Sarah Schafer, MD
HCQ II - why treat Sjogren's? (updated 01-08-2023)
Updated: Jan 9
Hydroxychloroquine (HCQ, aka “Plaquenil”) is the primary systemic medication used to treat Sjogren’s. Rheumatologists vary greatly when it comes to HCQ and Sjogren’s. Some prescribe it for most of their Sjogren’s patients. Others almost never use it, telling their patients that it does not work. Others reserve it for sicker patients, which seems odd considering this core rheumatology principle: early treatment almost always results in better outcomes. The risk of not treating diseases must always be weighed against the risk of taking medications. HCQ is one of the safest rheumatologic treatments. It is routinely used for systemic lupus erythematosus (SLE), and occasionally for rheumatoid arthritis (RA) and other diseases. A small number of patients do have absolute contraindications.
Despite being common and serious, Sjogren’s research lags decades behind other rheumatic diseases. This means that treatment decisions are backed up by limited data. The clinical experience of rheumatologists with Sjogren’s expertise should not be underestimated. Treatment decisions should be made considering the entire range of treatment goals, including long term outcomes.
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). A study published in showed a lowered rated 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.
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)
Multiple studies show that HCQ improves all eight treatment goals for SLE, Sjogren's closest biologic cousin.
With few, mostly inadequate, studies for Sjogren’s (129, 130), how do patients make a decision about taking 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 these resources when recommending HCQ for Sjogren’s:
1. Clinical practice guidelines (CPGs). These 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 suggesting that HCQ reduces Sjogren’s progression and complications. (8, 60)
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 practice experience. Rheumatologists who treat a large number of Sjogren’s patients can’t help but notice that most appear to benefit from HCQ treatment. Rheumatologists would love to have better studies to confirm their clinical experience.
Given the serious nature of Sjogren’s, why are so many patients left untreated with HCQ or any other systemic medication?
1. are disengaged with Sjogren’s, and don’t take the disease seriously. Sjogren's is a serious systemic disease, and should be managed accordingly.
2.fail to recognize the importance improving of long-term outcomes.
3. lack awareness that Sjogren’s shares many serious comorbidities in common with other systemic inflammatory diseases.
4. remain unaware that CPGs exist, or do not use them to guide clinical decision making.
5. are unfamiliar with the flaws and limitations of the few Sjogren’s treatment studies, including hydroxychloroquine.
Rheumatologists who tell patients that HCQ does not work often cite a single, flawed study (the “JOQUER" trial)
Why is the JOQUER trial flawed?
The HCQ treatment arm was stopped at 6 months. (136) This study design makes no sense. Sjogren's is a slowly progressive disease. Treating it with a long-acting medication that takes many months to make an impact and then calling it ineffective is ludicrous. Six months is not enough time to address any of the eight treatment goals listed above, including symptom relief. Sjogren’s symptoms, complications, and damage tend to develop over long periods of time. A significant number of patients describe feeling symptom relief only after taking the medication for 9 months to a year. Others don't notice improvement, stop the drug, and then find out that it actually was helping their symptoms, especially fatigue and pain. This study is often touted for being (the only) large, prospective, well-designed, randomized controlled trial of HCQ in Sjogren's. Yet it does not follow treated vs. untreated patients over a time period that makes sense. It takes 6 months of treatment to achieve steady state blood levels of HCQ. That explains why some patients take longer than 6 months to notice symptomatic improvement. A "well-designed” study is not helpful when the wrong questions are asked. Sjogren’s patients deserve HCQ studies that follow patients over years, not months! Even if the right questions were asked, a single study is never adequate to prove or disprove treatment outcomes.
This HCQ study from Japan was presented in a poster session at the 2022 EULAR annual meeting. 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. EULAR is the professional rheumatology organization in Europe. 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.
There is a great need for HCQ studies that look at a wide variety of Sjogren's outcomes over years, not months. HCQ is the mainstay of treatment in Sjogren's, yet there are only two studies that follow patients over time, each with weaknesses. The 6 month JOQUER trial (see above) aborted HCQ treatment before it had a chance to take full effect. This study from Japan should be repeated with a larger sample size, control subjects, and follow patients for years, not months. Neither study tells us anything about the impact of HCQ on long-term disease progression, which is of the utmost importance. Researchers looking at whether HCQ reduces Alzheimer's disease in RA or multiple sclerosis progression designed their studies to account for the 6 months it takes for HCQ to reach steady state. Unlike the JOQUER trial, these studies take look at outcomes starting at 6 months, and continue to do this over 18 months-3 years. This is logical because at 6 months HCQ would not have much chance to have a significant impact (239).
Sjogren's researchers have failed to study HCQ in a meaningful way. HCQ is a long-acting drug. Sjogren's is usually a slowly progressing disease. Meaningful outcomes require: - 6 month induction period - evaluation for wide variety of features that includes screening asymptomatic patients for systemic features. - 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)
Next up: HCQ III- Practical considerations for HCQ treatment.