CE / CME
Physician Assistants/Physician Associates: 1.00 AAPA Category 1 CME credit
Nurse Practitioners: 1.00 Nursing contact hours, includes 1.00 hour of pharmacotherapy credit
Released: November 21, 2024
Expiration: November 20, 2025
2020 EULAR Recommendations for Sjögren’s Syndrome Management
Fortunately, we have now reached a stage in the management of Sjögren’s disease where practice guidelines are emerging. These guidelines, primarily based on expert opinion due to limited data available on Sjögren’s, are becoming a crucial part of disease management.
The first treatment recommendation, that patients be managed with a multidisciplinary approach, is logical given that Sjögren’s syndrome affects multiple organ systems, including the mouth, eyes, joints, kidneys, and lungs. Another common manifestation is peripheral neuropathy, necessitating a multidisciplinary approach to both diagnosis and management.25
A significant aspect of managing the disease involves symptomatic relief. For ocular symptoms, artificial tears and ointments are commonly prescribed, along with immunosuppressive eye drops such as cyclosporine. Similarly, artificial saliva can be helpful for managing oral dryness. Analgesics and anti‑inflammatory medications are often used to alleviate musculoskeletal pain. There are also medications designed to stimulate the production of saliva and tears, which may help reduce symptoms of dryness.
Patients are often advised to try these medications and continue them if it helps. However, if patients experience side effects such as tachycardia or excessive sweating, discontinuation is recommended, as the medications only address symptoms and have no disease‑modifying activity.25
In patients with severe extraglandular manifestations, systemic therapy, particularly glucocorticoids, may be required. Glucocorticoids should be used at the lowest effective dose and for the shortest possible duration. One of the most common indications for use of glucocorticoids in Sjögren’s syndome is skin vasculitis, where a short course may be necessary. Patients with arthritis may require disease-specific agents such as methotrexate.
For patients with severe disease, B-cell targeted therapies such as rituximab may be considered, although randomized trials of rituximab have failed to meet their primary endpoints. Nonetheless, rituximab may still be beneficial in selected patients.25
Hydroxychloroquine for Primary Sjögren’s Syndrome
Hydroxychloroquine is not traditionally considered an immunosuppressant, yet it remains the most commonly prescribed systemic therapy for patients with primary Sjögren’s disease. However, evidence supporting its efficacy is limited.
For instance, a randomized, double‑blind, placebo‑controlled trial demonstrated no significant effect of hydroxychloroquine on symptoms of Sjögren’s syndrome. That being said, there were several limitations to this trial, one of the most notable being its potentially insufficient duration, given hydroxychloroquine’s long pharmacokinetic profile and extended half-life.
However, a recent meta‑analysis showed some overall improvement with hydroxychloroquine, especially in terms of oral symptoms, for patients with Sjögren’s disease. Despite this, the effect of hydroxychloroquine remains moderate at best, underscoring the need for new disease‑modifying therapies for this patient population.26,27
Disease-Modifying Drug Candidates in Later-Stage Development
To this end, there is a strong, ongoing effort to develop disease‑modifying therapies for patients with Sjögren’s disease, resulting in a relatively long list of drugs that have completed phase II trials. Of note, all the agents currently in phase III trials are thought to mitigate Sjögren’s disease activity by modulating autoimmunity, albeit through different pathways. For example, dazodalibep is a CD40/L inhibitor, while telitacicept, ianalumab, and belimumab are BAFF inhibitors, but they are all thought to suppress autoimmunity by modulating T-cell and B-cell signaling. On the other hand, deucravacitinib is a JAK inhibitor that blocks inflammatory signaling.28-32
Some of these drugs are available in the United States, although they are not yet FDA-approved for treatment of Sjögren’s syndrome. For instance, belimumab is approved to treat lupus, and efgartigimod is approved to treat myasthenia gravis, whereas dazodalibep, telitacicept, ianalumab, and deucarvacitinib are new investigational agents.
Several of these drugs are recruiting for phase III trials for Sjögren’s disease and we anticipate results in the near future. If these trials demonstrate efficacy, we could see several of these drugs become available for treatment of Sjögren’s disease within the next few years.
Next, I will discuss the drugs from this list that completed phase II trials and are currently in phase III trials.
Dazodalibep in Primary Sjögren’s Syndrome
Dazodalibep is a CD40 ligand antagonist that blocks costimulatory signaling between T-cells, B-cells, and antigen-presenting cells. It is thought that blocking this interaction may help suppress autoimmunity in Sjögren’s syndrome.
To assess whether dazodalibep had any effect on treatment of Sjögren’s syndrome, investigators conducted a randomized, placebo-controlled, phase II trial. The trial’s primary endpoints were the change in ESSDAI and ESSPRI score from baseline to Day 169.
The study focused on a population with moderate disease activity (ESSDAI score ≥5) but also included patients with low disease activity who have a high symptom burden (NCT04078386).28
Dazodalibep: Primary Endpoint
Here are the results from this study. Population 1, represented on the left side, consisted of patients with high disease activity, who experienced a significant decrease in their ESSDAI score with dazodalibep, compared to placebo.
Population 2 included patients with a high symptom burden but lower disease activity, who demonstrated a significant decrease in their ESSPRI score. Although this population’s baseline disease activity scores were not as high as in the first population, these patients still demonstrated a meaningful reduction in their symptoms.
