Dermatitis Herpetiformis: Monitoring, Biomarkers, and Neurological Comorbidities#

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Part 1: Monitoring, Biomarkers, and Disease Tracking#

1. Serological Monitoring on a Gluten-Free Diet#

Available Antibody Markers#

Four main serological markers are used in DH/celiac monitoring:

Marker	What It Measures	Sensitivity in DH	Best Use
Anti-TG2 IgA (anti-tissue transglutaminase)	Gut mucosal autoimmunity	~79% in untreated DH	GFD compliance, intestinal damage proxy
Anti-TG3 IgA (anti-epidermal transglutaminase)	Skin-specific autoimmunity	~86-95% in untreated DH	DH-specific diagnosis and monitoring
EMA IgA (endomysial antibody)	Gut mucosal autoimmunity	Moderate	Confirmatory, high specificity
Anti-DGP IgA/IgG (deamidated gliadin peptide)	Gluten immune response	~91% (IgA), ~95% (IgG in combo)	Useful in IgA-deficient patients

Sources: Autoantibodies against epidermal transglutaminase in DH, ARUP Laboratories - DH Testing, Labcorp - DGP Antibodies

How Antibodies Change on GFD#

Anti-TG2 IgA: Disappears within 1-3 years on strict GFD, indicating small bowel villous atrophy has healed. Good marker for dietary compliance, but insensitive to minor, transient dietary indiscretions.
Anti-TG3 IgA: Positivity drops from ~86% to ~21% after one year on strict GFD. In patients who are lesion-free and off dapsone, anti-TG3 is undetectable. In patients who still require dapsone despite GFD, anti-TG3 often persists even when anti-TG2 has cleared. This makes anti-TG3 the more sensitive indicator of ongoing DH disease activity.
EMA IgA: Disappears on GFD in parallel with anti-TG2. Good specificity but similar limitations for minor gluten exposures.
Anti-DGP: Decreases after GFD initiation. Useful as a secondary marker, particularly in IgA-deficient patients (where IgG-DGP is used). Not recommended as primary screening due to lower specificity.
Reticulin antibodies: Historical marker; disappear within 11-47 months on GFD.

Sources: DH pathognomonic TG IgA deposits and prognosis on GFD, Celiac disease serology in DH, GFD effect on reticulin and gluten antibodies

Which Is Best for Tracking DH Specifically?#

Anti-TG3 IgA is the best DH-specific marker. Key evidence:

Anti-TG3 persists in DH patients who still require dapsone, even when anti-TG2 has normalized -- meaning TG3 tracks skin disease activity more faithfully than TG2.
Anti-TG3 levels correlate with the extent of enteropathy in DH specifically (but not in celiac without DH).
Anti-TG3 remains detectable for longer periods on GFD compared to anti-TG2, making it more sensitive for catching incomplete dietary adherence in DH patients.
Anti-TG2 is better for monitoring intestinal recovery and general GFD compliance.

Practical limitation: Anti-TG3 testing is not universally available. When unavailable, anti-TG2 serves as the primary monitoring tool.

Sources: Autoantibodies against eTG - sensitive marker in DH, Elevation of IgA anti-eTG in DH, DH Update on Diagnosis, Monitoring, and Management

Recommended Testing Frequency#

At diagnosis: Full panel (anti-TG2 IgA, anti-TG3 IgA if available, EMA, total IgA, anti-DGP if IgA-deficient)
6 months post-diagnosis: Repeat serology to assess GFD response
Annually thereafter: Anti-TG2 IgA at minimum; anti-TG3 IgA if available and previously elevated
When symptomatic: Repeat relevant markers to evaluate for dietary non-compliance vs. other causes

Sources: DH Update - Monitoring and Management, NIDDK - DH Provider Points

2. Anti-TG3 as a DH-Specific Biomarker#

Background#

TG3 (epidermal transglutaminase) is now considered the primary autoantigen in DH, distinct from TG2 (the primary autoantigen in celiac disease). The anti-TG3 antibody response is DH-specific and does not simply represent cross-reactivity with anti-TG2.

