Dihexa for Sjögren's Syndrome Brain Fog: Sjögren's Fog, CNS Involvement, the Ianalumab NEPTUNUS Phase 3, Nipocalimab DAHLIAS, BDNF, HGF/c-Met & the 2026 UK Review

“My eyes and mouth are dry — but the thing that’s really wrecking my life is the fog.” This is one of the most common things people with Sjögren’s syndrome say, and the research backs them up: brain fog and fatigue routinely rank above dryness as the symptoms that interfere most with daily life. Up to 500,000 people in the UK may live with Sjögren’s — it is the second most common autoimmune rheumatic disease after rheumatoid arthritis, affecting roughly 0.6% of adults and around nine women for every man. Measurable cognitive impairment on testing affects an estimated 44–50% of patients (2025 systematic review), neurological involvement around 25–30%, autonomic dysfunction up to ~50%, and disabling fatigue around 70%. After decades in which Sjögren’s had no disease-modifying drug at all, 2024–2026 has finally delivered the first targeted therapies. Novartis’ ianalumab (VAY736) — an afucosylated, B-cell-depleting anti-BAFF-receptor antibody — met the primary endpoint in both the NEPTUNUS-1 and NEPTUNUS-2 Phase 3 trials and received FDA Breakthrough Therapy designation in January 2026. Johnson & Johnson’s nipocalimab, a first-in-class FcRn blocker, was positive in the Phase 2 DAHLIAS trial published in The Lancet and is now in the Phase 3 DAFFODIL programme. Against this genuinely hopeful backdrop, does Dihexa — a synaptogenic HGF/c-Met peptide — have anything to offer the half-million UK patients living with Sjögren’s fog? This rigorous 2026 UK review covers what is actually known, what is speculation, and why the directionality and lymphoma-risk concerns are real. Readers may also want the closely related Dihexa for Lupus (SLE) Brain Fog & NPSLE review (frequent overlap), the Dihexa for Hashimoto’s & Hypothyroid Brain Fog review (common comorbid thyroid autoimmunity), the Dihexa for Fibromyalgia & Fibro Fog review (substantial central-sensitisation overlap), the Dihexa for ME/CFS review (shared fatigue biology), and the Dihexa for PoTS Brain Fog review (dysautonomia overlap).

Sjögren's Syndrome in the UK in 2026: Scale, Demographics & Why Brain Fog Matters

Sjögren’s syndrome (pronounced “SHOW-grens”) is a chronic, systemic autoimmune disease in which the immune system targets the body’s moisture-producing exocrine glands — classically the lacrimal (tear) and salivary glands — producing the hallmark sicca symptoms of dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia). But framing it as a “dryness disease” badly undersells it. Sjögren’s is a fully systemic condition that can involve the joints, skin, lungs, kidneys, peripheral nerves, autonomic nervous system and brain, and whose two most disabling symptoms for many patients are fatigue and cognitive dysfunction — the “Sjögren’s fog.”

It is far more common than most people realise. According to Sjögren’s UK (the charity formerly known as the British Sjögren’s Syndrome Association, founded in 1986) and the 2025 British Society for Rheumatology guideline, up to half a million people in the UK may be affected, making it the second most common autoimmune rheumatic disease after rheumatoid arthritis. It affects roughly 0.6% of adults, with a striking female predominance of around 9:1 and a mean age at onset of about 50 — though it is frequently undiagnosed for years, with patients bounced between optician, dentist, GP and multiple specialists before the underlying autoimmune thread is recognised.

Sjögren’s is described as primary when it occurs on its own, and secondary (or “associated”) when it accompanies another autoimmune disease — most often systemic lupus erythematosus, rheumatoid arthritis, or autoimmune thyroid disease. This overlap matters for anyone researching brain fog, because it means a person with Sjögren’s may be carrying more than one driver of cognitive symptoms at once.

