How can we ‘Think Outside the Box’ with Immunomodulation?

No medications have yet been approved by the U.S. FDA to treat Sjögren’s disease (SjD). That can feel discouraging, but it also opens the door for creativity and innovation. As rheumatologists, we often find ourselves thinking outside the box, and in SjD that means prescribing outside the box, often guided by what we know from science, experience, and emerging research.

Fortunately, we’re not without a compass. The ACR and EULAR have developed detailed practice guidelines that provide structure and safety around these decisions. They remind us that thoughtful care in SjD means understanding mechanisms, weighing risks and benefits, and tailoring therapy to each patient’s symptoms, organ involvement, and immune features.

The good news is that our toolbox is expanding. Over the past decade, studies have identified multiple immune pathways, particularly those involving B cells, interferons, and T-cell costimulation, that are now being targeted by both repurposed and novel therapies. Even if most studies to date are small or exploratory, every step brings us closer to personalized treatment strategies, and patients benefit when clinicians combine evidence, guidelines, shared decision-making, and careful monitoring to select therapies with the most biologic plausibility.

Most current late-stage trials in Sjögren’s target the B-cell and immune-interaction axis, including BAFF/BAFF-R blockade and CD40–CD40L interruption to quiet the overactive T–B cell dialogue in salivary glands. Others are exploring FcRn inhibitors, which lower autoantibody levels, and TYK2 inhibitors, which modulate type I interferon and cytokine signaling.

Below is a summary of the main immunomodulatory treatments that are currently available and its potential relevance to SjD. Again, these are not approved by the U.S. FDA to treat SjD. This summary is not intended to be comprehensive. It only includes agents that are approved for other indications and does not include agents only available in a clinical trial. Disclaimer: I am a full-time employee of Bristol Myers Squibb. All views expressed here are my own.

Conventional Synthetic DMARDs

Methotrexate – Inhibits folate metabolism and promotes adenosine release, reducing inflammation.
Key side effects: liver toxicity, cytopenias, lung inflammation, GI upset.
Relevance: Often considered for inflammatory arthritis in SjD, though controlled trial data are limited. Often considered when joint symptoms predominate.

Sulfasalazine – Modulates inflammatory cytokines. Mechanism unclear, but it is broken down to anti-inflammatory compounds sulfapyridine and mesalazine.
Side effects: GI upset, rash, cytopenias.
Relevance: Some consider limited benefit joint pain or arthritis; evidence base remains limited but safety profile is favorable.

Azathioprine – Inhibits purine synthesis, suppressing lymphocyte proliferation.
Side effects: bone-marrow suppression, liver toxicity, infection risk.
Relevance: Sometimes used for systemic disease or lung involvement; responses vary and intolerance is not uncommon.

Cyclosporine – Calcineurin inhibitor that blocks T-cell activation.
Side effects: kidney toxicity, hypertension, tremor, gum changes.
Relevance: Limited data, sometimes used with systemic features; also used topically for dry eyes.

Leflunomide – Inhibits pyrimidine synthesis (dihydroorotate dehydrogenase).
Side effects: liver toxicity, GI upset, teratogenicity.
Relevance: Shows immunologic activity in SjD in Phase II study when used with gydroxychloroquine and may benefit inflammatory joint disease.

Hydroxychloroquine – Modulates lysosomal activity and toll-like receptor signaling.
Side effects: GI upset, skin rash, retinal toxicity (rare and dose-related).
Relevance: Frequently used in SjD for its immune-modulating effects. Clinical trials show limited symptom improvement, but biologic benefits in case series (reduced immunoglobulins and interferon activity) and retrospective datasets are encouraging.

Mycophenolate mofetil – Inhibits inosine monophosphate dehydrogenase, reducing lymphocyte proliferation.
Side effects: GI upset, cytopenias, infection risk.
Relevance: Often considered for interstitial lung disease or vasculitis.

Cyclophosphamide – DNA alkylator that suppresses rapidly dividing immune cells.
Side effects: bone-marrow suppression, bladder irritation, infertility, malignancy risk.
Relevance: Reserved for severe, organ-threatening disease give side effect profile.

Biologic DMARDs

Abatacept – CTLA-4-Ig that blocks T-cell costimulation (CD80/86).
Side effects: infections, infusion reactions.
Relevance: Large trials did not meet primary endpoints, but some patients show improvement in systemic activity, especially when inflammation is T-cell-driven.

Belimumab – Anti-BAFF antibody that reduces B-cell survival.
Side effects: infections, depression (rare).
Relevance: Used in lupus. Open-label trials suggest improvements in systemic activity and glandular symptoms; further trials are ongoing.

Rituximab – Anti-CD20 antibody that depletes B cells.
Side effects: infusion reactions, infections.
Relevance: Mixed trial results, no improvement in dryness or fatigue in primary outcomes, but benefit in vasculitis, neuropathy, and cryoglobulinemia seen in case series. Often used off-label for systemic disease.

TNF inhibitors (adalimumab, etanercept, infliximab, golimumab, certolizumab) – Block TNF-α signaling.
Side effects: infections (including TB), demyelinating disease, malignancy risk.
Relevance: Despite success in RA, these agents have not demonstrated benefit in SjD and are not routinely used unless another indication exists such as overlap RA.

Anifrolumab – Anti–type I interferon receptor antibody.
Side effects: infections.
Relevance: Used in lupus. Targets a key molecular pathway in SjD; early studies are promising. Currently being studied in trial setting.

Tocilizumab – IL-6 receptor blocker.
Side effects: elevated liver enzymes, neutropenia, lipid changes.
Relevance: No consistent benefit yet shown in trials, but sometimes considered for overlap arthritis or systemic inflammation.

Targeted Synthetic DMARDs

JAK inhibitors (tofacitinib, upadacitinib) – Block JAK–STAT cytokine signaling.
Side effects: infections, elevated cholesterol, thrombosis.
Relevance: Used in RA and PsA. Preclinical studies show they reduce interferon-related and B-cell-activating signals. Clinical trials are ongoing.

TYK2 inhibitors (e.g., deucravacitinib) – Selectively inhibit TYK2, modulating multiple cytokine pathways.
Side effects: infection risk, cytopenias (rare).
Relevance: Used in psoriasis and being investigated for PsA. Mechanistically relevant in interferon-driven disease; clinical trials are ongoing.

Other Immunomodulators

Glucocorticoids – Broad anti-inflammatory effects via genomic and non-genomic mechanisms.
Side effects: weight gain, diabetes, hypertension, bone loss, infection risk.
Relevance: Short-term use can control flares and systemic features but should be minimized to reduce long-term toxicity.

Intravenous immunoglobulin (IVIG) – Immune modulation through Fc receptor blockade and anti-idiotype effects.
Side effects: headache, infusion reaction, thrombosis.
Relevance: Some report for benefit neuropathies and vasculitic features; data remain limited.

NSAIDs – Inhibit cyclo-oxygenase enzymes, reducing pain and inflammation.
Side effects: GI bleeding, renal injury, cardiovascular risk.
Relevance: Used symptomatically for arthralgia or myalgia; not disease-modifying.

Colchicine – Inhibits microtubule polymerization and neutrophil activity.
Side effects: GI upset, cytopenias, myopathy.
Relevance: Occasionally used for serositis or inflammatory arthropathy; evidence is limited but safety is acceptable with monitoring.