Treatment-Resistant Eczema: A Functional Medicine and Evidence-Based Approach

Treatment-Resistant Eczema:

A Functional Medicine and Evidence-Based Approach

From Biologics to the Gut-Skin Axis

Yoon Hang Kim, MD, MPH

Board-Certified in Preventive Medicine | Integrative & Functional Medicine Physician

Important: This article is for educational purposes only and does not constitute medical advice. Treatment decisions should be made in consultation with a qualified healthcare provider familiar with your individual health history. Nothing in this article establishes a provider-client relationship.

Introduction

Atopic dermatitis — what most people simply call eczema — is the most common inflammatory skin disease worldwide, affecting up to 10% of adults in industrialized countries. For the majority of people who live with it, a careful regimen of moisturizers and topical steroids keeps the disease manageable. But for a meaningful subset, the disease resists everything: potent topical corticosteroids, calcineurin inhibitors, even the newer biologics. When a case is labeled "treatment-resistant," what often follows is a frustrating cycle of escalation — stronger steroids, short bursts of prednisone, and a growing sense that nothing is working.

People living with treatment-resistant eczema frequently arrive at this point after years of that cycle: bags of half-used tubes, a history of steroid-induced skin thinning, disrupted sleep from unrelenting itch, and a reasonable question — What else is there?

This article examines that question with rigor. It walks through the full evidence-based treatment ladder — from topical foundations through phototherapy, conventional systemic agents, and biologics including dupilumab — and then layers in the functional medicine approach, focusing on the gut-skin axis, barrier repair, and immune modulation. It also addresses two questions that come up often: whether sirolimus or related mTOR inhibitors have a role in eczema, and where low-dose naltrexone (LDN) fits as an adjunct for eczema-associated pruritus.

Step One: Reconsider the Diagnosis

Before reaching for systemic immunosuppression, the most important question in "treatment-resistant" eczema is whether the diagnosis is correct. A 2015 review in the Journal of Allergy and Clinical Immunology noted that treatment resistance can reflect inadequate treatment quantity, premature discontinuation, poor adherence, superimposed contact allergy, secondary infection, or an incorrect diagnosis rather than truly refractory atopic dermatitis [4].

The differential diagnosis that must be actively excluded includes:

• Allergic contact dermatitis — especially with facial, eyelid, neck, hand, or treatment-site predominance

• Dermatophyte infection — particularly annular, asymmetric, advancing-border, or steroid-modified tinea

• Scabies — nocturnal itching, household contacts itching, finger-web or genital involvement

• Seborrheic dermatitis or psoriasis overlap

• Drug eruption

• Bullous pemphigoid — especially in older adults with intense pruritus and urticarial plaques

• Cutaneous T-cell lymphoma — rare, but worth considering with persistent asymmetric patches and failure of adequate therapy

Expanded patch testing is one of the highest-yield evaluations in this population. The AAD diagnostic guidance recommends considering patch testing when dermatitis is treatment-resistant or its distribution suggests allergic contact dermatitis [4]. Allergens hiding in supposedly "safe" products — fragrance, preservatives, botanical extracts, even the corticosteroid vehicle itself — are a common culprit. This single step changes the trajectory of care more often than any systemic medication, yet it is frequently skipped in the rush to escalate therapy.

The Conventional Treatment Ladder

What follows is a review of the evidence-based treatment ladder for moderate-to-severe atopic dermatitis, from topical foundations through targeted biologics. Cost remains a real consideration — dupilumab's list price can exceed $36,000 per year with no biosimilar expected until at least the early 2030s [28] — but the treatment discussion should begin with what works, not what costs.

Emollients and Barrier Repair: The Non-Negotiable Foundation

Every guideline — AAD and AAAAI/ACAAI alike — places moisturizers and barrier repair at the base of the treatment pyramid [1, 3]. Regular moisturization reduces dryness, decreases eczema severity, lengthens the interval between flares, and reduces the amount of anti-inflammatory medication needed. Ointments generally outperform creams for dry, eczema-prone skin and contain fewer preservatives, though acceptance and body location matter. A practical low-cost protocol: short lukewarm baths, fragrance-free cleanser used only where needed, patting rather than rubbing the skin dry, and applying a thick ointment or cream within a few minutes of bathing. Plain petrolatum is a reasonable option when ingredient sensitivity or cost is a concern. No systemic or advanced therapy substitutes for consistent barrier care — it is the platform everything else is built on.

