No medications have yet been approved by the U.S. Food & Drug Administration to treat Sjögren’s disease (SjD). So as rheumatologists, we are often challenged to think outside the box, and thinking outside of the box often means prescribing outside the box. But what’s the most thoughtful and effective way to do this? We can rely on clinical practice guidelines from the ACR and EULAR when available, review the available evidence (although the pickings are sometimes slim) and/or phone a friend.
For this article, I phoned two friends, both of whom are SjD experts at the Penn Sjögren’s Center: Chadwick R. Johr, MD, associate professor of medicine and Dana DiRenzo, MD, MHS, assistant professor of medicine, both at the Perelman School of Medicine, University of Pennsylvania, Philadelphia. They provide a tips for navigating the therapeutic challenges of SjD.
Fatigue, Myalgia & Arthralgias
Fatigue remains one of the most debilitating and frustrating symptoms for patients with SjD, often rivaling dryness in its impact on quality of life.
Dr. Johr
Dr. Johr begins with a comprehensive assessment to identify modifiable and treatable contributors. “I rule out obstructive sleep apnea in patients for whom I have a suspicion (e.g., patients with obesity, snoring or morning headaches),” he says. “I think about restless leg syndrome as well because this impedes sleep and causes fatigue. I check ferritin levels and treat with iron supplements if ferritin is low—even if the patient isn’t anemic—because I’ve seen this help a lot of patients. I treat vitamin B12 deficiency and thyroid disease when present, and I evaluate for depression.”
Beyond modifiable contributors, Drs. Johr and DiRenzo both advocate for non-pharmacologic management techniques often used to treat people with fibromyalgia. “I focus on the four pillars of health: mental health, diet, exercise and sleep,” says Dr. DiRenzo.
As for medications, both Drs. Johr and DiRenzo sometimes prescribe low-dose naltrexone (LDN), despite the availability of limited trial data. LDN requires a compounding pharmacy, so the patient needs to have insurance that covers this. Dr. Johr notes, “It’s not evidence-based, yet many of my patients report real benefits, and a lot of physicians in SjD circles are using it.” Dr. DiRenzo echoes these sentiments, noting that a lot of her patients like it, too.
When it comes to hydroxychloroquine, Drs. Johr and DiRenzo differ in their approach. Dr. Johr will try it to see if it helps because it’s a relatively low-risk drug, especially when used for a six- to 12-month trial period, and some patients seem to truly benefit (as noted in a subgroup analysis, retrospective cohort data, and his own observations).1,2 Dr. DiRenzo, on the other hand, doesn’t use it since two clinical trials have shown a lack of benefit when it comes to fatigue or aches.3,4
Inflammatory Arthritis
When SjD patients present with inflammatory arthritis, Dr. DiRenzo uses a combination of leflunomide and hydroxychloroquine, citing supportive data from a 2020 Lancet Rheumatology article.5 Methotrexate is also an option for those with significant joint involvement.
Dr. DiRenzo
Biologics are reserved for refractory cases of inflammatory arthritis. “If there are prominent glandular symptoms in addition to inflammatory arthritis and they haven’t responded to disease modifying anti-rheumatic drugs (DMARDs), anti-CD20 therapy like rituximab is a good choice,” explains Dr. DiRenzo.
“Tumor necrosis factor inhibitors can be a good option for synovitis when glandular symptoms don’t predominate,” adds Dr. Johr.
Dry Eye
When it comes to dry eye, both Drs. Johr and DiRenzo first stress the importance of co-managing with ophthalmology and obtaining an ocular staining sore (OSS) to understand how severe the dryness is.
“If possible, have the patient see a dry eye expert with a specific interest and expertise in dryness,” Dr. Johr notes.
Most of us know enough to recommend eye drops, such as preservative-free, single-use artificial tears, or prescription drops, such as cyclosporine or lifitegrast ophthalmic solutions. But what can we do as rheumatologists when those aren’t enough?
“A lot of patients don’t use thicker artificial tears (eye lubricants) at night, so that’s an easy place to start. Omega-3 fatty acid supplements are controversial since data for them is mixed, but our cornea specialists here at Penn find them helpful,” says Dr. Johr. “Intranasal varenicline has recently been approved by the FDA for dry eye, but a lot of people don’t know about it. There are no contraindications, but it’s expensive and and causes a lot of sneezing when first used.”
“A short course of steroid drops can accelerate healing in severe cases of dry eye, too,” says Dr. DiRenzo.
As for differential diagnosis, Dr. DiRenzo noted, “There’s an outstanding New England Journal of Medicine review on dry eye, and SjD only makes up a small portion of the causes.6 A more common cause is meibomian gland dysfunction, which is allergy driven. When allergies flare up, they clog the meibomian glands that make oil by the lash line. This oil is needed to make good tears—without it, tears evaporate too quickly, leading to dry eye. This is the cause of dry eye for many people, and there’s a specific treatment for this. Ophthalmologists can use perfluorohexyloctane ophthalmic solution [i.e., Miebo], allergy medications and warm compresses.”
Dry Mouth
Managing xerostomia remains a challenge, particularly when patients don’t respond to over-the-counter agents or cholinergic agonists like pilocarpine or cevimeline. However, Dr. Johr notes the maximum dose of pilocarpine (30 mg daily) is often underused.
