Inflammatory Skin Diseases

The Importance of Immunological Signatures

Background: The understanding and classification of inflammatory skin diseases is shifting from a historical-descriptive perspective to a molecular-pathophysiological one based on immune response patterns. These are derived from a few key immunological mediators, each of which induces its own characteristic clinical, histopathological, and molecular patterns in the skin.

Methods: This discussion of the definition of the immune response patterns of inflammatory skin diseases is based on information from pertinent publications retrieved by a selective literature search. A systematic literature search was also conducted on the response of inflammatory skin diseases to treatment with specific biologic agents.

Results: The described immune response patterns are: autoinflammation; type 1, cytotoxic; type 2a, eczematous; type 2b, blistering; type 3, psoriasiform; type 4a, fibrosing; and type 4b, granulomatous. Each signature can usually be treated in a targeted manner. In general, each therapeutic target structure is associated with an adequate treatment response if and only if the skin disease under treatment has the relevant signature type. Hardly any biomarkers are currently available for the determination of immune response patterns in routine clinical practice.

Conclusion: The classification of inflammatory skin diseases by their immune response patterns opens up the prospect of specifically targeted immunotherapy for each immune response pattern regardless of the historical-descriptive disease entity. Targeting is intended to improve response rates. Initial findings suggest that this strategy is likely to succeed.

Cite this as: Garzorz-Stark N, Weidinger S, Sticherling M, Ghoreschi K, Enk A, Eyerich K: Inflammatory skin diseases: The importance of immunological signatures. Dtsch Arztebl Int 2025; 122: 277–82. DOI: 10.3238/arztebl.m2025.0045

The current classification of inflammatory skin diseases has been in place for over 150 years (1, 2). In the mid- to late 19th century, when science was dominated by morphological research, dermatologists such as Ferdinand von Hebra (3) and Eduard Jacobi classified the hundreds of skin diseases known at the time according to the typical gross appearance and distribution of the skin lesions. Microscopic dermatopathology later improved the scientific understanding of these diseases and made diagnosis more accurate. This traditional descriptive ontology of inflammatory skin diseases is now inadequate, however, in the light of a rapidly improving understanding of disease pathogenesis and a steadily expanding armamentarium of specific treatments.

Similar developments can be seen in other disciplines, such as rheumatology, where Schett et al. proposed abandoning the traditional organ-based classification of diseases to a molecular classification based on pathogenetic mediators (4). The overarching concept is that of stratified medicine, in which disease groups are defined in terms of immunological response patterns (signatures) to enable targeted treatment (5). These response patterns are found in relation to a few key messenger substances, known as master cytokines, which are released by immune cells that migrate into the skin or tissue and induce characteristic clinical, histopathological, and molecular patterns in the skin. This classification of diseases by immune response patterns is an improvement over the historical-descriptive classification but does not (yet) constitute truly personalized medicine, in which it is hoped that clinically relevant predictions, especially of the response to treatment, will soon be possible on the level of the individual patient.

Methods

A selective literature search on the efficacy of targeted treatments for inflammatory skin diseases was conducted both in PubMed and with the academic AI-based search engine “Consensus.” Evidence of the highest available level is cited in what follows. For further details and hierarchical clustering, see Figure 1 and eMethods.

Figure 1

Hypothesis-free clustering of inflammatory skin diseases based on the response to specific treatments

The immunological response patterns of inflammatory skin diseases

Inflammatory and autoimmune skin diseases can generally be divided on the basis of their immunological response patterns into autoinflammatory diseases, which are mostly of genetic origin, and common diseases caused by the interaction of adaptive immune cells with the cells of the skin.

Autoinflammatory diseases triggered by key cytokines of the interleukin (IL)-1 family can be further divided into classic autoinflammatory skin diseases, often manifesting with urticaria (hives) or nonspecific skin changes, and a group of diseases in which epidermal changes play a pathogenetic role. The latter are collectively known as autoinflammation with keratinization disorder (AIKD) (6).

These diseases are much rarer than inflammatory skin diseases mediated by the adaptive (learning) immune system, to which the T and B cells belong. Diseases in this category are classified by their dominant T cell subtype (1, 7):

Certain subpopulations of T cells, such as T helper 1 cells (Th1), T killer cells (Tc1), innate lymphoid cells 1 (ILC1), natural killer cells (NK), and/or NKT cells, play a key role in the pathogenesis of type 1 diseases. Common to all these cell types are the transcription factor T-bet and the secretion of the master cytokines IFN-γ and TNF-α. In the non-diseased context, this cellular toxicity is directed against (pre-)malignant or infected body cells. If the target cells are keratinocytes, however, a lichenoid pattern and an interface dermatitis (8, 9) result: such histopathological signs of keratinocyte death along the basement membrane are seen in lichen planus (e1), cutaneous lupus, and many viral or drug-induced exanthems. If the target cells are melanocytes, the result is vitiligo (e2). Alopecia areata is also pathogenetically classified as a type 1 disease (10).

