and what the team monitors.

  1. Step 1

    Randomization and Assignment to Treatment Group

    After enrollment, you will be randomly placed into one of two groups. One group receives methotrexate, the other receives hydroxychloroquine. The assignment is made by the study staff and you will be informed which medication you will take.

  2. Step 2

    Start of Study Medication

    If you are assigned to the methotrexate group, you will begin receiving a subcutaneous injection of 2.14 mg methotrexate. The injection is given using a pre‑filled syringe as directed by the study team.

    If you are assigned to the hydroxychloroquine group, you will begin taking an oral tablet containing 400 mg hydroxychloroquine sulfate. The tablet is taken by mouth according to the schedule given by the study team.

  3. Step 3

    Medication Administration Schedule

    You will continue the assigned medication for the entire treatment period, which lasts until Week 74 of the study. The exact frequency of each dose (for example, weekly or daily) will be explained by the study staff and recorded in your study diary.

  4. Step 4

    Regular Follow‑up Visits

    Throughout the 74‑week period, you will attend scheduled clinic visits. During each visit, the study team will evaluate your disease activity, safety, and any side effects.

    Assessments include the ESSDAI score (a measure of systemic disease activity), the ESSPRI score (a measure of patient‑reported symptoms), salivary flow measurements, and the DAS28‑CRP score (a measure of joint inflammation).

  5. Step 5

    Mid‑study Evaluations

    At predetermined times before Week 74, you will undergo additional evaluations to monitor changes in disease activity and to ensure the medication is well tolerated.

  6. Step 6

    Final Assessment at Week 74

    At Week 74, a final study visit will be performed. The primary outcome is the change in the ESSDAI score from the start of the study to this visit.

    Secondary outcomes, such as changes in the ESSPRI score, salivary flow, and DAS28‑CRP score, will also be recorded.

  7. Step 7

    Study Completion

    After the final assessment, your participation in the trial ends. The study team will discuss any further medical care you may need.

Who can join the trial?

8 criteria

  • You must be at least 18 years old but younger than 75 years when you sign the consent form.
  • You need to have a confirmed diagnosis of primary Sjögren’s disease that meets the 2016 ACR/EULAR Classification Criteria (these are official guidelines doctors use to be sure the diagnosis is correct).
  • You must have moderate to severe disease activity, shown by an ESSDAI score of 5 or higher. ESSDAI is a number that doctors use to measure how active the disease is throughout the body; a score of 5 means the disease is affecting you more than mildly.
  • You must test positive for anti‑SSA/Ro antibodies (these are special proteins in the blood that are often present in people with Sjögren’s disease).
  • You need to still have some saliva production, measured as a stimulated whole salivary flow greater than 0.1 mL per minute. This means your salivary glands can still make a small amount of saliva when stimulated.
  • If you are already taking medicines for Sjögren’s disease, your treatment must be stable (the dose has not changed recently) before the screening and should stay the same during the study unless a safety issue requires a change.
  • You must be able and willing to sign a written consent form and follow the study’s procedures.
  • If you are a woman who could become pregnant, you must agree to use a highly effective method of birth control during the study and for a set time after the last dose of the study medication.

Who cannot join the trial?

16 criteria

  • Having another systemic autoimmune disease (a condition where the immune system attacks the body’s own organs) that could confuse the study results.
  • Receiving a live attenuated vaccine (a vaccine that contains a weakened germ) within the last 4 weeks or planning to get one during the study.
  • Being pregnant, breastfeeding, or planning to become pregnant while in the study.
  • Having current or past serious eye problems such as maculopathy (damage to the central part of the retina) or retinopathy (damage to the retina) from any cause, which could hide eye side effects of the study drug.
  • Having significant interstitial lung disease (a group of lung disorders that cause scarring) or active pulmonary fibrosis (hardening of lung tissue) that needs ongoing treatment.
  • Having had lung inflammation (pneumonitis) caused by methotrexate or a similar drug reaction.
  • Having an active hepatitis B infection (positive hepatitis B surface antigen test).
  • Having an active hepatitis C infection (positive hepatitis C antibody with detectable virus in the blood).
  • Participating in another clinical trial of a new treatment within the past 30 days.
  • Having any other health condition that the doctor believes could make the study unsafe or affect the results.
  • Having a history of lymphoproliferative disease (a disorder where certain white‑blood cells grow excessively) or an active cancer, except for small cancers that have been fully treated.
  • Having serious cardiovascular (heart), pulmonary (lung), renal (kidney), or neurological (nervous system) disease that could interfere with the study.
  • Having an active or severe infection, including ongoing or repeated infections, or testing positive for HIV, hepatitis B or C, or tuberculosis.
  • Having major laboratory abnormalities at screening, such as liver problems, low blood cell counts (cytopenias), or poor kidney function.
  • Being known to have an allergy (hypersensitivity) to methotrexate or hydroxychloroquine, or having reasons why these medicines should not be used.
  • Taking prohibited immunosuppressive or biologic therapies, or having taken high‑dose corticosteroids (15 mg or more of prednisone each day) within the last 6 weeks.
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Investigated drugs

  • Methotrexate

    is a medication that works by suppressing the activity of the immune system. In this study it is given by injection under the skin and is being tested to see if it can lower the overall disease activity in people with moderate‑to‑severe primary Sjögren’s disease. Participants receive methotrexate for the full 74‑week treatment period, and the researchers will compare how much their disease scores improve compared with the other treatment group.

  • Hydroxychloroquine

    is an oral tablet that also modifies the immune system, but in a different way from methotrexate. In the trial it serves as the comparison treatment for participants with the same type and severity of Sjögren’s disease. Patients take hydroxychloroquine for the same 74‑week period, allowing the study team to evaluate whether it reduces disease activity as effectively as methotrexate.

What is already known about the treatment

  • Methotrexate

    Methotrexate is given as a subcutaneous injection of a clear solution in a pre‑filled syringe. It is an established drug that has been used for many years to treat autoimmune diseases such as rheumatoid arthritis and psoriasis. It works by blocking a step in the folic‑acid pathway, which slows down the growth of immune cells that cause inflammation. It belongs to the class of disease‑modifying antirheumatic drugs (DMARDs) known as antimetabolites.

  • Hydroxychloroquine

    Hydroxychloroquine is taken orally as a coated tablet. It is a long‑standing medication used for malaria prevention and for autoimmune conditions like lupus and rheumatoid arthritis. It works by raising the internal pH of certain cells and interfering with signals that activate the immune system, which reduces inflammation. It is classified as an antimalarial drug with immunomodulatory properties.

Investigated diseases

Primary Sjögren’s disease - Primary Sjögren’s disease is a chronic autoimmune condition that primarily targets the moisture‑producing glands. It leads to persistent dryness of the eyes and mouth and may cause swelling of the salivary glands. Over time, the immune attack can spread to other organs such as joints, lungs, kidneys, and nerves, producing a range of systemic symptoms. The disease often develops gradually, with symptoms worsening as glandular function declines. Some patients experience increasing fatigue, joint pain, and occasional skin rashes as the condition advances. The course varies, but many individuals notice a steady accumulation of extra‑glandular manifestations.
Trial detailsLast updated 17 Oct 2026
Age18+ yearsPhasePhase IITrial ID2026-526767-38-00Protocol codeGR-2024-12379251Estimated enrolment70 patientsSponsorFondazione Policlinico Universitario Campus Bio-medico In Forma A Bbreviata Fon

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