Rare Dermatologic Diseases Require Mechanism-Based Thinking

Dermatology has entered an era defined by targeted therapeutics, pathway-specific interventions, and increasingly sophisticated immunologic understanding. Yet, despite the remarkable expansion of our therapeutic armamentarium, many dermatologic diseases remain without US Food and Drug Administration (FDA)-approved treatments—and likely always will.

This reality creates a growing challenge for clinicians managing rare inflammatory disorders such as lichen planus (LP), pityriasis rubra pilaris (PRP), pyoderma gangrenosum, granuloma annulare, Behçet disease, morphea, dermatomyositis, necrobiosis lipoidica diabeticorum (NLD), disseminated superficial actinic porokeratosis (DSAP), graft-versus-host disease (GVHD), toxic epidermal necrolysis (TEN), and SAPHO syndrome.

Many of these diseases are simply too uncommon to support large registrational trials. Others are too heterogeneous, too difficult to standardize, or too economically impractical for pharmaceutical development programs to pursue. Waiting for formal approvals in these settings is often unrealistic.

That does not mean patients should be left without options.

Instead, dermatologists increasingly must rely on a mechanistic understanding of both disease pathophysiology and therapeutic mechanisms of action (MOAs) in order to thoughtfully apply off-label therapies. Understanding “what’s under the hood” of both the disease state and the therapeutic target has become essential to modern dermatologic practice.

MECHANISM OF ACTION MATTERS

The future of rare disease management in dermatology may depend less on disease-specific approvals and more on pathway-based prescribing.

For example, JAK inhibitors have demonstrated how broadly applicable targeted immune modulation can become once clinicians understand inflammatory signaling cascades.¹ Although many inflammatory diseases may never receive dedicated trials, the biologic rationale for targeting cytokine signaling pathways can still be compelling.

The same inflammatory pathways implicated in psoriasis or atopic dermatitis often overlap with those involved in conditions such as granuloma annulare, LP, or dermatomyositis. Cytokine signaling involving IL-23, interferons, Th17 pathways, and JAK-STAT activation extends across multiple inflammatory disorders rather than remaining isolated to a single diagnosis.^2,3

As dermatologists, understanding these overlaps allows us to make informed therapeutic decisions even when evidence is limited to case reports, smaller series, or mechanistic rationale.

Equally important is understanding the histopathology and inflammatory architecture of disease. Successful off-label treatment is not simply about trying available drugs. It requires understanding how the inflammatory engine of the disease aligns with the molecular target of the therapy.

LUPUS AND TYK2 INHIBITION

Selective TYK2 inhibition represents one of the clearest examples of pathway-driven therapy expansion.⁴

Deucravacitinib, currently approved for psoriasis, has demonstrated potential in systemic lupus erythematosus (SLE) through selective inhibition of TYK2-mediated signaling pathways. Data from the phase 2 PAISLEY trial highlighted the ability of TYK2 inhibition to modulate IL-12, IL-23, and interferon signaling while potentially avoiding some of the broader hematopoietic and metabolic effects associated with less selective JAK inhibition.⁵

This matters because lupus shares substantial immunologic overlap with psoriasis and psoriatic arthritis. The inflammatory pathways do not exist in isolation, and increasingly we are learning that selective pathway inhibition may be transferable across disease states.

For dermatologists treating cutaneous lupus or overlapping connective tissue disorders, understanding these cytokine relationships becomes clinically valuable long before formal labeling changes occur.

The same principle applies broadly across dermatology: once we understand the pathway, we begin to understand where else that pathway may matter.

ACNE AS A MODEL OF TRANSLATIONAL BIOLOGY

Acne vulgaris may not be considered a rare disease, but it serves as an excellent example of how advances in sebaceous biology and inflammatory signaling can reshape therapeutic development.

Several emerging therapies target pathways previously underappreciated in acne pathogenesis, including metabolic signaling, lipid synthesis, and mechanistic target of rapamycin (mTOR) activation. The development of fatty acid synthase (FASN) inhibitors such as denifanstat illustrates this evolution.⁶

FASN inhibition targets sebum production at the level of de novo lipogenesis while also influencing inflammatory signaling and Th17 activation. Early studies have demonstrated reductions in sebaceous lipid synthesis and inflammatory lesion counts.⁷

At the same time, increasing attention has focused on how Western dietary patterns influence insulin signaling, IGF-1 activation, FoxO1 suppression, and mTOR complex 1 (mTORC1) activation.⁸ These pathways contribute not only to sebaceous gland activity but also to broader inflammatory signaling.