Type 2 skin diseases are triggered by Th2 or ILC2 cells, which secrete the master cytokines IL-4, IL-5, IL-9, IL-13, and IL-31. While their physiological role is to defend against parasites, they also cause many type 2-dominant humoral skin diseases, such as blistering autoimmune skin diseases (11, 12, e3). Type 2 immune cells have three effects in the skin: they impair epidermal barrier function (e4), lessen the efficiency of the epithelial innate immune system (13), and neuroimmunologically induce and maintain the sensation of itch (14). Diseases in this group, such as atopic dermatitis and other eczemas, are characterized by dry skin, a tendency for the skin to be colonized by (non-pathogenic or pathogenic) microorganisms, and itch.

Type 3 skin diseases are induced by Th17, ILC3, and Th22 cells, whose physiological role is to maintain homeostasis at barrier organs including the skin and defend against extracellular pathogens (e5). They do this by means of cytokines including IL-17A/F, IL-21, IL-22, and IL-26 (e6). A misdirected type 3 immune response increases metabolism in the skin, lessens the differentiation of epithelial cells, and induces the innate immune system, with recruitment of neutrophil granulocytes into the skin. The prototype disease is psoriasis (15), with its variants. Many other type 3 diseases also have an autoinflammatory component, e.g., hidradenitis suppurativa and the acne syndromes (e7, e8).

Finally, type 4 skin diseases are chiefly mediated by regulatory T cells. Their physiologic role is to temper the immune response, preventing excessive responses that might endanger the entire organism – as can be seen, for example, in the “cytokine storm” caused by an immune response to infection or autoinflammation (e9). Type 4 skin diseases manifest themselves either with granuloma formation due to an imbalance of pro- and anti-inflammatory cytokines in granuloma formation or with tissue remodeling due to fibrosis and/or the deposition of substances within the skin. TGF-ꞵ plays a key role in the latter process (16). Fibrosing skin diseases are often a consequence of other inflammatory reactions: for example, dermatomyositis and chronic graft-versus-host disease arise from a type 1 reaction (17), morphea and eosinophilic fasciitis from a type 2 reaction (18).

Stratified medicine: differential therapeutics based on immunological response patterns

The above classification is simplified, but clinically useful, as can be seen from the fact that both autoinflammatory and adaptive type 2 and type 3 immune response patterns are amenable to specific treatment (Figure 2). In broad terms, specific treatment with biologic drugs is now approved as first-line treatment for moderate to severe forms of the disease; moreover, there is current approval only for the treatment of psoriasis vulgaris, generalized pustular psoriasis, hidradenitis suppurativa, atopic dermatitis, pemphigus vulgaris, and chronic idiopathic urticaria. It may be possible to treat any of the diseases that share a particular signature (immune response pattern) with the corresponding specific drug, even if that drug has not been approved for the particular disease in question (off-label use). This is especially important because the traditional nosology includes many rare, poorly defined disease entities (Figure 1) whose sufferers have been unable to benefit from recent therapeutic advances. If a patient has severe manifestations of one of these diseases, without response to conventional treatment, it is reasonable to apply to the health insurance carrier for reimbursement of off-label treatment. specific treatments for individual immune response patterns, along with the corresponding levels of evidence, therapeutic efficacy, and common side effects, are shown in the Table. Conversely, if the treatment for a particular immune response pattern is used for a skin disease with a different immune response pattern, there will be no benefit, and harm may result (eTable 1). Nearly all of the currently available evidence (mostly from small randomized and controlled trials, prospective and retrospective single-arm studies, and case series) is derived from studies of immunotherapy directed against the historical-descriptive disease entities, without any specific use according to the particular immune response pattern. The sole exception is a recently published study demonstrating that treatment with the aid of immune signatures at the patient level yields much better clinical responses than treatment for the conventional indications (19).

Figure 2

The differential treatment of inflammatory dermatoses according to their immune response patterns

Table

The efficacy and side-effect profile of specific treatments for the index diseases of the immune response patterns

Classic autoinflammatory diseases such as cryopurine-associated periodic syndromes (CAPS), familial Mediterranean fever, and Schnitzler syndrome have been effectively treated symptomatically with antibodies against cytokines of the IL-1 family (20). Autoinflammatory diseases with keratinization disorders (AIKDs) such as pustular psoriasis can also be effectively controlled with antibodies against the IL-36 receptor (21).