Why brain fog matters so much here: in patient-reported outcome studies, fatigue and cognitive difficulty consistently top the list of what interferes most with daily activity — a UK cross-sectional study of 149 primary Sjögren’s patients assessed exactly how pain, fatigue, mood, dryness and brain fog / mental fatigue interfere with everyday life, and the cognitive and fatigue domains loomed large. Yet there is no licensed therapy aimed specifically at Sjögren’s cognitive dysfunction. That treatment vacuum is precisely the gap that unproven “cognitive” peptides try to fill — which is why a clear-eyed review is worth writing.

What "Sjögren's Fog" Actually Is

Patients describe Sjögren’s fog as difficulty concentrating, word-finding trouble, slowed thinking, short-term memory lapses, and the sense of mental effort required for tasks that used to be automatic. On formal neuropsychological testing, the pattern is fairly consistent: the executive-function and processing-speed domains are most affected, often with attention and working-memory difficulties, while gross memory storage is relatively spared. This is the same broad signature seen in other systemic-inflammatory and post-infectious fog states reviewed on this site — long COVID, ME/CFS and fibromyalgia.

Prevalence estimates vary widely by how cognition is measured. Older “psycho-cognitive” estimates range from 10% to 60%; more focused neurocognitive studies put measurable cognitive dysfunction at roughly 44–50%. A striking case series of primary Sjögren’s patients with small fibre neuropathy found cognitive dysfunction in all of them, predominantly in the executive domain — hinting that the neuropathic and central manifestations travel together. Importantly, a 2025 PLOS One study linked elevated BACE1 activity and inflammatory blood biomarkers to objectively measured cognitive performance in Sjögren’s — concrete evidence that the fog is a biological phenomenon with measurable correlates, not a vague complaint.

The Mechanistic Picture: Interferon, B-Cells, the Blood-Brain Barrier & HGF

Anti-Ro/SSA, Anti-La/SSB & the Autoantibody Story

Sjögren’s is defined immunologically by autoantibodies against the ribonucleoprotein antigens Ro/SSA (Ro52 and Ro60) and La/SSB, usually on a background of a positive antinuclear antibody (ANA). Anti-Ro/SSA is the most clinically important: it is associated with more systemic and extraglandular disease and, crucially in pregnancy, with neonatal lupus and congenital heart block — one reason pregnancy is such a high-stakes consideration in this predominantly female, reproductive-age population. Diagnosis in 2026 also leans on the labial salivary gland biopsy (focal lymphocytic sialadenitis with a focus score ≥1), ocular staining and salivary flow tests, brought together by the 2016 ACR/EULAR classification criteria.

Type I Interferon & the BAFF / BLyS Axis

Like lupus, Sjögren’s is dominated by a type I interferon (IFN-alpha/beta) signature and by B-cell hyperactivity driven by the B-cell activating factor BAFF (BLyS). This is not an academic detail — it is exactly why the two most promising new drugs target these nodes. Ianalumab blocks the BAFF receptor and depletes B cells; nipocalimab lowers circulating pathogenic IgG autoantibodies via FcRn blockade. The B-cell-centric biology also explains the disease’s most feared complication: a markedly elevated risk of B-cell non-Hodgkin lymphoma, classically mucosa-associated lymphoid tissue (MALT) lymphoma — a point we return to in the risk section, because it bears directly on any pro-proliferative intervention.

Central Nervous System Involvement & Neuroinflammation

The 2025 systematic review of neurological complications in Sjögren’s describes a broad spectrum: peripheral neuropathy is the single most prevalent complication, followed by cognitive impairment and CNS vasculitis, with autonomic dysfunction found in around half of patients. Central involvement is associated with immune-mediated small-vessel inflammation, diffuse white-matter lesions visible on MRI, and, in a minority, focal syndromes such as optic neuritis, transverse myelitis and aseptic meningitis. The dominant explanation for the diffuse cognitive picture is chronic neuroinflammation and small-vessel disease rather than a single discrete lesion — mechanistically similar to the microglial-activation and vascular stories explored in our vascular cognitive impairment and long COVID reviews.