Overall, this phase II trial was successful, and investigators are now actively recruiting for a phase III trial.29
Telitacicept in Primary Sjögren’s Syndrome
Like dazodalibep, telitacicept also may suppress autoimmunity in Sjögren’s syndrome by blocking B-cell signaling, albeit via a different mechanism. Telitacicept is a fusion protein that inhibits BAFF and suppresses the development and survival of mature B-cells.
This drug was recently studied in a phase II, double‑blind, placebo‑controlled trial, focusing on patients with high disease activity (ESSDAI score ≥5). Patients were followed for 24 weeks and randomized to receive 1 of 2 different doses of the drug or placebo. The primary outcome was the change in ESSDAI score at 24 weeks, with additional assessments including various quality of life measures and the ESSPRI score (NCT04078386).28
Telitacicept: Primary Endpoint
This slide shows the change in disease activity, as quantified by ESSDAI score, after treatment with 2 different doses of telitacicept, compared to placebo.
The lower dose led to significant reduction in disease activity, with the average ESSDAI score decreasing from approximately 10 to 4, indicating a substantial improvement.
There was no significant increase in ESSDAI score observed with the higher dose of 240 mg. As a result, only the lower dose proceeded to phase III clinical trials. Investigators are in the process of recruiting patients for the upcoming phase III trial.28
Ianalumab in Primary Sjögren’s Syndrome
Like telitacicept, ianalumab is a BAFF inhibitor, although ianalumab is a monoclonal antibody rather than a fusion protein. In addition to blocking BAFF signaling, ianalumab also depletes B-cells expressing BAFF.
A phase IIb trial of ianalumab enrolled patients with Sjögren’s syndrome who had high disease activity (ESSDAI score ≥6) and were anti‑Ro positive.
Participants were randomized into 4 groups: 3 groups received different doses of ianalumab given subcutaneously, and 1 group received a placebo. Similar to the previous trial, the treatment duration was 24 weeks.
The primary endpoint was the change in ESSDAI score, with secondary endpoints including quality of life measures and salivary flow rate (NCT02962895).30
SC Ianalumab: Primary Endpoint
The data demonstrated a trend towards reduction in ESSDAI score over time, with a clinically relevant decrease in disease activity, as measured by the change in the ESSDAI score, at the highest dose.
In addition to decreased disease activity, stimulated salivary flow also numerically improved across all 3 dosing groups by Week 24, although investigators did not report statistical significance for this finding.
These findings are promising, as they suggest that ianalumab not only reduces extraglandular manifestations but also dryness by increasing salivary flow. A phase III trial is currently in progress.30
Belimumab + Rituximab in Primary Sjögren’s Syndrome
Next, I want to discuss the combination of belimumab and rituximab. Although clinical trials of rituximab alone for Sjögren’s syndrome failed to meet their endpoints, this drug is now under investigation in combination with belimumab.
Belimumab and rituximab are both monoclonal antibodies that are thought to suppress autoimmunity by reducing B-cell activity. However, belimumab is a BAFF inhibitor, while rituximab binds to CD20 on B-cells to promote cell death.
In a phase II trial, patients were randomized to receive either rituximab alone, belimumab alone, a combination of both, or a placebo. Participants were required to have moderately active disease based on the disease activity index, along with positive anti‑Ro or anti‑La antibodies.
The primary endpoint for this study was safety, given the potential risks associated with combining 2 biologics, such as increased immunosuppression and infection risk. The secondary endpoint to assess efficacy was the change in disease activity as measured by ESSDAI score (NCT02631538).
Sequential Belimumab With Rituximab for Sjögren’s Syndrome
With regards to the primary endpoint, investigators concluded that the safety profile of belimumab and rituximab combined was similar to that of each as a monotherapy.
In terms of efficacy, the investigators concluded there was a trend towards a decrease in disease activity as measured by ESSDAI, as illustrated on the left. The middle graph demonstrates a trend towards increased salivary flow, with the greatest numerical improvement observed in patients receiving both belimumab and rituximab.
However, there was no difference in ESSPRI score, indicating little change in symptoms of pain, fatigue, and dryness.
This combination of therapies is now advancing to a phase IV trial for Sjögren’s syndrome in adolescents.31
Deucravacitinib for Modulation of IFN Inflammatory Pathways
Lastly, I want to discuss deucravacitinib, a JAK inhibitor that downregulates inflammatory pathways.
Although this drug has not yet undergone phase II trials for Sjögren’s syndrome, the results of a phase II trial for systemic lupus erythematosus demonstrated remarkable reduction of interferon gene expression at all doses tested, with reductions of over 60% compared to baseline.
These findings suggest that deucravacitinib may also be effective in managing Sjögren’s syndrome, given the disease's close ties to interferon pathways. A phase III trial is currently recruiting to further assess its efficacy in patients with Sjögren's (NCT05946941).32,33
Conclusions
For many years, patients with Sjögren’s syndrome faced limited therapeutic options, especially when compared to those with other autoimmune diseases such as lupus, rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis.
Sjögren’s syndrome has been largely overlooked and treated as an orphan disease. However, with the emergence of new drugs and ongoing studies evaluating their efficacy in Sjögren’s—in terms of both reduced disease activity and reduced symptoms—the landscape is changing. I believe this will shift the approach to Sjögren’s syndrome, making early diagnosis and identification of active disease more achievable, ensuring patients receive the appropriate treatments.
I anticipate these developments will transform the management of Sjögren’s in the next few years.
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