Key 2023 Research: Separate Plasma Cell Populations#

A landmark 2023 study by Das et al. in Advanced Science demonstrated that:

TG2- and TG3-specific antibodies are produced by separate gut plasma cell populations in DH patients.
There is no TG2-TG3 cross-reactivity -- these are distinct autoimmune responses.
Both TG2- and TG3-specific plasma cells have few immunoglobulin mutations, suggesting they arise through parallel but independent mechanisms.
TG3-specific plasma cells show distinct V-gene usage (preferential IGHV2-5 with IGKV4-1), confirming they are a separate B-cell lineage.
Anti-TG2 production appears skewed/dominant in most DH patients, but anti-TG3 is the DH-defining response.

This is significant because it means DH is not simply "celiac disease plus skin involvement" -- it involves an additional, distinct autoimmune response against TG3 that drives the cutaneous disease.

Sources: Das et al. 2023 - Separate Gut Plasma Cell Populations in DH, PMC Full Text

Correlation with Skin Symptoms#

Anti-TG3 IgA sensitivity for untreated DH: 60-95% (varies by study and assay used).
Anti-TG3 specificity: 92.8-100% (distinguishes DH from other pruritic skin diseases).
Celiac patients without skin disease can produce anti-TG3 antibodies, but only in DH are the antibodies high affinity.
Anti-TG3 levels correlate with the extent of enteropathy in DH but not in celiac disease without DH.
In patients on GFD who remain symptomatic (still requiring dapsone), anti-TG3 persists while anti-TG2 may have cleared.

Sources: Antibody Responses to TG3 in DH - Lessons from Celiac Disease, DH Update - Diagnosis and Management

Can Anti-TG3 Predict Flares?#

Not definitively established. Current evidence:

Circulating anti-TG3 disappears on strict GFD and reappears with gluten re-exposure, so rising titers could theoretically signal impending flare.
However, no prospective studies have specifically validated anti-TG3 as a flare predictor.
The lag between gluten exposure, antibody rise, and clinical skin symptoms is not precisely characterized.
Anti-TG3 is better characterized as a marker of ongoing disease activity rather than a prospective flare predictor.

This is an area needing further research.

Sources: Missing Insight Into T and B Cell Responses in DH, DH Novel Perspectives

3. Direct Immunofluorescence (DIF) Changes Over Time#

The Gold Standard Finding#

Granular IgA deposits at the dermal papillae (demonstrated by DIF on perilesional skin biopsy) remain the gold standard for DH diagnosis. This pattern is pathognomonic and distinguishes DH from linear IgA bullous dermatosis and other blistering conditions.

Timeline for IgA Deposit Clearance on GFD#

This is one of the most frustrating aspects of DH monitoring:

Clinical symptoms: Improve within weeks to months on GFD; total clearance averages ~2 years.
Circulating antibodies (TG2, TG3): Clear within months to 1-3 years.
Cutaneous IgA deposits: Extremely slow to clear. Estimated clearance time is up to 10 years on strict GFD. In one study, only 24% (10/41) of patients on strict GFD lost skin IgA deposits, over a range of 3-16 months after complete rash control by diet alone. The remaining 76% retained deposits for years.
IgA and TG3 deposits in the papillary dermis may persist even after patients have been asymptomatic for several years.

Sources: DH Wikipedia - Comprehensive Overview, GFD in DH - Morphological and Immunological Findings, Granular Deposits of IgA in Celiac Patients

Can Repeat DIF Biopsy Be Used to Monitor Progress?#

Technically yes, but practically no for routine monitoring:

Repeat DIF can confirm clearance of IgA deposits, which is a strong indicator of disease remission.
However, the procedure requires a skin biopsy (invasive), and clearance takes so long (years to a decade) that frequent biopsies are not informative.
Serial serology (anti-TG2, anti-TG3) is far more practical for routine monitoring.
Repeat DIF is most useful in specific clinical scenarios: confirming remission before attempting to liberalize diet, or in research settings.
One practical use: if a patient has been on strict GFD for many years and wants to know if deposits have cleared, a single repeat DIF could provide that answer.

Sources: DH - Diagnosis and Treatment, DH Update 2021

4. Intestinal Biopsy Monitoring#

Villous Atrophy in DH Patients#

~72-75% of DH patients have villous atrophy at diagnosis.
The remaining 25-28% have celiac-type inflammatory changes (increased intraepithelial lymphocytes) without overt villous atrophy.
No correlation exists between severity of skin disease and degree of small bowel damage. A patient with severe rash may have minimal enteropathy, and vice versa.

