UPDATED 01-15-2025
Hydroxychloroquine (HCQ, aka Plaquenil) is the primary systemic medication used to treat Sjogren’s. Even though Sjogren's is a serious systemic disease, studies about the effectiveness of HCQ in Sjogren's are limited and flawed. However, recent evidence has been building, showing an overall benefit for its use in Sjogren's. Many rheumatologists use HCQ routinely for Sjogren's; others almost never use it, citing a single, poorly designed research study, the JOQUER trial, as evidence that HCQ does not work for Sjogren's. I describe the problem with the JOQUER trial below and why it should not be used to guide HCQ use in Sjogren's. The safety of HCQ has been well established because of its routine use in systemic lupus erythematosus (SLE) and its occasional use in other rheumatic diseases such as rheumatoid arthritis (RA). The risk of not treating diseases must always be weighed against the risk of taking a medication. Some rheumatologists prescribe HCQ for most of their Sjogren’s patients. Others almost never use it, inappropriately telling their patients that HCQ does not work for Sjogren's. Others reserve it for sicker patients, which seems odd considering this core rheumatology principle: early treatment almost always results in better outcomes.
Treatment decisions should be made considering the entire range of treatment goals, including long term outcomes.
There are eight treatment goals for Sjogren’s:
1. Relieve symptoms
Until recently, Sjogren’s treatment has largely focused on managing sicca, even though patients usually name fatigue, pain, brain fog, and flu-like malaise as their top priorities for care. Other common symptoms that impact quality of life include chronic cough, neuropathies, dysautonomias, GI symptoms, headaches, sleep disturbance, and more.
2. Prevent disease flares
Stabilizing symptoms can prevent patients from spiraling into a lower baseline state.
3. Prevent progression and reduce the accumulation of damage
Progression includes the accumulation of damage from sicca, organ and nervous system involvement, vasculitis, lymphoma, etc. Lower rates of systemic involvement were seen in patients taking HCQ therapy versus those without HCQ therapy in a retrospective study of 284 Sjogren's patients (8).
4. Prevent complications
This means stopping complications and damage from happening in the first place.
5. Reduce mortality
SLE, RA, and Sjogren’s are related diseases that share overlapping features. All three are associated with early mortality, caused by both direct (complications) and indirect manifestations (comorbidities). Most Sjogren’s patients live a normal life span, but 10% die from direct disease complications. (30)
As is true of SLE and RA patients, Sjogren's patients have an increased risk of premature mortality. The impact of HCQ on Sjogren’s mortality has not been studied. HCQ reduces mortality in SLE by a remarkable 50%. (127)
6. Prevent, reduce, and manage comorbidities
Sjogren’s shares a number of serious comorbidities with other systemic inflammatory diseases. These include cardiovascular disease (strokes and heart attacks), diabetes thromboembolic events (blood clots), osteoporosis and others. HCQ has demonstrates benefits in each of these areas in SLE (126). HCQ appears to lower the risk of cardiovascular disease by lowering inflammation, cholesterol, blood sugar, and the tendency to form blood clots. Learn more about Sjogren's and heart health here.
HCQ use is associated with reduced risk of new onset diabetes mellitus in Sjogren's patients (133). One study showed a lower rate of Alzheimer's disease risk in older RA patients who take HCQ, but not in those who take methotrexate (239).
7. Improve pregnancy outcomes
SSA positive and APA (anti-phospholipid antibody) positive women are at increased risk for pregnancy complications. High risk pregnancy management, often including treatment with HCQ, is indicated in Sjogren’s patients who carry these antibodies.
8. Lower the risk of polyautoimmunity (having multiple autoimmune diseases)
At least half of Sjogren’s patients are diagnosed with one or more additional autoimmune diseases. There is some evidence that HCQ lowers the risk of acquiring additional autoimmune diseases (128).
With few, mostly inadequate, studies for Sjogren’s (129, 130), how do patients make a decision about whether or not to take HCQ?
The short answer, find a rheumatologist who is knowledgeable about Sjogren’s. An up-to-date, engaged rheumatologist will understand the limitations of current studies, and rely on the resources listed below when recommending HCQ for Sjogren’s.