Specifically effective biologic drugs are also available for the treatment of type 2 skin diseases. The anti-IL-4Rα antibody dupilumab and the anti-IL-13 antibodies tralokinumab and lebrikizumab are effective against atopic dermatitis (see Table) and have been approved for this indication (22). The concept of stratified medicine implies that these drugs should be effective against other type 2 diseases as well. Current knowledge suggests that this is the case: dupilumab has already been approved for nodular prurigo (23), and there are positive case reports or case series for nummular eczema (24) and non-atopic hand eczema (e10). Aside from the target structures IL-4Rα and IL-13, further clinical efforts center on the development of antibodies against other key molecules of the type 2 immune response; of these, the anti-IL-31R antibody nemolizumab (e11) has reached the most advanced stage of testing.

Humoral type 2 skin diseases can also be effectively treated with specific biologic drugs. Aside from dupilumab, which was already mentioned above and is in advanced clinical testing for the treatment of bullous pemphigoid and chronic spontaneous urticaria, these prominently include the anti-IgE antibodies omalizumab and ligelizumab and the anti-CD20 antibody rituximab. These antibodies were largely ineffective against primarily cell-mediated type 2 skin diseases (e12), but omalizumab is approved for the treatment of chronic spontaneous urticaria (25) and rituximab for the treatment of pemphigus vulgaris (26). Here, too, the mode of action is likely to be applicable beyond the currently approved indications. For example, evidence suggests that bullous pemphigoid can be effectively treated with omalizumab and rituximab (27).

A wider range of targeted drugs is available for psoriasis vulgaris than for any other skin disease. Psoriasis vulgaris is a type 3-mediated disease that can be treated effectively, and with a favorable side effect profile, with antibodies against TNF-α, IL-17A, IL-17A/F, IL-17RA, IL-12p40, and IL-23p19 (Table). Among these, anti-TNF-α antibodies display the broadest efficacy and are not limited to diseases mediated by type 3 immunity. Case series and case reports have documented the successful use of adalimumab or infliximab against granulomatous (type 4a) diseases and diseases with an autoinflammatory component (see below); conversely, however, biologic drugs directed against IL-17 or IL-23 are even more effective against pure type 3 skin diseases than anti-TNF-α antibodies (28). Three type 3 biologic drugs have been approved for the treatment of hidradenitis suppurativa, namely adalimumab, the anti-IL-17A antibody secukinumab, and the anti-IL-17A/F bispecific antibody bimekizumab. Despite the lack of approval to date for type 3 biologic drugs against any skin disease other than psoriasis vulgaris and hidradenitis suppurativa, numerous case reports, case series, and clinical studies document their efficacy against psoriasis variants (e.g., palmoplantar pustular psoriasis) and other type 3 skin diseases such as folliculitis decalvans, severe acne, and pityriasis rubra pilaris. For skin diseases with a type 1 or type 4 immune response pattern, no drugs are yet available that neutralize individual cytokines or receptors, and broad-spectrum drugs are therefore the agents of choice.

For type 1 skin diseases, Janus kinase (Jak) inhibitors are emerging as the probable treatment of choice. The PanJak inhibitor ruxolitinib has already been approved as a topical treatment of vitiligo, and many other Jak inhibitors are now in clinical trials (29). The systemic JAK1/JAK2 inhibitor baricitinib and the JAK3/TYK2 inhibitor ritlecitinib have been approved for the treatment of alopecia areata, and other topical and systemic Jak inhibitors are in clinical trials (30). The pan-Jak inhibitor ruxolitinib is available for the treatment of graft-versus-host disease (e13). No drugs have yet been approved for other type 1 skin diseases such as lichen ruber planus, virus- or checkpoint inhibitor-associated skin diseases, and cutaneous lupus erythematosus, but JAK inhibitors are likely be effective against thee diseases as well, as can be concluded from numerous case reports and case series (e1, e14).

Among type 4 skin diseases, granulomatous diseases such as granuloma annulare and cutaneous sarcoidosis can be treated, under certain circumstances, with TNFα inhibitors such as adalimumab or infliximab. Conversely, however, TNFα inhibitors can also induce granulomatous changes as a side effect (e15, 31). An effect that is desirable in the treatment of sterile granulomas can lead to the unwanted endogenous reactivation of, e.g., tuberculosis in infectious granulomas (e16). In any case, such effects on granulomatous reactions are largely limited to TNFα inhibitors and are not seen with other type 3 biologic drugs. Indolent tuberculosis must be ruled out before the start of any treatment with anti-IL-17 and anti-IL-23 biologic drugs (32).

There are very few therapeutic options to date against skin collagenoses or fibrosing diseases. Rituximab has shown good results against systemic sclerosis, but not morphea (e17). Broad-spectrum immunomodulators such as methotrexate remain the treatment of choice for this group of diseases (33). JAK inhibitors are now being studied in multiple trials (e18).