Is Repeat Endoscopy Useful?#

Generally not recommended for routine DH monitoring:

Anti-TG2 IgA levels serve as a reliable non-invasive proxy for intestinal mucosal recovery. When anti-TG2 normalizes (typically within 1-3 years on GFD), it indicates villous atrophy has likely healed.
Clinical recovery on GFD does not differ significantly between DH patients with and without villous atrophy at diagnosis.
Repeat endoscopy may be indicated if:
Persistent GI symptoms despite strict GFD
Concern for refractory celiac disease or complications (ulcerative jejunitis, lymphoma)
Anti-TG2 remains elevated despite reported strict GFD (to assess for ongoing mucosal damage)

Skin vs. Gut Recovery Correlation#

Skin improvement does NOT reliably correlate with intestinal healing -- they are partially independent processes.
Intestinal healing (villous recovery) typically occurs within 1-2 years on strict GFD.
Skin clearance averages ~2 years for clinical symptoms, but dermal IgA deposits persist much longer.
A patient can have complete intestinal recovery with persistent skin IgA deposits.

Sources: Prognosis of DH Patients With and Without Villous Atrophy, DH - Comparative Assessment of Skin and Bowel, DH Update - Diagnosis and Management

5. Clinical Scoring Systems#

Current State#

There is no widely validated, DH-specific severity scoring system comparable to EASI (for atopic dermatitis) or SCORAD. This is a significant gap in DH research and clinical practice.

What Exists#

Ad hoc severity classifications: Some studies classify DH as mild, moderate, or severe based on clinical assessment. One study of 122 patients categorized: mild (56.6%), moderate (39.3%), severe (4.1%). However, the specific criteria used vary between studies and are not standardized.
DASI (Dyshidrotic Eczema Area and Severity Index): Despite the similar acronym, this is designed for dyshidrotic eczema (palms/soles), not DH. Not applicable.
Dapsone dose as a proxy: Clinically, the dapsone dose required to control symptoms is sometimes used as an informal severity indicator -- higher doses suggest more active disease.
Lesion counts and affected body surface area: Used in clinical trials but not standardized across studies.
Anti-TG2 levels as a severity proxy: One study showed that quantification of IgA/IgG serum antibodies to TG2 could predict clinical and mucosal severity in DH.

Why This Matters#

The lack of a validated scoring system makes it difficult to: - Compare treatment efficacy across clinical trials - Objectively track individual patient progress - Standardize care recommendations

This represents an unmet need in DH research.

Sources: DH Duhring - Evaluation of Disease Severity, Prediction of Severity by TG2 Antibody Quantification

6. Predictors of Flares#

Prodromal Symptoms#

Patients commonly report a characteristic prodromal phase: - Burning or stinging sensation at typical lesion sites, occurring 8-12+ hours before visible lesions appear. - This prodromal itch/burn is well-described clinically but poorly characterized in research.

Known Flare Triggers#

Gluten exposure: The primary trigger. Even small amounts can trigger flares in sensitive patients.
Iodine: Well-documented flare trigger. Both dietary iodine (supplements, iodine-rich foods like seaweed) and topical iodine can precipitate DH flares.
NSAIDs: Aspirin, ibuprofen, and naproxen have been reported to trigger flares.
Stress: Anecdotally reported but poorly studied.

Immunological Correlates of the Prodromal Phase#

Research on the itch mechanism in DH provides some insight:

IL-31 (interleukin-31): Identified as a key mediator of itch in DH. IL-31 is produced by Th2 cells, macrophages, dendritic cells, and eosinophils. It signals through IL-31RA on dorsal root ganglia neurons, directly linking the immune system to neural itch perception. Elevated IL-31 could theoretically precede visible lesion formation.
IL-17 and IL-36: Elevated serum levels found in DH patients, involved in the inflammatory cascade.
Neutrophil chemotaxis: The accumulation of neutrophils at the dermal papillae (the histological hallmark of early DH lesions) likely begins before visible lesion formation, potentially explaining prodromal symptoms.