Topical Corticosteroids: Still the Foundation

The AAD strongly recommends topical corticosteroids as the most effective and affordable treatment for active eczema [1]. The most common reason topical therapy "fails" is not the medication — it is the quantity and application technique. A small tube prescribed for a large body surface area, applied thinly and intermittently, will not control moderate-to-severe disease. Site-appropriate potency matters: low-potency for face, eyelids, and folds; medium-potency for trunk and extremities; and brief high-potency courses for thick lichenified areas.

Topical Tacrolimus: The Steroid-Sparing Workhorse

A 2015 Cochrane review of 20 randomized controlled trials (n=5,885) provided convincing evidence that topical tacrolimus 0.1% was significantly more effective than low-potency topical corticosteroids, pimecrolimus 1%, and tacrolimus 0.03% [11]. A subsequent 2023 systematic review and meta-analysis confirmed the efficacy of intermittent and sequential tacrolimus strategies for flare management [12].

Tacrolimus is a calcineurin inhibitor that suppresses T-cell activation by blocking NFAT signaling — the same pathway targeted by cyclosporine, but applied topically and without systemic immunosuppression. It does not cause skin atrophy, making it the preferred maintenance agent for steroid-sensitive areas: eyelids, face, neck folds, and genital skin. Both AAD and AAAAI/ACAAI guidelines support twice-weekly proactive application to recurrent "hot spots" [4, 7]. Generic tacrolimus is now widely available and affordable. Pimecrolimus 1% is a related, milder calcineurin inhibitor suited to mild disease and sensitive areas.

Newer Nonsteroidal Topicals

Several nonsteroidal topical agents now offer steroid-sparing options, several of them added to the 2025 AAD focused update [5]. Crisaborole (Eucrisa), a topical PDE4 inhibitor, is approved for mild-to-moderate AD and is useful for sensitive areas, though transient application-site stinging is common. Topical ruxolitinib (Opzelura), a JAK inhibitor cream, is effective for mild-to-moderate disease but carries a boxed warning as a class effect and has body-surface-area limits on use. Roflumilast cream (a once-daily PDE4 inhibitor) and tapinarof cream (an aryl hydrocarbon receptor agonist) are newer additions with favorable tolerability. These agents are generally more expensive than generic corticosteroids and tacrolimus, but they expand the toolkit for people who cannot tolerate steroids or need long-term treatment of sensitive sites.

A Note on Sirolimus: Related but Not Equivalent

This question comes up with some regularity: if tacrolimus works for eczema, would sirolimus (rapamycin) work too? The names suggest a family relationship, and indeed both drugs bind to the same intracellular protein, FK-binding protein 12 (FKBP12). But what happens after binding is fundamentally different.

Tacrolimus-FKBP12 inhibits calcineurin, blocking T-cell activation and IL-2 production. Sirolimus-FKBP12 inhibits mTOR Complex 1, blocking the downstream response to IL-2 — arresting cell cycling and suppressing T and B cell proliferation. Sirolimus does not interact with calcineurin at all [8, 9].

The mTOR pathway is involved in AD pathogenesis. IL-13 activates the mTOR/miR-143 axis, which downregulates epidermal barrier proteins, and preclinical mouse models have shown rapamycin can attenuate AD-like skin lesions [10, 11]. However, there is no clinical trial evidence supporting sirolimus for human atopic dermatitis.

In fact, there is a clinical paradox: mTOR inhibitors, including sirolimus and everolimus, can actually cause eczematous eruptions as an adverse effect. Habu et al. documented severe eczematous eruptions from everolimus, and induction of eczema by sirolimus has been reported in transplant patients [18]. In an ironic twist, a 2025 case report described a transplant patient whose systemic tacrolimus caused de novo atopic dermatitis — and switching to sirolimus improved the skin, not because sirolimus treats eczema, but because removing the offending tacrolimus resolved the drug-induced disease [19].

Bottom line: Topical tacrolimus is well-established for eczema. Sirolimus has no clinical evidence for AD, and systemic mTOR inhibitors can paradoxically induce eczema. The basic science around mTOR in AD is interesting but not yet clinically actionable.

