Prurigo nodularis forecast: Light type 2 inflammation with high chances of fibrosis

Two recent publications1Alkon N. Assen F.P. Arnoldner T. Bauer W.M. Medjimorec M.A. Shaw L.E. et al.Single-cell RNA sequencing defines disease-specific differences between chronic vnodular prurigo and atopic dermatitis.J Allergy Clin Immunol. 2023; 152: 420-435Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar,2Ma F. Gharaee-Kermani M. Tsoi L.C. Plazyo O. Chaskar P. Harms P. et al.Single-cell profiling of prurigo nodularis demonstrates immune-stromal crosstalk driving profibrotic responses and reversal with nemolizumab.J Allergy Clin Immunol. 2024; 153: 146-160Abstract Full Text Full Text PDF Scopus (3) Google Scholar in the Journal of Allergy and Clinical Immunology set out to better understand the pathogenesis of a skin disease that has remained a conundrum in dermatology for ages, namely, prurigo nodularis (PN). PN is a chronic skin disease characterized by intensely pruritic, hyperkeratotic nodules symmetrically distributed on the extremities and the trunk. The severe pruritus forces patients to engage in self-mutilating scratching, leading to disfigurement and poor quality of life. Despite this significant disease burden, therapeutic options in PN have been very limited until recently, as evidenced by the majority of patients with PN reporting dissatisfaction with their therapy.3Misery L. Chronic prurigo.Br J Dermatol. 2022; 187: 464-471Crossref PubMed Scopus (15) Google Scholar The previous lack of effective therapies is reflective of our poor understanding of PN pathogenesis. Although a broad range of pathogenetic factors have been proposed, including a dysregulated immune response and activation of neuroinflammatory circuits, a precise picture of the cellular and molecular events driving PN has been lacking. The work by Alkon et al1Alkon N. Assen F.P. Arnoldner T. Bauer W.M. Medjimorec M.A. Shaw L.E. et al.Single-cell RNA sequencing defines disease-specific differences between chronic vnodular prurigo and atopic dermatitis.J Allergy Clin Immunol. 2023; 152: 420-435Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar and Ma et al2Ma F. Gharaee-Kermani M. Tsoi L.C. Plazyo O. Chaskar P. Harms P. et al.Single-cell profiling of prurigo nodularis demonstrates immune-stromal crosstalk driving profibrotic responses and reversal with nemolizumab.J Allergy Clin Immunol. 2024; 153: 146-160Abstract Full Text Full Text PDF Scopus (3) Google Scholar now sheds new light on the pathogenesis of PN by providing a map of lesional PN skin at single-cell resolution, while at the same time delineating PN from atopic dermatitis (AD), a type 2–driven inflammatory skin disease that shares certain clinical and pathophysiologic commonalities with PN. In fact, an atopic predisposition or even active AD is found in up to 50% of patients with PN, which has led some authors to hypothesize that PN might be a variant of AD rather than a disease entity on its own.3Misery L. Chronic prurigo.Br J Dermatol. 2022; 187: 464-471Crossref PubMed Scopus (15) Google Scholar However, the newly published data show that PN displays unique functional characteristics in multiple cellular compartments, allowing for a clear distinction from AD. To obtain a comprehensive view of PN pathogenesis, both studies1Alkon N. Assen F.P. Arnoldner T. Bauer W.M. Medjimorec M.A. Shaw L.E. et al.Single-cell RNA sequencing defines disease-specific differences between chronic vnodular prurigo and atopic dermatitis.J Allergy Clin Immunol. 2023; 152: 420-435Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar,2Ma F. Gharaee-Kermani M. Tsoi L.C. Plazyo O. Chaskar P. Harms P. et al.Single-cell profiling of prurigo nodularis demonstrates immune-stromal crosstalk driving profibrotic responses and reversal with nemolizumab.J Allergy Clin Immunol. 2024; 153: 146-160Abstract Full Text Full Text PDF Scopus (3) Google Scholar performed single-cell RNA sequencing (scRNA-seq) of lesional PN and AD skin and compared it to skin from healthy controls. Ma et al2Ma F. Gharaee-Kermani M. Tsoi L.C. Plazyo O. Chaskar P. Harms P. et al.Single-cell profiling of prurigo nodularis demonstrates immune-stromal crosstalk driving profibrotic responses and reversal with nemolizumab.J Allergy Clin Immunol. 