Focus Sector: Autoimmune Research & Clinical Access

MISSION

The Flare audits unpublished, shelved, withdrawn, and terminated clinical trial data in the autoimmune and oncology sectors. We translate raw data into transparent briefings for patients, families, advocacy groups, and independent researchers.

Sjögren's disease is not just a dryness disease. Published research suggests that up to 70% of Sjögren's patients experience broad neurological symptoms — and in many cases, those symptoms appear before the dry eyes and dry mouth that typically trigger a diagnosis. This briefing covers what neurological Sjögren's looks like, why it is missed, a critical diagnostic test most patients are never offered, and a landmark set of clinical guidelines published in December 2025 that represent the first time rheumatology and neurology have formally agreed on how to evaluate and treat nerve involvement in this disease. If you are new to The Flare, our previous briefing covers the full Sjögren's symptom picture and current drug pipeline — this issue goes deeper on the neurological dimension specifically.

One of the most consequential and least-discussed facts about Sjögren's disease is this: neurological symptoms frequently come first.

A 2025 review published in Rheumatology International documented five patient cases in which neurological manifestations appeared before sicca symptoms in four of them, and cites research suggesting that up to 70% of Sjögren's patients experience broad neurological involvement. A separate systematic review and meta-analysis found that neuropathic symptoms precede or lead to the Sjögren's diagnosis at a 2:1 ratio — nerve symptoms came first twice as often as the dryness did.

This is why so many patients spend years cycling through specialists before anyone considers an autoimmune workup. The documented misdiagnoses are striking: patients with neurological Sjögren's have been initially diagnosed with multiple sclerosis, neuromyelitis optica, neurosarcoidosis, epilepsy, and Parkinson's disease before the underlying autoimmune disease was identified.

Neurological involvement falls into two categories: peripheral nervous system (PNS) and central nervous system (CNS). Peripheral is more common. Central is less common but can be severe.

Small fiber neuropathy is the form most likely to be missed and the one most frequently described by patients who have been told their standard nerve tests came back normal. It affects the smallest, unmyelinated nerve fibers in the body — the ones responsible for pain, temperature sensation, and autonomic function. Symptoms include burning, tingling, or shooting pain; widespread tingling throughout the body; hypersensitivity to light touch or temperature; numbness that does not follow a clear anatomical pattern; and autonomic symptoms such as dizziness on standing, digestive problems, abnormal sweating, and bladder dysfunction.

Sensory ataxic neuropathy affects nerve cell bodies near the spine and can produce balance and coordination problems, unsteady gait, and loss of positional awareness.

Trigeminal neuropathy affects the trigeminal nerve in the face and presents as facial numbness or tingling. It is frequently mistaken for dental problems or temporomandibular joint issues.

CNS involvement can include white matter changes that resemble MS on imaging, optic neuritis, cognitive dysfunction, and a chronic relapsing course. Brain fog in Sjögren's is not a vague complaint — it is documented neurological involvement affecting 54% of patients in published survey data.

Standard EMG and nerve conduction studies evaluate large myelinated nerve fibers. They cannot detect small fiber neuropathy. A patient can have significant, debilitating small fiber neuropathy and a completely normal EMG. This is confirmed by the new Sjögren's Foundation clinical practice guidelines published in December 2025.

The test that detects it is a punch skin biopsy with intraepidermal nerve fiber density (IENFD) testing. A 3mm circular punch biopsy is taken from the skin under local anesthesia — typically 10 centimeters above the ankle. The sample is stained with a protein marker called PGP 9.5, nerve fibers are counted, and that count is compared to age- and sex-matched normative values. A density below the fifth percentile is diagnostic for small fiber neuropathy. The procedure takes minutes, heals within a week, and leaves no permanent deficit. Published accuracy: approximately 80% sensitivity and 90% specificity. It was developed and standardized at Johns Hopkins and the University of Minnesota and carries a Grade A recommendation from the European Federation of Neurological Societies.

In December 2025, the Sjögren's Foundation published the first-ever clinical practice guidelines for peripheral nervous system manifestations in Sjögren's disease, accepted in Arthritis Care & Research. The guidelines were three years in development, involving a multidisciplinary panel of rheumatologists, neurologists, and a patient representative.

The process revealed a foundational problem: rheumatologists and neurologists were not using consistent terminology to describe the same nerve conditions. Communication between specialties was described at ACR Convergence 2025 as "haphazard and chaotic." The guidelines created unified nomenclature across seven peripheral nervous system categories for the first time.

Key findings for patients:

Partially, but not specifically. The major Phase 3 programs — ianalumab, nipocalimab, efgartigimod, dazodalibep, deucravacitinib — all use ESSDAI as their primary endpoint, which includes peripheral and central nervous system domains. A drug reducing total ESSDAI is by definition reducing activity across those domains.

What no current trial does is enroll patients specifically for neurological Sjögren's. Additionally, while none use a neurological endpoint as the primary measure, PNS is still a core component of the composite endpoint. That is a documented gap in the pipeline worth naming.

The efgartigimod UNITY trial (NCT06684847, argenx) is currently the only Phase 3 program actively recruiting. If neurological Sjögren's is your dominant presentation, discuss with your rheumatologist whether your ESSDAI score across all domains — including neurological ones — makes you eligible. Full pipeline details are in Briefing #005.

What is a Punch Skin Biopsy and Where Do You Get One?

A punch skin biopsy for IENFD testing is the only widely validated, minimally invasive test that can confirm small fiber neuropathy when nerve conduction studies are normal. It is available at academic neurology centers and some community practices. Not all insurance plans cover it — verify before scheduling. Ask your neurologist specifically for a referral for IENFD skin biopsy testing, or contact the Sjögren's Foundation for a provider referral at sjogrens.org.

Sjögren's Foundation Virtual National Patient Conference 2026 Date: April 10–11, 2026
Format: Virtual — open nationally
Focus: Symptom and organ involvement updates, current research pipeline, clinician and researcher Q&A
Register: sjogrens.org/get-involved/national-patient-conference

International Symposium on Sjögren's Disease 2026 Date: September 29, 2026
Location: Paris, France
Focus: Basic and translational research, clinical trial updates, emerging biomarker data
Information: https://issjd-paris2026.com/

The Flare is an independent investigative journalism outlet. We are not medical providers, clinical trial sites, or financial advisors. This information is for educational and journalistic purposes only and does not constitute medical advice. Individuals seeking guidance on neurological symptoms, diagnostic testing, or treatment decisions should consult a licensed physician, rheumatologist, or neurologist.