Narrow-Band UVB Phototherapy

Narrow-band UVB (NB-UVB) is the most reasonable nonbiologic escalation when optimized topical treatment is insufficient. The AAD conditionally recommends phototherapy for refractory adult atopic dermatitis [2]. Dermatology guidelines rate both NB-UVB and medium-dose UVA1 as effective in significantly decreasing eczema severity, with NB-UVB preferred over broadband UVB (Level of evidence 1+, Grade of recommendation A) and preferred for chronic eczema in adults [23].

The most recent randomized trial, the BRONTE study published in July 2026 in the British Journal of Dermatology, compared narrowband versus broadband UVB in 69 adults with moderate-to-severe AD [20]. The UPDATE trial — a large pragmatic Dutch multicenter PROBE trial of 316 adults — is still underway and should provide the strongest evidence to date [21].

An important practical development: a 2024 study found that at-home handheld NB-UVB devices achieved disease improvement in 67% of 52 patients after 12 weeks of three-times-weekly self-administered treatment, with extremely high satisfaction scores [22]. This removes the biggest practical barrier — the need to drive to a dermatology clinic two to three times per week.

Advantages of NB-UVB: no systemic immunosuppression, no daily medication, no organ toxicity monitoring. Limitations: gradual onset, cumulative UV exposure concerns, and burning risk if dosing is not carefully managed.

Methotrexate: The Cost-Conscious Systemic Option

When systemic treatment becomes necessary and biologics are inaccessible, methotrexate is the most practical conventional option. A 2024 PRISMA-compliant meta-analysis found response rates of 77% for short-term therapy and 88.9% for medium/long-term therapy in adults with moderate-to-severe AD [24]. A 2024 international eDelphi consensus standardized dosing: guidelines predominantly proposed starting doses of 7.5–15 mg/week, with maintenance at 14.5–25 mg/week [20, 21].

The head-to-head comparison against cyclosporine is instructive. At week 8, methotrexate was clearly inferior — only 8% of patients achieved SCORAD 50 versus 42% with cyclosporine. However, after dose escalation, the picture reversed: by week 20, 92% of methotrexate patients reached EASI 50 versus 87% on cyclosporine, with fewer treatment-related adverse events [27]. Methotrexate is a slow starter, but it catches up and is safer for longer-term use.

Required monitoring includes CBC, hepatic and renal function, hepatitis screening, and folic acid supplementation. This medication should be prescribed and monitored by a clinician experienced with systemic immunomodulators.

Cyclosporine: A Bridge, Not a Destination

Cyclosporine acts faster than methotrexate and is conditionally recommended for severe refractory eczema [2]. It is generally a short-term option due to nephrotoxicity, hypertension, and extensive drug interactions. In the head-to-head trial with methotrexate, it won at week 8 but tied by week 20 with more adverse events [27]. For someone who needs rapid disease control — to break a severe flare or stabilize while methotrexate ramps up — cyclosporine is valuable. As a maintenance strategy, it is generally unattractive.

Azathioprine, Mycophenolate, and a Caution on Oral Steroids

The AAD conditionally recommends azathioprine and mycophenolate mofetil for selected adults with refractory disease [2]. Both are off-label, immunosuppressive, and monitoring-intensive, and generally sit behind methotrexate and cyclosporine in the conventional systemic sequence. Azathioprine requires TPMT enzyme testing before use to reduce the risk of severe bone-marrow suppression.

One point deserves emphasis because it is such a common trap: repeated courses of oral prednisone or injected corticosteroids should be avoided. Both the AAD and AAAAI/ACAAI guidelines recommend against systemic corticosteroids for routine eczema management because of cumulative toxicity and the rebound flares that predictably follow each taper [1, 3]. The short-term relief they provide is almost always paid back with interest.

Dupilumab (Dupixent): The Biologic Standard

Dupilumab has fundamentally changed the treatment landscape for moderate-to-severe atopic dermatitis since its FDA approval in 2017. It is a fully human monoclonal antibody that blocks the IL-4 receptor alpha subunit, simultaneously inhibiting both IL-4 and IL-13 signaling — two central drivers of type 2 inflammation, barrier dysfunction, and pruritus. The AAD strongly recommends dupilumab for moderate-to-severe AD [2].