2024; 153: 146-160Abstract Full Text Full Text PDF Scopus (3) Google Scholar also included nonlesional PN skin. Methodologically, Alkon et al1Alkon N. Assen F.P. Arnoldner T. Bauer W.M. Medjimorec M.A. Shaw L.E. et al.Single-cell RNA sequencing defines disease-specific differences between chronic vnodular prurigo and atopic dermatitis.J Allergy Clin Immunol. 2023; 152: 420-435Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar further used T-cell receptor sequencing to measure clonal diversity of the infiltrating T cells, whereas Ma et al2Ma F. Gharaee-Kermani M. Tsoi L.C. Plazyo O. Chaskar P. Harms P. et al.Single-cell profiling of prurigo nodularis demonstrates immune-stromal crosstalk driving profibrotic responses and reversal with nemolizumab.J Allergy Clin Immunol. 2024; 153: 146-160Abstract Full Text Full Text PDF Scopus (3) Google Scholar additionally performed spatial sequencing, thus obtaining information regarding the location of the cell clusters identified by scRNA-seq. Finally, Ma et al2Ma F. Gharaee-Kermani M. Tsoi L.C. Plazyo O. Chaskar P. Harms P. et al.Single-cell profiling of prurigo nodularis demonstrates immune-stromal crosstalk driving profibrotic responses and reversal with nemolizumab.J Allergy Clin Immunol. 2024; 153: 146-160Abstract Full Text Full Text PDF Scopus (3) Google Scholar integrated their findings with previously published bulk RNA-seq data from patients with PN who were treated with nemolizumab, an IL-31Rα–blocking antibody showing promising results in clinical trials of PN (see later in this article). Thus, both studies show considerable overlap in their methodologic approach, thereby providing a welcome opportunity for cross-validation of key findings; however, they still complement each other by either zooming in on the T-cell diversity (Alkon et al1Alkon N. Assen F.P. Arnoldner T. Bauer W.M. Medjimorec M.A. Shaw L.E. et al.Single-cell RNA sequencing defines disease-specific differences between chronic vnodular prurigo and atopic dermatitis.J Allergy Clin Immunol. 2023; 152: 420-435Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar) or the effects of therapeutic IL-31Rα blockade (Ma et al2Ma F. Gharaee-Kermani M. Tsoi L.C. Plazyo O. Chaskar P. Harms P. et al.Single-cell profiling of prurigo nodularis demonstrates immune-stromal crosstalk driving profibrotic responses and reversal with nemolizumab.J Allergy Clin Immunol. 2024; 153: 146-160Abstract Full Text Full Text PDF Scopus (3) Google Scholar). Key common findings of the 2 studies show that PN is characterized by a strong fibrotic response in the stromal compartment, an abnormal activation of keratinocytes, and a dampened type 2 inflammatory response as compared with that characterizing AD. The stromal compartment shows activated fibroblasts and endothelial cells with increased features of angiogenesis, fibrosis, and extracellular matrix production. PN seems to display a unique mesenchymal dysregulation, thus clearly distinguishing PN from AD. This is consistent with a well-known histologic characteristic of PN: dermal fibrosis. At the epidermal level, keratinocytes in PN show a highly inflammatory phenotype and altered epidermal differentiation. Network and correlation analyses suggest that these changes are downstream of a TH2 cell/TH22 cell immune response in both AD and PN, which may explain why histologically, both diseases show hyperkeratosis and acanthosis. Overall, the epidermal response did not show strong distinguishing features between AD and PN, with the exception of a minor type 1 immune response seen in PN keratinocytes, which might reflect cellular stress as a result of repeated scratching. Finally, in the immune compartment in PN, both studies find abundant lymphoid and myeloid cells showing a type 2 polarization that is dampened compared with that in AD. Nevertheless, TH2 cytokines and type 2 response genes are still clearly upregulated in PN skin versus in healthy skin. Interestingly, and in line with the findings of a previous bulk RNA-seq study,4Tsoi L.C. Hacini-Rachinel F. Fogel P. Rousseau F. Xing X. Patrick M.T. et al.Transcriptomic characterization of prurigo nodularis and the therapeutic response to nemolizumab.J Allergy Clin Immunol. 