Interestingly, mTOR dysregulation also plays a central role in tuberous sclerosis complex (TSC), creating intriguing translational connections between acne biology and therapies traditionally associated with genetic disorders.⁹

As our understanding deepens, therapies originally developed for one disease may ultimately find utility in entirely different inflammatory or proliferative conditions.

MTOR INHIBITION BEYOND TUBEROUS SCLEROSIS

The expanding role of mTOR inhibition extends beyond acne biology.

Rapamycin has emerged as a promising therapeutic option for vascular anomalies and lymphatic malformations because of its ability to inhibit the PI3K/AKT/mTOR pathway. Topical rapamycin formulations have demonstrated potential in reducing endothelial proliferation, vascular endothelial growth factor signaling, and abnormal lymphatic growth.^10-12 

This again reflects the growing importance of pathway-based thinking. Once clinicians recognize that overactivation of mTOR signaling contributes to aberrant vascular proliferation, the rationale for repurposing mTOR inhibitors becomes biologically intuitive.

Many of these applications remain off-label, but the mechanistic foundation is increasingly strong.

HAIR DISORDERS AND ANDROGEN SIGNALING

Androgenetic alopecia (AGA) represents another area where off-label use and mechanistic insight continue to evolve rapidly.

Low-dose oral minoxidil has already become widely used off-label in hair disorders, despite originally being developed as an antihypertensive medication. New extended-release formulations currently in development aim to optimize exposure within the therapeutic hair-growth window while minimizing cardiovascular adverse effects.¹³

The pharmacokinetic rationale is straightforward: sustained plasma concentrations above the follicular growth threshold but below recognized cardiac activity thresholds may improve efficacy while reducing systemic risk.

Similarly, clascoterone topical solution for AGA builds directly on mechanistic understanding of androgen receptor signaling.¹⁴ Unlike spironolactone, clascoterone functions as a topical androgen receptor inhibitor that competes directly with dihydrotestosterone for receptor binding.^15-17

By interrupting downstream androgen signaling, clascoterone may reduce follicular miniaturization and sebaceous activity without systemic hormonal effects.

Many dermatologists had already begun applying clascoterone off-label on the scalp before dedicated solution formulations entered development. This reflects a broader reality in dermatology: clinicians often identify mechanistically rational applications well before formal approvals emerge.

THE CHALLENGE OF RARE DISEASE THERAPEUTICS

One of the most important realities facing dermatology is that many rare diseases, unlike AGA, will never receive adequately powered phase 3 trials. The economics simply do not support it. That reality places increasing responsibility on clinicians to thoughtfully evaluate emerging data, understand immune signaling pathways, and appropriately balance therapeutic risk against disease burden. It also requires comfort with therapeutic creativity—not reckless prescribing but informed application of biologic rationale.

In many cases, the greater risk may actually be therapeutic inertia.

Patients with severe inflammatory disease, painful ulcerations, debilitating mucosal involvement, or progressive connective tissue disease cannot always wait for perfect evidence. As our understanding of inflammatory biology expands, so too does our ability to apply therapies more intelligently across diseases.

PROTECTING THE BREADTH OF DERMATOLOGY

The expansion of targeted therapeutics also raises a broader professional issue for dermatology.

As systemic immune therapies become increasingly central to disease management, dermatologists must maintain fluency in inflammatory signaling, biologic therapy, and systemic immune disease. Conditions such as lupus, psoriatic arthritis, and chronic spontaneous urticaria increasingly overlap with rheumatology, allergy, and immunology.

If dermatologists retreat from these disease spaces, future generations may lose familiarity with managing complex inflammatory disorders altogether.

At the same time, dermatology cannot abandon topical innovation. Topical therapies remain foundational to our specialty, yet the topical pipeline remains comparatively limited in several disease states. Preserving therapeutic diversity—from topicals to biologics to small molecules—remains critical for the long-term health of the specialty.

Ultimately, the future of dermatology will depend not only on discovering new drugs but on understanding how to apply existing therapies more intelligently.

For rare diseases especially, mechanism-based thinking may be the most important therapeutic tool we have.