The efficacy data are robust. In the pivotal LIBERTY AD SOLO 1 and SOLO 2 trials, 37% and 36% of adults achieved IGA 0/1 at 16 weeks with dupilumab monotherapy, compared to 10% and 8% with placebo. In the CAFÉ trial — which enrolled patients who had failed or could not tolerate cyclosporine — 63% achieved EASI-75 with dupilumab every two weeks plus topical corticosteroids, compared to 30% with placebo plus TCS (P < 0.0001) [43]. Itch improvement was equally striking: a 54% reduction in peak pruritus NRS versus 25% with placebo.

Long-term data are now available out to five years. The phase 3 LIBERTY AD OLE trial demonstrated sustained efficacy: 88.9% of patients achieved EASI-75 and 76.2% achieved EASI-90 at five years. Two-thirds achieved clinically meaningful itch relief. The safety profile remained consistent with shorter-term studies, with no new safety signals emerging and no increased risk of serious infections [44]. This durability is critical — atopic dermatitis is a chronic disease requiring chronic management, and dupilumab is one of the few systemic treatments with five-year safety data to support that.

Conjunctivitis and injection-site reactions are the most common treatment-emergent adverse events. Unlike JAK inhibitors, dupilumab carries no boxed warning for serious infection, thrombosis, cardiovascular events, or malignancy.

The practical barrier is cost. At a list price exceeding $36,000 per year with no biosimilar expected until at least the early 2030s [28], many people — particularly those in cash-pay, high-deductible, or Medicare arrangements — cannot access it. Manufacturer copay assistance programs can reduce out-of-pocket cost to near zero for commercially insured patients, and patient assistance programs exist for uninsured individuals, but these do not cover everyone. When cost is the obstacle, the conventional immunosuppressant ladder and the functional medicine approach described below become essential.

Other Biologics and JAK Inhibitors

The biologic and targeted therapy landscape has expanded considerably. Tralokinumab (Adbry) and lebrikizumab (Ebglyss) are IL-13-selective biologics that offer alternatives for people who experience conjunctivitis or other issues with dupilumab. Nemolizumab (Nemluvio) targets the IL-31 receptor and addresses the itch pathway directly. Oral JAK-1 inhibitors — upadacitinib (Rinvoq) and abrocitinib (Cibinqo) — can be highly effective but carry boxed warnings for serious infection, thrombosis, cardiovascular events, and malignancy that require careful risk-benefit discussion, particularly in older adults [2, 5].

Adjunctive Interventions: What Holds Up

Wet Wrap Therapy

Wet wrap therapy is conditionally supported by the AAD for acute severe flares [1]. The 2023 AAAAI/ACAAI guideline includes it among recommended topical interventions [3]. A systematic review and meta-analysis found promising results, though most evidence is pediatric and heterogeneous [29]. The key safety point: occlusion increases corticosteroid absorption substantially. Potency, duration, and body-surface exposure must be explicitly prescribed — not improvised at home.

Bleach Baths: A Closer Look at the Evidence

This is a recommendation that deserves scrutiny. While bleach baths are commonly prescribed and the 2023 AAAAI/ACAAI guideline conditionally supports them for moderate-to-severe infection-prone disease, the meta-analysis by Silverberg et al. found that bleach baths did not appear to be more effective than water baths alone [30]. Of four studies comparing bleach with plain water baths, only two found significantly greater improvement with bleach, one found greater improvement with water, and one found no difference. Pooled analyses showed no significant differences between bleach and water for EASI at 4 weeks [31].

This does not mean baths are useless — regular lukewarm bathing followed by immediate moisturization is itself therapeutic. But the specific added value of sodium hypochlorite over plain water is uncertain. Bleach baths are not a substitute for systemic antibiotics when clinical bacterial infection is present.

Low-Dose Naltrexone: An Evidence-Based Adjunct for Eczema-Associated Pruritus

Low-dose naltrexone (LDN) deserves serious consideration in treatment-resistant eczema, particularly when pruritus is a dominant feature. LDN transiently blocks opioid receptors, resulting in increased endogenous ligand and receptor expression, favoring κ over μ receptors, and decreasing inflammatory mediators and itch. It also antagonizes the pro-inflammatory toll-like receptor 4, providing a dual mechanism that addresses both the neurogenic itch pathway and the underlying inflammatory drive [33].