Assigning a skin disease to an immune response pattern

The immunological response patterns (signatures) discussed above manifest themselves with the typical clinical and histopathological features that are described. In practice, however, overlapping phenotypes and clinical pictures are common. For example, nummular eczema (24) and eczematized psoriasis (34) clinically, histologically, and immunologically display mixed type 2 and type 3 response pattern—yet, for each of these two diseases, only one response pattern reflects the causative mechanism of the disease: nummular eczema has been successfully treated with type 2 biologic drugs, and eczematous psoriasis with type 3 biologic drugs (34). It follows that the specification of the immune response pattern is useful for diseases with overlapping features as well, and indeed especially for these diseases. Even when the skin changes are prominent on specific locations such as the hands or scalp, or when they are generalized, as in erythroderma, a specific immune response pattern may be difficult to assign. For example, when the changes affect the palms of the hands, the differential diagnosis between psoriasis and eczema cannot be made on clinical grounds alone in an estimated 50% of cases (35). In such situations, biomarkers that enable assignment to a specific immune response pattern can be vital aids to therapeutic decision-making.

Such biomarkers were defined in a recent study of 201 patients with various inflammatory skin diseases (19). An algorithm derived from 600 immune-associated genes enabled the assignment of a skin sample to key immune response patterns or immune modules. This classification was found to be superior to diagnosis on conventional clinical grounds: specific treatment for clinical type 2 (eczema) and type 3 (psoriasis) diseases was effective only when the drug corresponded to the immune response pattern of the individual patient’s disease. 6 of the 78 patients tested were treated with a mismatched drug, unsuccessfully in all cases; when treatment with a well-matched drug was given afterward, it was successful in all six cases (19).

Perspectives

Mild inflammatory skin diseases are usually treated topically in accordance with the existing guidelines. Systemic therapies are recommended for moderate to severe disease, or when there is rapid clinical progression. The guidelines do not specify under what circumstances conventional or biologic agents should be given as first-line treatment for type 2 and type 3 diseases. With the advent of biosimilar drugs, conventional options have lost much of their relevance in the field of psoriasis. Most patients with atopic dermatitis, in Germany are given a biologic drug as first-line treatment if systemic treatment is indicated. Stratified medicine based on immune response patterns is taking on an expanding role in routine clinical practice, as it enables a more accurate classification of inflammatory skin diseases which, in turn, can be used to select the targeted drugs that are most likely to be effective. The treatment of many rare skin diseases also stands to benefit from the clinical advances and the new biologic agents and small-molecule drugs that will come about through the immunological reclassification of inflammatory skin diseases. Barriers still remain to the full integration of stratified medicine in dermatoimmunology:

• the frequent lack of valid biomarkers for assigning a skin disease to a particular immune response pattern (36);
• practical impediments to the use and measurement of these biomarkers in routine clinical practice;
• and the approval process, which, unlike the approval process for anticancer drugs, does not currently allow approval based on an immune response pattern, with the result that modern systemic treatment for many rare diseases can only be provided off label (37). In any case, stratified medicine can only be a stepping stone for dermatoimmunology, on the way toward truly personalized medicine, in which we will be able to predict clinically relevant parameters on the level of the individual patient, such as the risk of developing a comorbidity or the likelihood of response to a particular treatment.

Conflict of interest statement
NGS has received lecture honoraria from, and is a member of the advisory boards of, the Abbvie, Janssen, and Novartis companies. NGS is a co-founder of, and holds shares in, Dermagnostix and Dermagnostix R&D.

SW has received lecture honoraria from, and is a member of the advisory boards of, the Abbvie, Almirall, Boehringer Ingelheim, Galderma, GSK, Leo Pharma, Lilly, Pfizer, Sanofi, and Regeneron companies.

MS has received lecture honoraria from, and is a member of the advisory boards of, the Abbvie, Amgen, BMS, Celgene, Galderma, GSK, Janssen, Leo, Lilly, MSD, Mundipharma, Novartis, Regeneron, Pfizer, Sanofi, and UCB companies.

KG has received lecture honoraria from, and is a member of the advisory boards of, the Abbvie, Almirall, Bristol Myers Squibb, Boehringer Ingelheim, Celltrion, Eli Lilly, Janssen Cilag, Leo Pharma, Novartis, Pfizer, UCB Pharma, and Viatris companies.

AE has received lecture honoraria from, and is a member of the advisory boards of, the Biotest, MSD, Galderma, Janssen, Abbvie, BMS, Roche companies.

KE has received lecture honoraria from, and is a member of the advisory boards of, the Abbvie, Almirall, BMS, Boehringer Ingelheim, Galderma, Leo, Lilly, Janssen, Incyte, Novartis, Pfizer, Sanofi, and UCB companies. He is a co-founder of, and holds shares in, Dermagnostix and Dermagnostix R&D.

Manuscript received on 23 May 2024, revised version accepted on
28 February 2025.

Translated from the original German by Ethan Taub, M.D.

Corresponding author
Prof. Dr. med. Kilian Eyerich, PhD

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