Can We Predict Flares Before They Happen?#

Not yet with any validated biomarker. The current state:

No serum biomarker has been validated as a prospective flare predictor.
Rising anti-TG3 or anti-TG2 titers after known or suspected gluten exposure could theoretically predict a flare, but the kinetics (how quickly antibodies rise relative to skin symptoms) are not well characterized.
IL-31 levels are a research finding, not a practical clinical test.
The prodromal burning sensation remains the most reliable "predictor," but it is subjective and not measurable externally.

This is a major area for future research -- particularly whether point-of-care anti-TG3 testing or cytokine panels could provide early warning.

Sources: IL-31 and Itch in DH and Bullous Pemphigoid, DH Etiopathogenesis, DH Novel Perspectives, DH - StatPearls

7. Practical Monitoring Protocol#

Recommended Monitoring Schedule#

At Diagnosis: - Baseline serology: Anti-TG2 IgA, anti-TG3 IgA (if available), EMA, total IgA - If IgA-deficient: Add anti-TG2 IgG, anti-DGP IgG - Skin biopsy with DIF (diagnostic, not monitoring) - Consider small bowel biopsy (standard of care for celiac diagnosis, though some guidelines accept serology alone in DH with positive DIF) - Baseline CBC, liver function, renal function (especially if starting dapsone) - G6PD level (mandatory before dapsone) - Nutrient panel: Iron, ferritin, B12, folate, vitamin D, zinc - Thyroid function (TSH, free T4) -- due to autoimmune thyroid disease association - Consider anti-TG6 IgA if available (neurological risk assessment; see Part 2)

If on Dapsone: - CBC with differential: Weekly for 4 weeks, then every 2 weeks until week 12, then every 3-4 months - Liver and renal function: Every 3-4 months - Methemoglobin level: If symptomatic (cyanosis, shortness of breath, fatigue) - Reticulocyte count: As needed (if hemolytic anemia suspected) - Expected: Loss of 1-2 g/dL hemoglobin, increased reticulocytes (2-12%), shortened RBC lifespan -- these are dose-related and nearly universal

6 Months Post-Diagnosis: - Repeat serology (anti-TG2, anti-TG3) - Dietitian review for GFD compliance - Assess skin symptoms, dapsone dose requirements - Repeat nutrient panel if deficiencies found at baseline

Annually Thereafter: - Anti-TG2 IgA (and anti-TG3 if available) - CBC, liver function, renal function - Nutrient panel (iron, B12, folate, vitamin D) - Thyroid function - Screen for associated autoimmune conditions (Type 1 diabetes, pernicious anemia, thyroid disease) - Dietitian consultation - Assess for lymphoma risk (especially in long-standing disease)

Sources: DH Update - Monitoring and Management, NIDDK - DH for Professionals, Dapsone - StatPearls, Merck Manual - DH

What a DH Patient Should Track#

Daily/Ongoing: - Skin symptom diary: location, severity, number of lesions, itch intensity (0-10 scale) - Dietary log (especially when learning GFD; can reduce frequency once established) - Dapsone dose and any side effects - Prodromal symptoms (burning/stinging before lesions appear)

After Suspected Gluten Exposure: - Document exposure details (what, when, how much) - Time to symptom onset - Severity and duration of flare - This personal data helps establish individual sensitivity patterns

Periodic Self-Assessment: - Energy levels, mood, cognitive function (brain fog) - GI symptoms (even if not primary complaint) - Any neurological symptoms (numbness, tingling, balance issues) - Weight changes

Part 2: Neurological and Psychiatric Comorbidities#

Overview#

Neurological involvement in celiac disease/DH is increasingly recognized as a significant extraintestinal manifestation. While most research focuses on celiac disease broadly, DH patients share the same autoimmune process and are subject to the same neurological risks -- with some evidence suggesting potentially higher rates of certain antibodies (particularly anti-TG6).

1. Gluten Ataxia#

What It Is#

Gluten ataxia is an autoimmune cerebellar ataxia triggered by gluten ingestion in genetically susceptible individuals. It is mediated primarily by anti-TG6 antibodies (transglutaminase 6, the brain isoform), though anti-gliadin antibodies also play a role.

Prevalence#

Gluten ataxia accounts for up to 40% of sporadic idiopathic cerebellar ataxias.
In celiac disease patients with neurological symptoms, anti-TG6 antibodies are found in ~73%.
In DH patients specifically: A Finnish study found anti-TG6 positivity in 39% (13/33) of DH patients -- significantly higher than in classic celiac disease (14%). This is a striking finding, as most of these patients had no overt neurological symptoms.
An intriguing inverse correlation was found: TG6 antibodies were more common in DH patients without enteropathy (60%) than in those with overt enteropathy (17%).