2022; 149: 1329-1339Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar there is a minor TH17 cell/TH22 cell response seen in PN that might reflect an immune response to extracellular microbes invading the excoriated skin and might help explain the partly psoriasiform epidermal changes seen in histology. Moreover, this minor TH17 cell response might help prevent infections of skin lesions in PN, which are observed less commonly than in AD. Treatment with the IL-31Rα antibody nemolizumab has previously shown rapid reduction of itch intensity in patients with AD.5Ruzicka T. Hanifin J.M. Furue M. Pulka G. Mlynarczyk I. Wollenberg A. et al.Anti-interleukin-31 receptor A antibody for atopic dermatitis.N Engl J Med. 2017; 376: 826-835Crossref PubMed Scopus (415) Google Scholar Accordingly, the rapid pruritus improvement in patients receiving nemolizumab was not unexpected in patients with PN.6Stander S. Yosipovitch G. Legat F.J. Lacour J.P. Paul C. Narbutt J. et al.Trial of nemolizumab in moderate-to-severe prurigo nodularis.N Engl J Med. 2020; 382: 706-716Crossref PubMed Scopus (163) Google Scholar However, given the marked fibrotic changes of PN and its resistance to treatment with conventional therapy, how quickly the skin lesions healed after initiation of treatment with nemolizumab came as a surprise.6Stander S. Yosipovitch G. Legat F.J. Lacour J.P. Paul C. Narbutt J. et al.Trial of nemolizumab in moderate-to-severe prurigo nodularis.N Engl J Med. 2020; 382: 706-716Crossref PubMed Scopus (163) Google Scholar Interestingly, besides revealing reduction of both TH2 cell/IL-13 and TH17 cell/IL-17 responses,4Tsoi L.C. Hacini-Rachinel F. Fogel P. Rousseau F. Xing X. Patrick M.T. et al.Transcriptomic characterization of prurigo nodularis and the therapeutic response to nemolizumab.J Allergy Clin Immunol. 2022; 149: 1329-1339Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar gene expression analyses under IL-31Rα blockade revealed stabilization of extracellular matrix remodeling. In line with this observation, IL-31 has been shown to have a profibrotic effect by directly promoting excessive collagen production in fibroblasts. IL-31–stimulated fibroblasts, in turn, were shown to further drive TH2 cell polarization and IL-31 production.7Kuzumi A. Yoshizaki A. Matsuda K.M. Kotani H. Norimatsu Y. Fukayama M. et al.Interleukin-31 promotes fibrosis and T helper 2 polarization in systemic sclerosis.Nat Commun. 2021; 12: 5947Crossref PubMed Scopus (30) Google Scholar These processes would thus form a self-perpetuating loop via the IL-31/IL-31Rα axis and eventually lead to chronic fibrosis. These findings provide the basis for potential therapeutic exploration of IL-31Rα blockade in fibrotic skin diseases beyond PN, such as morphea or scleroderma. In fact, an IL-31Rα antibody attenuated skin fibrosis in a mouse model for systemic sclerosis.7Kuzumi A. Yoshizaki A. Matsuda K.M. Kotani H. Norimatsu Y. Fukayama M. et al.Interleukin-31 promotes fibrosis and T helper 2 polarization in systemic sclerosis.Nat Commun. 2021; 12: 5947Crossref PubMed Scopus (30) Google Scholar Given the rapid resolution of skin lesions and fibrotic changes during treatment with nemolizumab, it appears tempting to evaluate the effects of IL-31Rα blockade on debilitating sclerotic connective tissue disorders such as scleroderma or systemic sclerosis. The studies by Alkon et al1Alkon N. Assen F.P. Arnoldner T. Bauer W.M. Medjimorec M.A. Shaw L.E. et al.Single-cell RNA sequencing defines disease-specific differences between chronic vnodular prurigo and atopic dermatitis.J Allergy Clin Immunol. 2023; 152: 420-435Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar and Ma et al2Ma F. Gharaee-Kermani M. Tsoi L.C. Plazyo O. Chaskar P. Harms P. et al.Single-cell profiling of prurigo nodularis demonstrates immune-stromal crosstalk driving profibrotic responses and reversal with nemolizumab.J Allergy Clin Immunol. 