He also encourages patients to think beyond simply sipping water. “If your skin were dry, you wouldn’t just repeatedly wet it with water—you’d use an emollient. It’s the same for the mouth. Patients can try artificial saliva sprays or oil pulling. Green tea may help. It’s also important to avoid medications that worsen dryness.”
Interstitial Lung Disease
For patients with Sjögren’s-related interstitial lung disease (SjD-ILD), the 2023 ACR guidelines (see p. 18) serve as a management framework. Drs. Johr and DiRenzo both follow these. They stress the importance of collaboration with pulmonologists, especially as anti-fibrotic therapies become more common.
“Recent pulmonary literature demonstrates the ILD patients at especially high risk of developing respiratory failure are those with progressive pulmonary fibrosis,” says Dr. Johr. “I keep an eye out for such patients and consider adding an antifibrotic agent in those who don’t respond to initial therapy as recommended in the Consensus Guidelines for the Evaluation and Management of Pulmonary Disease in SjD published in Chest in 2021.”7
Neuropathy
Sensory neuropathy is underappreciated and highly variable feature of SjD. “When it comes to sensory neuropathy, a lot depends on the timing,” says Dr. DiRenzo. “What’s the tempo of it? If it’s not rapidly progressive, treat the symptoms with neuropathic pain medications. If quickly progressing, think about a skin biopsy to look for evidence of vasculitis as a driver. If vasculitis is present, consider immunomodulation.”
“I offer alpha-lipoic acid for milder cases,” says Dr. Johr.
Autonomic neuropathy presents its own challenges. “LDN may help. But in cases of significant dysfunction,” says Dr. Johr, “I consider intravenous immunoglobulin (IVIG). I tell the patient that the evidence behind it isn’t strong, counsel them on the potential risks and warn them that insurance often won’t cover the costs. This is where shared decision making comes in. I find that most patients who are significantly debilitated from their neuropathy are open to it.”
Of note, the Sjögren’s Foundation is slated to release guidelines for neurologic manifestations of SjD later this year.
Cutaneous Manifestations
For rashes in SjD, Dr. DiRenzo uses hydroxychloroquine, and escalates to mycophenolate mofetil if needed. Dr. Johr notes that methotrexate and quinacrine are also options.
Leukocytoclastic vasculitis (LCV) should prompt a deeper look. “LCV rarely occurs in isolation in SjD,” Dr. DiRenzo notes. “Screen for cryoglobulins, high immunoglobulin or a possible hematologic malignancy driving it.”
New Drugs, New Hope
After years of no trials in sight, the SjD drug development landscape is finally shifting. Nine drugs have entered phase 2 and phase 3 trials.8 One investigational agent generating buzz is dazodalibep, a CD40 ligand antagonist (see p. 21). “Dazodalibep has me very excited,” Dr. Johr says. “Not only did it reduce disease activity, but it improved symptoms. And that’s what our patients want—to feel better,” he concludes.
Conclusion
Treating SjD requires creativity, empathy, nuance and a patient-centered approach. In the absence of FDA-approved therapies, we must blend evidence-based medicine with empiric strategies and shared decision making. And we’ve got to stay tuned. Believe it or not, targeted SjD drugs are coming to a clinic near you … soon.
Samantha C. Shapiro, MD, is a clinician educator who writes for both medical and lay audiences, and practices telerheumatology.
References
- Collins A, Lendrem D, Wason J, et al. Revisiting the JOQUER trial: Stratification of primary Sjögren’s syndrome and the clinical and interferon response to hydroxychloroquine. Rheumatol Int. 2021 Sep;41(9):1593–1600.
- Demarchi J, Papasidero S, Medina MA, et al. Primary Sjögren’s syndrome: Extraglandular manifestations and hydroxychloroquine therapy. Clin Rheumatol. 2017 Nov;36(11):2455–2460.
- Gottenberg JE, Ravaud P, Puéchal X, et al. Effects of hydroxychloroquine on symptomatic improvement in primary Sjögren syndrome: The JOQUER randomized clinical trial. JAMA. 2014 Jul 16;312(3):249–258.
- Kruize AA, Hené RJ, Kallenberg CG, et al. Hydroxy-chloroquine treatment for primary Sjögren’s syndrome: A two year double blind crossover trial. Ann Rheum Dis. 1993 May;52(5):360–364.
- van der Heijden EHM, Blokland SLM, Hillen MR, et al. Leflunomide-hydroxychloroquine combination therapy in patients with primary Sjögren’s syndrome (RepurpSS-I): A placebo-controlled, double-blinded, randomised clinical trial. Lancet Rheumatol. 2020 May;2(5):e260–e269.
- Clayton JA. Dry eye. N Engl J Med. 2018 Jun 7;378(23):2212–2223.
- Lee AS, Scofield RH, Hammitt KM, et al. Consensus guidelines for evaluation and management of pulmonary disease in Sjögren’s. Chest. 2021 Feb;159(2):683–698.
- St Clair EW. Living with Sjögren disease: Prospects for disease-modifying therapies. Arthritis Rheumatol. 2025 May;77(5):499–502.