Sources: TG6 Auto-Antibodies in DH, TG6 Auto-Antibodies in DH - PMC

Mechanism#

TG6 is expressed by activated astrocytes, microglia, and neuronal cells in the cerebellum, basal ganglia, and brainstem.
TG6 can deamidate gliadin peptides (similar to TG2 in the gut), creating immunogenic TG6-gliadin complexes.
Anti-TG6 and anti-gliadin antibodies cross-react with Purkinje cells in the cerebellum, causing direct neuronal damage.
Perivascular inflammation and blood-brain barrier disruption allow pathogenic antibodies access to the CNS.
Chronic exposure leads to irreversible Purkinje cell loss.

Sources: Gluten T cell epitope targeting by TG3 and TG6, Celiac Disease and Neurological Manifestations - From Gluten to Neuroinflammation

Symptoms#

Gait ataxia (unsteady walking) -- most common
Limb ataxia (difficulty with fine motor tasks)
Dysarthria (slurred speech)
Nystagmus (involuntary eye movements)
Can present insidiously over months to years

Reversibility with GFD#

Early disease is reversible; late disease is not.
Clinical improvement typically seen after 1 year on strict GFD, continuing over a 2-year period.
Some patients show faster improvement: ~40% improvement within 3 months.
98% of patients on strict GFD showed significant cerebellar improvement on MR spectroscopy vs. only 26% in those on GFD but still positive for anti-gliadin antibodies, and 5% in those not on GFD.
Anti-TG6 antibodies decrease on GFD: 85% (11/13) showed reduced titers after 1 year, with 7 becoming antibody-negative.
Critical window: Loss of Purkinje cells is irreversible. Response to GFD depends on duration of ataxia prior to diagnosis. The longer the delay, the less recovery is possible.
It takes 6-12 months for antibodies to disappear, which serves as a key marker of dietary adherence.

Sources: Gluten Sensitivity - Potentially Reversible Cause of Cerebellar Ataxia, Effect of GFD on Cerebellar MR Spectroscopy in Gluten Ataxia, Neurological Manifestations of Neuropathy and Ataxia in CD - Systematic Review

Implications for DH Patients#

The 39% TG6 positivity rate in DH patients is concerning. It suggests that DH patients may be at elevated risk for subclinical cerebellar damage even without overt ataxia symptoms. Whether routine anti-TG6 screening should be performed in DH patients is an open question, but the Finnish study data supports at minimum considering it, especially in patients with any balance, coordination, or gait complaints.

2. Peripheral Neuropathy#

Prevalence#

Estimates of peripheral neuropathy in celiac disease range from 0% to 39% depending on the study and detection method.
More specific data: 23% of established celiac patients on GFD had evidence of axonal peripheral neuropathy.
Some studies suggest up to 50% of celiac patients may experience some form of peripheral neuropathy.
DH-specific data is limited. Given DH is a celiac disease variant, similar rates are plausible, but formal prevalence studies in DH populations are lacking.

Sources: Neuropathy Associated with Gluten Sensitivity, Peripheral Neuropathy and Celiac Disease, Celiac Neuropathy

Types#

Most common forms (in descending frequency):

Length-dependent symmetrical sensorimotor axonal neuropathy (~75% of cases)
Affects distal extremities first (feet, then hands -- "stocking-glove" pattern)
Numbness, tingling, burning pain
Both sensory and motor involvement
Small fiber neuropathy
Painful burning sensation in a length-dependent pattern
Often missed by standard nerve conduction studies (requires skin biopsy for diagnosis)
Can present with neuropathic pain as the dominant symptom
Celiac/gluten sensitivity should be screened for in patients with idiopathic small fiber neuropathy
Sensory ganglionopathy
Asymmetric pure sensory neuropathy
Affects cell bodies of sensory neurons in dorsal root ganglia
Autonomic neuropathy
Among the top three types seen in celiac disease
Can cause orthostatic hypotension, gastroparesis, sweating abnormalities
Underdiagnosed
Motor neuropathies
Multifocal motor or sensorimotor patterns
Less common but can be disabling
Can progress from motor to sensorimotor with continued gluten exposure