2024; 153: 146-160Abstract Full Text Full Text PDF Scopus (3) Google Scholar differ in a few important respects. On the one hand, Alkon et al1Alkon N. Assen F.P. Arnoldner T. Bauer W.M. Medjimorec M.A. Shaw L.E. et al.Single-cell RNA sequencing defines disease-specific differences between chronic vnodular prurigo and atopic dermatitis.J Allergy Clin Immunol. 2023; 152: 420-435Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar focus in detail on the T-cell compartment and find an oligoclonally expanded CD8A+IL9R+IL13+ cytotoxic T-cell population unique to AD, suggesting an antigen-driven, disease-specific function of this previously undescribed subset of T cells. Alkon et al1Alkon N. Assen F.P. Arnoldner T. Bauer W.M. Medjimorec M.A. Shaw L.E. et al.Single-cell RNA sequencing defines disease-specific differences between chronic vnodular prurigo and atopic dermatitis.J Allergy Clin Immunol. 2023; 152: 420-435Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar further find that TH2 cells with a "pathogenic" TH2 cell phenotype (IL17RB+IL9R+PTGDR2+)8Bertschi N.L. Bazzini C. Schlapbach C. The Concept of Pathogenic TH2 Cells: Collegium Internationale Allergologicum update 2021.Int Arch Allergy Immunol. 2021; 182: 365-380Crossref PubMed Scopus (8) Google Scholar are a major source of the itch cytokine IL31 in both AD and PN, further underscoring the central role of TH2 cells in itch mediation in both diseases. On the other hand, Ma et al2Ma F. Gharaee-Kermani M. Tsoi L.C. Plazyo O. Chaskar P. Harms P. et al.Single-cell profiling of prurigo nodularis demonstrates immune-stromal crosstalk driving profibrotic responses and reversal with nemolizumab.J Allergy Clin Immunol. 2024; 153: 146-160Abstract Full Text Full Text PDF Scopus (3) Google Scholar expand their single-cell findings by integrating transcriptomic data from PN skin following treatment with the IL-31Rα antagonist nemolizumab.4Tsoi L.C. Hacini-Rachinel F. Fogel P. Rousseau F. Xing X. Patrick M.T. et al.Transcriptomic characterization of prurigo nodularis and the therapeutic response to nemolizumab.J Allergy Clin Immunol. 2022; 149: 1329-1339Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar,6Stander S. Yosipovitch G. Legat F.J. Lacour J.P. Paul C. Narbutt J. et al.Trial of nemolizumab in moderate-to-severe prurigo nodularis.N Engl J Med. 2020; 382: 706-716Crossref PubMed Scopus (163) Google Scholar They find that nemolizumab reverts the pathologic transcriptomic profile toward healthy skin in both stromal and immune cell populations, most prominently in fibroblasts and keratinocytes. Given that these cell populations are a major cellular target of IL-31 (ie, IL-31Rα+ cells), these results provide insights into the mechanism of action of nemolizumab in unprecedented detail, showing that IL-31R blockade suppresses the immune-stromal cross talk at the heart of PN pathogenesis. Given their similar methodologic setup, the 2 studies share some limitations. Using scRNA-seq, it is difficult to detect certain cell types that are known to be important for PN pathogenesis, such as nerve fibers. Yet, neural dysregulation has long been implicated in PN pathogenesis, manifesting as altered architecture and distribution of nerve fibers and pathologic secretion of neuropeptides.3Misery L. Chronic prurigo.Br J Dermatol. 2022; 187: 464-471Crossref PubMed Scopus (15) Google Scholar Future studies, potentially deploying novel technologies, will need to address the neural component of PN in more detail. Furthermore, both the newly described cell populations as well as the quantification of biologically active proteins such as cytokines still await confirmation at the protein level. Finally, harmonizeing scRNA-seq data and analysis thereof from different studies and then generalizing the findings remain a challenge. This is illustrated by the somewhat arbitrary definition of clusters from scRNA-seq data. For example, Ma et al2Ma F. Gharaee-Kermani M. Tsoi L.C. Plazyo O. Chaskar P. Harms P. et al.Single-cell profiling of prurigo nodularis demonstrates immune-stromal crosstalk driving profibrotic responses and reversal with nemolizumab.J Allergy Clin Immunol. 