Small Fibre Neuropathy & Dysautonomia

Sjögren’s is one of the leading autoimmune causes of small fibre neuropathy — damage to the small, thinly-myelinated A-delta and unmyelinated C fibres that carry pain, temperature and autonomic signals. A 2025 cohort study specifically examined small A-delta fibre neuropathy prevalence in the disease. The autonomic overlap — orthostatic intolerance, palpitations, gut dysmotility — produces a clinical picture that frequently shades into PoTS territory, and the cerebral-hypoperfusion contribution to fog is shared across that dysautonomia cluster.

Where HGF/c-Met & BDNF Enter the Picture

Dihexa’s entire rationale rests on activating the hepatocyte growth factor (HGF) / c-Met system and, downstream, augmenting BDNF-dependent dendritic-spine formation and synaptogenesis (the Benoist 2014 mechanism). There are two superficially attractive threads in Sjögren’s. First, HGF/c-Met is a protective regulator of the blood-brain barrier and cerebral endothelium — the very interface that small-vessel inflammation disrupts. Second, HGF is a master regulator of epithelial repair, including in salivary and lacrimal gland tissue, so one could imagine a gland-regeneration story. But both threads are speculative and unstudied in Sjögren’s, and — as the next section shows — they are heavily outweighed by the proliferation/oncogenicity concern in a disease defined by B-cell expansion and lymphoma risk. There is also no clean BDNF-deficit signal in Sjögren’s to motivate a BDNF-augmenting peptide in the first place.

The 2026 UK Treatment Landscape: From Symptomatic Care to the First Targeted Biologics

For decades, the defining frustration of Sjögren’s medicine has been the absence of any disease-modifying drug. The 2025 British Society for Rheumatology guideline on the management of adult and juvenile-onset Sjögren disease — produced through a NICE-accredited process — therefore still rests heavily on symptomatic, multidisciplinary management, while flagging the targeted therapies now on the horizon.

1. Symptomatic & Glandular Management

Ocular dryness: preservative-free artificial tears and lubricating ointments, ciclosporin eye drops, and punctal plugs, under ophthalmology, with monitoring for corneal damage. Oral dryness: saliva substitutes, scrupulous dental care (dry mouth dramatically accelerates tooth decay), sugar-free stimulation, and the muscarinic agonists pilocarpine or cevimeline to stimulate residual secretion. Lifestyle: humidification, vaginal moisturisers, and skin care for associated dryness.

2. Antimalarials & Conventional Immunosuppression

Hydroxychloroquine is widely used for fatigue and arthralgia, despite the landmark JOQUER randomised controlled trial (JAMA, 2014) finding no significant improvement in the primary symptom outcomes over 24 weeks — it is continued pragmatically for symptom relief and its favourable safety and interferon-lowering profile, but patients should understand the evidence is weak. For systemic or organ-threatening disease, rheumatologists escalate to corticosteroids and conventional immunosuppressants (methotrexate, azathioprine, mycophenolate) as appropriate. Rituximab, a B-cell-depleting anti-CD20 antibody, is used off-label for selected severe systemic manifestations despite the largely negative TRACTISS and TEARS trials in primary Sjögren’s — a reminder of how hard this disease has been to treat.

3. The Ianalumab NEPTUNUS Breakthrough

The headline development of 2025–2026 is ianalumab (VAY736, Novartis). Mechanistically it is elegant: an afucosylated IgG1 monoclonal antibody that combines enhanced antibody-dependent cellular-cytotoxicity B-cell depletion with BAFF-receptor blockade — hitting the B-cell axis at two points. In the two global, randomised, placebo-controlled, 52-week Phase 3 trials, NEPTUNUS-1 and NEPTUNUS-2 both met their primary endpoint, with ianalumab 300 mg monthly delivering a statistically significant and clinically meaningful improvement in disease activity and a reduction in patient burden, and a safety profile comparable to placebo. Novartis framed it as the first drug to reduce both disease activity and patient burden in Phase 3. In January 2026 the FDA granted ianalumab Breakthrough Therapy designation, with global regulatory submissions planned from early 2026. This is, potentially, the first targeted, disease-modifying therapy in the history of Sjögren’s.