Sources: Neurological Manifestations in CD - Systematic Review, Small Fiber Neuropathy in Celiac Disease, Small-Fiber Neuropathy Associated with CD - JAMA Neurology

Relationship to Gluten Exposure#

Continued gluten exposure can cause progression (e.g., motor neuropathy progressing to sensorimotor involvement).
GFD adherence appears to improve neuropathy symptoms, but recovery may be incomplete.
Some neurological manifestations can persist or develop independent of ongoing gluten exposure, suggesting established autoimmune damage may become self-sustaining.
The neuropathy is multifactorial: autoimmune (anti-neuronal antibodies), inflammatory, and nutritional (B-vitamin deficiencies from malabsorption).

Sources: Neuropathy Associated with Gluten Sensitivity, Treatment of Neurological Manifestations of Gluten Sensitivity

3. Brain Fog and Cognitive Symptoms#

Is It Real?#

Yes. Brain fog in celiac disease is well-documented and measurable:

In a Beyond Celiac survey, 90% of respondents with celiac disease or non-celiac gluten sensitivity reported experiencing brain fog (89% celiac, 95% NCGS).
Cognitive testing in untreated celiac patients shows measurable deficits that improve over the first 12 months of GFD.
A validated measurement tool now exists: the Brain Fog Assessment and Severity Scale (BFASS), published in May 2024 in Alimentary Pharmacology & Therapeutics.

Sources: Beyond Celiac - Brain Fog, Brain Fog Improves on GFD - Celiac Disease Foundation, Development and Validation of Brain Fog Scale for CD

Symptoms#

The most common brain fog descriptors (from the BFASS validation study): - Difficulty focusing - Difficulty thinking - Difficulty finding the right words and communicating - Feeling mentally slow - Episodic memory deficiency - Disorientation or confusion episodes - Declined mental acuity - Feeling lost or detached

The BFASS is a 12-item scale with two subscales: 1. Perceived cognitive impairment (e.g., difficulty thinking, feeling mentally slow) 2. Somatic and affective experience (e.g., feeling lost, feeling detached)

Interestingly, the BFASS did not significantly correlate with objective cognitive tests, suggesting brain fog may be a distinct subjective experience that standard cognitive testing does not fully capture.

Sources: Development and Validation of Brain Fog Scale, Gluten-Induced Cognitive Impairment in CD

Neuroimaging Evidence#

White matter changes are documented in celiac disease:

A cohort of 100 newly diagnosed celiac patients showed: 60% had abnormal brain imaging, including abnormal MR spectroscopy of the cerebellum (46%) and/or white matter lesions (25%).
A population-based study found significantly increased axial diffusivity in widespread white matter locations in celiac patients vs. controls, with changes in the brainstem, thalamus, and corpus callosum.
White matter lesions may be ischemic (from vasculitis) or inflammatory demyelination.
Compared to controls, celiac patients had significant deficits in reaction time.
Transcranial magnetic stimulation (TMS) studies show impaired central motor conductivity and a "hyperexcitable celiac brain" that partially reverts on long-term GFD.
CD also results in brain atrophy and changes in white matter on MRI.

Sources: Brain White-Matter Lesions in CD, Cognitive Deficit and White Matter Changes in CD, Brain Images Show CD-Related Damage, Neurophysiology of the Celiac Brain

Mechanism#

Current evidence suggests brain fog is likely multifactorial rather than caused by a single mechanism: - Neuroinflammation from systemic immune activation - Nutrient deficiencies (B12, folate, iron) - White matter changes - Possibly direct effects of cross-reactive antibodies - Interestingly, one review concluded "it is more likely that the causal factor is not directly related to exposure to gluten" -- suggesting the cognitive effects may be driven by downstream inflammatory and nutritional consequences rather than gluten itself.

4. Depression and Anxiety#

Prevalence#

Depression and anxiety are significantly more common in celiac disease than the general population:

Condition	Celiac Disease	General Population	Risk Ratio
Major depression (lifetime)	30.0%	8.3%	~3.6x
Panic disorder (lifetime)	18.3%	5.4%	~3.4x
Depression (any)	6-69% (varies by study)	--	3.36x higher risk
Anxiety (any)	16-84% (varies by study)	--	2.26x higher risk
Children with celiac	39% clinically significant anxiety/depression	--	Elevated

A meta-analysis across multiple psychiatry scales confirmed that patients with celiac disease have a 2.26x higher risk of anxiety and 3.36x higher risk of depression compared to controls.