The clinical evidence supports this approach. A double-blind, placebo-controlled study of 38 patients with atopic eczema found that naltrexone was significantly more effective than placebo in decreasing pruritus VAS scores after one week (P < 0.005) and two weeks (P < 0.001) [34]. A systematic review confirmed efficacy across multiple pruritic conditions including atopic dermatitis, prurigo nodularis, cholestasis, burn injury, systemic sclerosis, Hailey-Hailey disease, and lichen planopilaris [35]. A 2025 clinical review in the Journal of the American Academy of Dermatology further validated LDN's anti-inflammatory and antipruritic properties across dermatologic conditions [33].

The mechanism is particularly relevant to AD. Chronic pruritic disorders demonstrate downregulation of the μ-opioid receptor. Topically administered naltrexone has been shown to cause upregulation of the μ-opioid receptor and provide better relief of pruritic symptoms relative to placebo. Oral LDN at 1.5 to 4.5 mg nightly addresses the systemic inflammatory component through TLR-4 antagonism, while the opioid receptor rebound effect enhances endogenous anti-itch signaling.

LDN is generic, inexpensive (typically compounded), well-tolerated, and does not carry the immunosuppressive risks of methotrexate, cyclosporine, or JAK inhibitors. It can be used alongside any rung of the conventional treatment ladder. For people with treatment-resistant eczema where pruritus drives sleep disruption, scratch-induced barrier damage, and secondary infection, LDN addresses a component of the disease that topical anti-inflammatories alone often cannot fully control.

The Functional Medicine Layer: The Gut-Skin Axis

This is where the integrative approach diverges most meaningfully from the conventional ladder — not as a replacement for it, but as a parallel investigation into why the skin is inflamed, rather than only suppressing how it expresses that inflammation.

Gut Dysbiosis and Short-Chain Fatty Acid Deficiency

The gut-skin axis has moved from theoretical framework to measurable biology. A 2026 review in Dermatology & Venereology demonstrated that atopic dermatitis is associated with altered gut microbiota composition, reduced short-chain fatty acid (SCFA) production, and gram-negative bacterial overgrowth, promoting systemic inflammation through impaired intestinal barrier function and endotoxin-mediated immune activation [36]. Reduced circulating levels of microbial metabolites — particularly butyrate and propionate — correlate inversely with EASI and SCORAD scores and positively with inflammatory biomarkers [37].

AD-associated gut dysbiosis results in impaired intestinal barrier integrity and reduced production of SCFAs, mainly anti-inflammatory butyrate and propionate [38]. A 2025 case report described a patient with biopsy-confirmed, treatment-refractory eczema of four years' duration who achieved 80% reduction in eczema severity within four weeks of a phased, gut-directed protocol targeting dysbiosis and SCFA deficiency [39]. Single case — causal conclusions cannot be drawn — but the speed and magnitude of the response warranted attention.

Microbiome-Directed Interventions

The evidence here is promising but heterogeneous. Probiotic and synbiotic interventions have shown strain-specific and context-dependent effects in AD [37]. Postbiotics, fecal microbiota transplantation, and metabolite-directed approaches remain investigational. A 2025 review in Clinical & Molecular Allergy noted that microbiome-based therapies offer a promising approach by focusing on restoring healthy microbiota rather than just suppressing immune responses, with significant progress in skin microbiota transplantation research [40].

From a functional medicine perspective, the practical approach involves:

• Comprehensive stool analysis to identify dysbiosis patterns, SCFA production capacity, and pathobiont overgrowth

• Targeted probiotic supplementation — strain-specific, not shotgun — guided by individual findings

• Dietary support for SCFA production: prebiotic fibers, fermented foods, adequate plant diversity

• Assessment and support of intestinal barrier integrity

• Identification and removal of barrier-disrupting exposures: unnecessary antibiotics, NSAIDs, alcohol, processed food additives

Skin Microbiome and Staphylococcal Colonization

AD is associated with marked loss of commensal skin diversity and dominant colonization by pathogenic Staphylococcus aureus. This dysbiosis is associated with more severe disease, more pronounced type 2 immune abnormality, and barrier impairment. Conversely, restoration of commensal diversity may precede and indicate disease resolution [38]. This is why infection assessment and culture of suspicious lesions matters — not just to treat active infection, but to understand the microbial ecology driving disease persistence.