4. Nipocalimab & the FcRn-Blocker Route

Running in parallel is nipocalimab (Johnson & Johnson), a first-in-class FcRn (neonatal Fc receptor) blocker that accelerates the clearance of circulating IgG, including pathogenic autoantibodies. In the Phase 2 DAHLIAS trial — 163 adults with moderate-to-severe primary Sjögren’s, seropositive for anti-Ro60 and/or anti-Ro52, randomised to intravenous nipocalimab (5 or 15 mg/kg) or placebo every two weeks — nipocalimab met its primary endpoint of improved ClinESSDAI disease activity at Week 24, with substantial reductions in Sjögren’s-related autoantibodies. The results were published in The Lancet in 2025. Nipocalimab received FDA Breakthrough Therapy designation in November 2024 and Fast Track in April 2025, and the Phase 3 DAFFODIL programme is enrolling. It is the first FcRn blocker with a positive targeted-therapy signal in Sjögren’s.

5. Managing the Fog Itself

There is still no drug licensed specifically for Sjögren’s cognitive dysfunction. Evidence-informed management mirrors the approach used in other inflammatory fog states: optimise overall disease control; treat the amplifiers (sleep disturbance, depression, anxiety, pain, dryness-related discomfort); manage vascular risk factors given the small-vessel contribution; address autonomic symptoms and orthostatic intolerance; pace activity for fatigue; and use cognitive-rehabilitation and compensatory strategies. None of this is glamorous, and none of it is a peptide — but it is what actually has an evidence base.

Where Could Dihexa Theoretically Fit in Sjögren's Biology?

The honest summary: the few superficially appealing threads (BBB protection, epithelial repair) are speculative and unstudied, while the single most disease-specific consideration — the elevated B-cell lymphoma risk in a condition defined by B-cell proliferation — points firmly away from a chronic, pro-proliferative c-Met stimulant. This is a worse risk/benefit setup than most conditions in this review series.

Risks & Theoretical Concerns Specific to Sjögren's

Beyond the generic risks set out in the Dihexa side-effects review, Sjögren’s-specific concerns include: lymphoma / c-Met oncogenicity (the standout concern — Sjögren’s carries one of the highest B-cell non-Hodgkin lymphoma risks of any autoimmune disease, and c-Met is a recognised proliferative and oncogenic signalling node; chronically driving it harder in this population is hard to justify); immune modulation (HGF/c-Met has been linked to B-cell and T-cell expansion in an immune system already biased toward autoreactive B-cell survival); pregnancy and anti-Ro risk (Sjögren’s predominantly affects women of reproductive age; anti-Ro/SSA antibodies carry neonatal-lupus and congenital-heart-block risk; teratogenicity of Dihexa is entirely unstudied and pregnancy is a strict contraindication); polypharmacy interactions (patients are frequently on antimalarials, immunosuppressants, muscarinic agonists and, increasingly, biologics — any unproven peptide risks unknown drug-drug interactions); dry-eye and mucosal effects (unknown); and misattribution and delay (any perceived change while self-treating with a research peptide could mask or delay appropriate diagnosis and the now-available targeted therapy). None of these has been formally studied — which is exactly the problem.

UK Resources, Charities & Specialist Services for Sjögren's

National charities & support: Sjögren’s UK (British Sjögren’s Syndrome Association); Versus Arthritis (broader rheumatology); Mind (for mood and the psychological load of chronic illness); Samaritans 116 123.