Sources: Psychiatric and Neurological Manifestations of CD, Burden of Depressive and Bipolar Disorders in CD, Anxiety and Depression Meta-Analysis, Anxiety and Depression in Adults with CD on GFD

Disease vs. Burden -- What Causes It?#

Both biological and psychosocial mechanisms are likely involved:

Biological (disease-driven): - Proinflammatory cytokines: Chronic systemic inflammation and cytokines can affect brain circuits related to mood regulation. Cytokines cross the blood-brain barrier and influence neurotransmitter metabolism. - Cerebral hypoperfusion: Hypothesized to contribute to psychiatric symptoms occurring before celiac diagnosis. - Nutrient deficiencies: Low folate contributes to depression and cognitive decline. B12 deficiency causes neuropsychiatric symptoms. Iron deficiency causes fatigue and cognitive impairment. - Gut-brain axis dysregulation: Chronic inflammation and malabsorption disrupt gut-brain signaling. - Serotonin: ~95% of serotonin is produced in the gut. Intestinal damage could impair serotonin production.

Psychosocial (burden-driven): - Restrictive diet causing social isolation - Hypervigilance about food - Chronic symptoms affecting quality of life - Delay in diagnosis (average 6-10 years for celiac) - Invisible illness -- lack of understanding from others

Sources: Psychological Morbidity of CD, Psychiatric and Neurological Manifestations of CD

Does GFD Improve Psychiatric Symptoms?#

Anxiety: Studies using the STAI-Y1 and STAI-Y2 scales show anxiety values improved after GFD for 1 year.
Depression: Some improvement reported, but results are mixed.
Important caveat: While some symptoms improve within months of GFD, many patients continue to experience significant psychological morbidity. GFD is necessary but may not be sufficient.
The psychosocial burden of GFD itself can contribute to or maintain psychiatric symptoms.

Sources: Anxiety and Depression in Adults with CD on GFD, Prevalence of Anxiety and Depression Among CD Patients

5. Headaches and Migraines#

Association with Celiac Disease#

Strong epidemiological evidence supports a celiac-migraine link:

Migraine prevalence in celiac patients: 20.7% vs. 11.9% in controls.
Headache prevalence: 30-34% of celiac patients vs. 14-27% of controls.
Hazard ratio: Prior celiac diagnosis linked to migraine with HR of 1.67 (95% CI: 1.48-1.87).
Headaches more common in female celiac patients than male.
In children with headaches of unknown cause, celiac disease prevalence is 2.4% (vs. ~1% general population), suggesting routine celiac screening may be warranted in pediatric headache patients.
Dysbiosis has been proposed as a linking mechanism between celiac disease and migraine.

Sources: Prevalence of Migraine in Adults with CD, Dysbiosis and Migraine in CD, Should We Rule Out CD in Recurrent Headache Disorders?, Celiac Disease and Headache in Children

DH-Specific Data#

Essentially absent. No studies have specifically examined headache/migraine prevalence in DH patients as a distinct population from celiac disease broadly. Given that DH is a celiac variant, the celiac-level data is likely applicable, but DH-specific confirmation is lacking.

6. Mechanisms: How Gluten/Celiac Autoimmunity Affects the Nervous System#

Overview of Pathogenic Mechanisms#

The neurological damage in celiac disease/DH is driven by multiple overlapping mechanisms:

1. Anti-TG6 Autoimmunity (Antibody-Mediated)#

TG6 is the brain isoform of transglutaminase, expressed in the cerebellum, brainstem, basal ganglia, and cortex.
TG6 can deamidate gliadin peptides, creating immunogenic TG6-gliadin complexes -- the same mechanism by which TG2 creates immunogenic complexes in the gut and TG3 in the skin.
Anti-TG6 antibodies cross-react with Purkinje cells and deep cerebellar nuclei, causing direct neuronal damage.
TG6 antibody development in children with celiac disease correlates with duration of gluten exposure -- longer exposure = higher risk.
TG2, TG3, and TG6 autoantibodies can develop years before onset of clinical symptoms of extraintestinal manifestations.