What Does Not Belong in the Protocol

An evidence-based functional approach should focus on modifiable exposures and documented abnormalities — not large empiric supplement protocols. Specifically:

• Broad elimination diets: The 2023 AAAAI/ACAAI guideline suggests against routine elimination diets for AD [3]. Targeted evaluation is more reasonable when there is a reproducible immediate reaction to a specific food.

• Food-IgG panels: The AAAAI states that food-specific IgG testing is unproven for diagnosing food sensitivity and that IgG may simply reflect normal exposure or tolerance [9]. These should not guide eczema treatment.

• Indiscriminate supplements: Omega-3 oils, evening primrose oil, vitamin E, zinc, selenium, and broad "immune" formulas do not have sufficiently consistent evidence for routine eczema treatment. Supplementation is more defensible for a documented deficiency.

• Complex botanical topicals: Essential oils and multi-ingredient botanical creams can cause irritant or allergic contact dermatitis, making both the disease and the diagnostic picture worse.

Putting It Together: A Cost-Conscious Evidence-Based Sequence

Weeks 1–2: Assessment and Topical Induction

• Document body sites, severity, sleep impairment, itch, and complete treatment history

• Review actual medication tubes, strengths, quantities, and application technique

• Examine for infection, scabies, tinea, psoriasis, bullous pemphigoid, and contact dermatitis

• Begin an adequately potent, site-appropriate topical corticosteroid induction course

• Institute aggressive bland moisturization: short lukewarm baths, fragrance-free cleanser, immediate thick moisturizer application

• Review and discontinue anticholinergic antihistamines in older adults per Beers Criteria

• Order comprehensive stool analysis for gut-skin axis assessment

Weeks 2–6: Maintenance Transition and Diagnostic Workup

• Transition recurrent areas to twice-weekly proactive tacrolimus or mid-potency corticosteroid maintenance

• Arrange expanded patch testing

• Remove fragrance, botanical products, dryer sheets, and unnecessary topical medications

• Culture recurrent or suspiciously infected lesions

• Address gut dysbiosis findings: targeted probiotics, prebiotic support, barrier repair

• Correct documented nutritional deficiencies — test first, supplement second

• Consider supervised wet wraps for severe areas

Weeks 6–12: Escalation if Needed

• If clinically important disease persists despite verified adherence and adequate quantities:

• Refer for narrow-band UVB (in-office or explore home device options)

• Pursue dupilumab or another biologic where accessible — the strongest systemic evidence base, including five-year safety data; explore copay and patient assistance programs to address cost

• Consider methotrexate if disease burden justifies systemic risk and monitoring, or a JAK inhibitor with appropriate risk counseling

• Consider short-term cyclosporine when rapid control is necessary and renal function permits

• Add LDN as an adjunct when pruritus is a dominant, treatment-limiting feature

• Avoid repeated prednisone bursts (both AAD and AAAAI/ACAAI guidelines recommend against systemic corticosteroids for routine eczema management)

• Reconsider biopsy or alternative diagnosis if response remains unexpectedly poor

Conclusion

Treatment-resistant eczema is a genuinely challenging clinical problem. The conventional ladder — adequate topical induction, tacrolimus maintenance, phototherapy, dupilumab when accessible, and monitored methotrexate when biologics are not — provides a well-evidenced pathway. The functional medicine contribution is not to replace that ladder but to investigate what is driving the immune dysregulation from underneath: gut dysbiosis, barrier disruption, environmental triggers, and contact sensitization.

The tools are there. LDN addresses the pruritus and neuroinflammatory component that topical anti-inflammatories often cannot fully reach. Sirolimus, despite its structural kinship with tacrolimus, has no clinical role in eczema and can paradoxically cause it. The path forward is not about finding one dramatic intervention — it is about systematically addressing each layer of dysfunction, confirming the diagnosis, and matching the treatment to the individual.

That is integrative medicine at its best: not ideology, but precision — guided by evidence, tempered by clinical experience, and always respectful of individual biochemistry.

References

GUIDELINES AND POSITION STATEMENTS

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TOPICAL THERAPIES AND TACROLIMUS

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SIROLIMUS, mTOR, AND CALCINEURIN INHIBITOR MECHANISMS

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PHOTOTHERAPY

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SYSTEMIC THERAPIES

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ADJUNCTIVE INTERVENTIONS

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[31] Bleach baths for atopic dermatitis: systematic review and meta-analysis including unpublished data, Bayesian interpretation, and GRADE. Ann Allergy Asthma Immunol. 2022. DOI: 10.1016/j.anai.2022.06.021.