1. Clinical practice guidelines (CPGs), which draw on the cumulative expertise of Sjogren’s specialists from all over the world. CPGs from multiple countries recommend HCQ treatment for many Sjogren’s patients (56, 57, 131, 132).
2. New research from several retrospective studies provide evidence that HCQ reduces Sjogren’s progression and complications (8, 60, 270).
3. Evidence of the beneficial impact of HCQ on comorbidities. HCQ use has been associated with lower diabetes risk and improved bone mineral density in Sjogren’s (133, 134), as well as reduced cardiovascular risks in patients with rheumatic diseases. (135)
4. Their own practical experience. Rheumatologists who treat a large number of Sjogren’s patients can’t help but notice that most appear to benefit from HCQ treatment, despite the lack of adequate studies.
Given the serious nature of Sjogren’s, why are so many patients left untreated with HCQ or any other systemic medication?
Many rheumatologists:
are disengaged with Sjogren’s and don’t take the disease seriously. Sjogren's is a serious systemic disease, and should be managed accordingly.
fail to recognize the importance improving long-term outcomes.
lack awareness that Sjogren’s shares many serious comorbidities in common with other systemic inflammatory diseases.
remain unaware that clinical practice guidelines exist, or do not use them.
are unfamiliar with the flaws and limitations of the few existing Sjogren’s treatment studies, including those on HCQ.
overestimate the risks of retinal damage from HCQ. NEW! A study tracked 4,677 Kaiser Permanente Northern California patients after starting HCQ and showed how low the absolute risk of retinal damage from HCQ use is. Just 125 patients developed retinopathy during 5 to 15 years of follow-up. This is a 2.6% risk (less than 3 in 100) over 5-15 years. (Years 1-5 are not monitored because the risk of retinal damage during the first 5 years is extremely low.)
Rheumatologists who tell patients that HCQ does not work often cite a single, flawed study, the JOQUER trial.
The JOQUER trial is flawed because the HCQ treatment arm was stopped at 6 months (136), an illogical endpoint given that it takes 6 months to reach steady state blood levels of HCQ. Sjogren's is a slowly progressive disease, and treating it with HCQ, a long-acting medication, for such a short period of time, is insufficient to determine it's impact on systemic manifestations, comorbidities, or symptoms. Furthermore, robust evidence requires larger, well-designed randomized controlled trials that follow patients over several years, not just six months. Even if the JOQUER trial had been better designed, a single study is never adequate to prove or disprove treatment outcomes.
NEW! Other studies show HCQ to be beneficial in Sjogren's.
This HCQ study from Japan was presented in a poster session at the 2022 EULAR* annual meeting. (*EULAR is the professional rheumatology organization in Europe.) While the study was small (26 patients) and did not include a control group, it did show a clear benefit of HCQ in Sjogren's at 8 and 52 weeks. Improvement at 52 weeks was greater than at 8 weeks, as would be expected for such a long-acting drug. This is the only prospective study of HCQ that goes beyond 6 months. This small study showed:
1. improved patient-reported symptom burden (but not for dryness), 2. lower IgG, a prognostic indicator (high IgG is a sign of disease activity), 3. lower ESSDAI (EULAR Sjogren's syndrome disease activity index), a measure of systemic disease activity used by researchers. Please see this page to learn about the ESSDAI.
A study by Demarchi et. al, (2017) of 221 Sjogren's patients (270) found that HCQ appears helpful in reducing at least some systemic manifestations.
"As it was demonstrated for RA and SLE, we found that arthritis was less frequent in patients on HCQ therapy. Unlike few previous reports, the same was found for fatigue, purpura, Raynaud phenomenon, and hypergammaglobulinemia."
There is a great need for HCQ studies that look at a wide range of Sjogren's outcomes over years, not months.
HCQ is a long-acting drug. Sjogren's is usually a slowly progressing disease. Meaningful outcomes require a 6-month induction period, monitoring patients for a wide variety of systemic manifestations, regardless of symptoms or SSA status, and a study duration of at least 3-5 years. Until this is done, there is no basis to say that HCQ does not work for Sjogren's.
“Clinical experience mandates HCQ as the DMARD of choice in pSS in the absence of other more potent options: it is generally well tolerated by patients, and has a known, manageable safety profile including proper follow-up by ophthalmologists.” ~ Robert Fox et al (129)
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