NHS specialist services: GP referral to consultant rheumatology and ophthalmology under the 2025 BSR Sjögren guideline; dental services for xerostomia-related caries prevention; neurology input for significant neuropathic or CNS involvement; and the UK Primary Sjögren’s Syndrome Registry research network.

Research & professional bodies: NIHR Be Part of Research for open Sjögren’s trials (including biologic programmes); British Society for Rheumatology (BSR); EULAR; American College of Rheumatology (ACR).

The 2026 Bottom Line

Sjögren’s fog is real, common and biological — and 2026 is, at last, a genuinely hopeful moment in this disease. The combination of the ianalumab NEPTUNUS-1/2 Phase 3 success and its January 2026 FDA Breakthrough Therapy designation, the positive nipocalimab DAHLIAS Lancet result and the Phase 3 DAFFODIL programme, and the 2025 BSR guideline pulling the field together, collectively represent the most consequential change Sjögren’s has ever seen — and not one piece of it involves a research peptide. No clinical trial of Dihexa has been conducted, registered or planned in any Sjögren’s population. The mechanism cuts the wrong way: the most disease-specific consideration is the elevated B-cell lymphoma risk, and Dihexa’s core action — chronic c-Met activation — is exactly the kind of pro-proliferative signal you would least want to add. The evidence-based 2026 UK pathway is GP-led assessment with rheumatology and ophthalmology referral under the 2025 BSR guideline, symptomatic management of dryness and fatigue, escalation to the new targeted biologics for moderate-to-severe systemic disease, and support from Sjögren’s UK. For Sjögren’s syndrome brain fog, Dihexa cannot be recommended in 2026 — the risk/benefit is, if anything, less favourable here than in most conditions this site has reviewed.

Selected References & External Sources

1. British Society for Rheumatology guideline on management of adult and juvenile onset Sjögren disease (2025). Rheumatology (Oxford). — Oxford Academic
2. Spectrum of Neurological Complications in Sjögren's Syndrome: A Comprehensive Review (2025). — PMC11970570
3. Cognitive impairment in Sjögren's syndrome: BACE1 activity, inflammatory blood biomarkers and neurocognitive testing. PLOS One (2025). — PLOS One
4. Activity interference in patients with Sjögren's syndrome: a cross-sectional study of 149 UK patients. — PMC9536794
5. Prevalence of Small A-Delta Fiber Neuropathy in Sjögren's Disease: a cohort study (2025). — PMC12732339
6. Cognition, depression, anxiety and sleep in primary Sjögren's syndrome. Scientific Reports (2022). — Nature Sci Reports
7. Gottenberg JE et al. (2014). Hydroxychloroquine in primary Sjögren syndrome: the JOQUER randomized clinical trial. JAMA. — JAMA
8. Novartis: both ianalumab Phase III trials met primary endpoint in Sjögren's disease (NEPTUNUS-1 / NEPTUNUS-2). — Novartis
9. Novartis: ianalumab first drug to reduce disease activity and patient burden in Sjögren's Phase III. — Novartis
10. Novartis: ianalumab receives FDA Breakthrough Therapy designation for Sjögren's (January 2026). — Novartis
11. Ianalumab meets primary endpoints in Phase 3 NEPTUNUS trials. — NeurologyLive
12. Nipocalimab in moderate-to-severe Sjögren's disease (DAHLIAS): a randomised, phase 2, placebo-controlled trial. The Lancet (2025). — The Lancet
13. J&J: nipocalimab FDA Breakthrough Therapy designation for Sjögren's disease (Nov 2024). — Johnson & Johnson
14. Sjögren's UK (British Sjögren's Syndrome Association). — sjogrensuk.org
15. Benoist et al. (2014). HGF/c-Met dependence of Dihexa procognitive / synaptogenic effects. JPET. — PubMed 24403718
16. Wright & Harding (2015). Brain HGF/c-Met system. — PubMed 25711386
17. NIHR Be Part of Research. — bepartofresearch.nihr.ac.uk