[32] FDA prescribing information for hydroxyzine. Includes sedation precautions and QT prolongation warnings. accessdata.fda.gov

LOW-DOSE NALTREXONE

[33] Low-dose naltrexone for treatment of dermatologic conditions: a clinical review. J Am Acad Dermatol. 2025. DOI: 10.1016/j.jaad.2025.09.048.

[34] Malekzad F, et al. Efficacy of oral naltrexone on pruritus in atopic eczema: a double-blind, placebo-controlled study. J Eur Acad Dermatol Venereol. 2009;23(8):948-50. DOI: 10.1111/j.1468-3083.2009.03196.x. PMID: 19453814.

[35] Ekelem C, et al. Utility of naltrexone treatment for chronic inflammatory dermatologic conditions: a systematic review. JAMA Dermatol. 2019. PMID: 30484835.

GUT-SKIN AXIS AND MICROBIOME

[36] Gut microbiome dysbiosis in atopic dermatitis: pathogenic mechanisms, gut-skin axis disruption, and emerging microbiota-targeted therapies. 2026. PMID: 42652094.

[37] Skin and gut microbiome in atopic dermatitis: mechanisms and therapeutic opportunities. PMC12701371. 2025.

[38] Resolution of chronic inflammation, restoration of epigenetic disturbances and correction of dysbiosis as an adjunctive approach to the treatment of atopic dermatitis. PMC11593003. 2024.

[39] Targeting gut dysbiosis and short-chain fatty acid deficiency in chronic eczema: a case report. PMC13218806. 2025.

[40] Managing the skin microbiome as a new bacteriotherapy for inflammatory atopic dermatitis. PMC10645580. 2023.

DIETARY AND PROBIOTIC EVIDENCE

[41] Oykhman P, Dookie J, Al-Rammahy H, et al. Dietary elimination for the treatment of atopic dermatitis: a systematic review and meta-analysis. J Allergy Clin Immunol Pract. 2022;10(10):2657-2666.e8. DOI: 10.1016/j.jaip.2022.06.044. PMID: 35987995.

[42] Makrgeorgou A, Leonardi-Bee J, Bath-Hextall FJ, et al. Probiotics for treating eczema. Cochrane Database Syst Rev. 2018;(11):CD006135. DOI: 10.1002/14651858.CD006135.pub3.

DUPILUMAB AND BIOLOGICS

[43] de Bruin-Weller M, Thaci D, Smith CH, et al. Dupilumab with concomitant topical corticosteroids in adult patients with atopic dermatitis who are not adequately controlled with or are intolerant to cyclosporine A, or when this treatment is medically inadvisable: a placebo-controlled, randomized phase 3 clinical trial (LIBERTY AD CAFÉ). Br J Dermatol. 2018;178(5):1083-1101. DOI: 10.1111/bjd.16156. PMID: 29193016.

[44] Beck LA, Bissonnette R, Deleuran M, et al. Long-term efficacy of dupilumab in adults with moderate-to-severe atopic dermatitis: results from a 5-year open-label extension trial (LIBERTY AD OLE). JAMA Dermatol. 2024;160(8):805-812. DOI: 10.1001/jamadermatol.2024.2008.

About Dr. Kim

Yoon Hang Kim, MD, MPH is board-certified in Preventive Medicine with more than 20 years of experience in integrative and functional medicine. A graduate of the University of Arizona Center for Integrative Medicine's Osher Fellowship under Dr. Andrew Weil, Dr. Kim holds additional certifications in preventive medicine, medical acupuncture, and integrative and holistic medicine. He specializes in low-dose naltrexone (LDN), autoimmune disease, chronic pain syndromes, integrative oncology, fibromyalgia, chronic fatigue syndrome, mast cell activation syndrome (MCAS), and mold-related illness.

Dr. Kim is the author of MCAS: Epidemic in Plain Sight and LDN Primer, both available on Amazon, and is the founder of the LDN Support Group. He has authored more than 25 peer-reviewed articles and 8 books.

Professional: www.yoonhangkim.com | Clinical: www.directintegrativecare.com