Sources: Anti-TG6 Antibody Development Correlates with Gluten Exposure Duration, TG6 Auto-Antibodies in DH, Neurological Gluten Sensitivity Linked to TG6

2. Neuroinflammation and Blood-Brain Barrier Disruption#

Perivascular cuffing with inflammatory cells compromises the blood-brain barrier (BBB), exposing the CNS to circulating pathogenic autoantibodies.
In longstanding celiac disease, prolonged microbial translocation increases LPS (lipopolysaccharide) accumulation that crosses the BBB and activates microglia, resulting in neuroinflammation and neuronal damage.
Perivascular macrophages and dendritic cells in the choroid plexus and subarachnoid space mediate this process.

Sources: Celiac Disease and Neurological Manifestations - From Gluten to Neuroinflammation, Neuropathology of Gluten-Related Neurological Disorders

3. Cross-Reactivity and Molecular Mimicry#

Anti-gliadin antibodies show reactivity with deep cerebellar nuclei, brainstem, and cortical neurons.
Cross-reaction with Purkinje cells leads to consequent damage.
This may explain neurological symptoms in patients with anti-gliadin antibodies but without overt enteropathy.

Sources: Celiac Disease and Neurological Manifestations, Dietary Gluten and Neurodegeneration

4. Nutrient Deficiencies from Malabsorption#

Key deficiencies with neurological consequences:

Nutrient	Prevalence in CD	Neurological Consequence
Vitamin B12	8-41% of adults	Peripheral neuropathy, cognitive impairment, depression, subacute combined degeneration
Folate	20-30% of adults	Cognitive decline, depression, peripheral neuropathy
Iron	14-41% (persists on GFD)	Fatigue, cognitive impairment, restless legs
Vitamin B1 (thiamine)	Reported in malnourished CD	Wernicke encephalopathy, peripheral neuropathy
Vitamin B6	Reported in CD	Peripheral neuropathy, seizures
Vitamin E	Reported in CD	Ataxia, peripheral neuropathy
Copper	Reported in CD	Myelopathy, neuropathy

Importantly, some deficiencies (particularly B12 and folate) may persist on GFD, requiring supplementation.

Sources: Appropriate Nutrient Supplementation in CD, Vitamin B12 Deficiency in Untreated CD, Nutritional Consequences of CD, Neurological Manifestations - Comprehensive Review

5. Gut-Brain Axis Dysregulation#

Chronic intestinal inflammation disrupts the gut microbiome.
Altered gut permeability ("leaky gut") allows translocation of bacterial products.
Dysbiosis affects neurotransmitter production (including serotonin, of which ~95% is gut-derived).
Inflammatory signals from the gut reach the brain via the vagus nerve and systemic circulation.

Sources: Neurophysiology of the Celiac Brain, Poorer Brain Health in CD Associated with Specific Antibody

Summary: Key Takeaways#

Monitoring: 1. Anti-TG3 IgA is the most DH-specific serological marker, but anti-TG2 IgA remains the workhorse for GFD compliance monitoring due to wider availability. 2. Cutaneous IgA deposits take up to a decade to clear -- do not use repeat DIF for routine monitoring. 3. No validated DH-specific severity scoring system exists. This is a gap. 4. No validated biomarker can predict flares prospectively. IL-31 is a promising research target. 5. Skin and gut disease severity are independent -- do not assume intestinal healing from skin improvement or vice versa.

Neurological: 1. 39% of DH patients have anti-TG6 antibodies, putting them at potential risk for neurological damage even without symptoms. 2. Gluten ataxia is reversible early but becomes irreversible with Purkinje cell loss -- early GFD is critical. 3. Peripheral neuropathy affects up to 23-50% of celiac patients, with small fiber neuropathy being underdiagnosed. 4. Brain fog is measurable and real, with documented white matter changes on neuroimaging. A validated assessment scale (BFASS) now exists. 5. Depression (3.36x) and anxiety (2.26x) rates are significantly elevated, driven by both biological inflammation and psychosocial burden. 6. Nutrient deficiencies (B12, folate, iron) compound the neurological picture and may persist on GFD, requiring supplementation.

Last updated: February 2026