2024; 153: 146-160Abstract Full Text Full Text PDF Scopus (3) Google Scholar propose that COL11A1+ fibroblasts are one of the key profibrotic cell populations associated with PN pathogenesis. Alkon et al,1Alkon N. Assen F.P. Arnoldner T. Bauer W.M. Medjimorec M.A. Shaw L.E. et al.Single-cell RNA sequencing defines disease-specific differences between chronic vnodular prurigo and atopic dermatitis.J Allergy Clin Immunol. 2023; 152: 420-435Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar however, identify COL11A1+ fibroblast as mesenchymal fibroblasts of cartilage component without PN-specific features. Conversely, Alkon et al1Alkon N. Assen F.P. Arnoldner T. Bauer W.M. Medjimorec M.A. Shaw L.E. et al.Single-cell RNA sequencing defines disease-specific differences between chronic vnodular prurigo and atopic dermatitis.J Allergy Clin Immunol. 2023; 152: 420-435Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar find a unique CXCL14–/IL24+ secretory papillary fibroblast population and speculate that they might be involved in itch mediation via their expression of endothelin 1 receptor. A similar subset of CXCL14–/IL24+ fibroblasts was also found by Ma et al2Ma F. Gharaee-Kermani M. Tsoi L.C. Plazyo O. Chaskar P. Harms P. et al.Single-cell profiling of prurigo nodularis demonstrates immune-stromal crosstalk driving profibrotic responses and reversal with nemolizumab.J Allergy Clin Immunol. 2024; 153: 146-160Abstract Full Text Full Text PDF Scopus (3) Google Scholar to be enriched in, but not specific to, PN skin without pathogenic attributes. Despite these limitations, the publications discussed here enhance our understanding of PN pathogenesis and raise intriguing questions that will guide future research in the field. For instance, the functional effects of IL-31 on its immune and nonimmune target cells remain incompletely understood, not least outside the skin. Both the bone marrow and lymphoid tissue contain IL31RA+ cells, including macrophages and monocytes (proteinatlas.org). It will be interesting to study the (long-term) effects of IL-31R blockade in humans on global immune homeostasis to better understand the biology of IL-31 and potentially expand the clinical application of IL-31 inhibitors beyond PN and AD. Further, one wonders why blockade of the IL-4Ra with dupilumab shows the profound therapeutic effects in PN seen in recent clinical trials9Yosipovitch G. Mollanazar N. Stander S. Kwatra S.G. Kim B.S. Laws E. et al.Dupilumab in patients with prurigo nodularis: two randomized, double-blind, placebo-controlled phase 3 trials.Nat Med. 2023; 29: 1180-1190Crossref PubMed Scopus (26) Google Scholar and in the real world, given the strong contribution of stromal cells and the limited type 2 skewing of the immune response in PN. One possible explanation is that a certain fibroblast subpopulation acts as key effector cell in PN and that this population is sensitive to multiple TH2 cytokines, including IL-4, IL-13, and IL-31. Similar to IL-31, IL-4 and IL-13 also induce collagen production in fibroblasts,10Lee C.G. Homer R.J. Zhu Z. Lanone S. Wang X. Koteliansky V. et al.Interleukin-13 induces tissue fibrosis by selectively stimulating and activating transforming growth factor beta(1).J Exp Med. 2001; 194: 809-821Crossref PubMed Scopus (820) Google Scholar thereby promoting fibrosis. Using data from clinical trials with targeted therapeutics in conjunction with studies such as those discussed here has the potential to address the unanswered questions and unravel novel biologic pathways and pathogenic circuits for the benefit of the patients. Thus, the long-term forecast for PN and sclerosing skin disease might actually be quite sunny. Disclosure of potential conflict of interest: C. Conrad has received honoraria for serving as an adviser to AbbVie, Actelion, Almirall, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Galderma, Incyte, Janssen, LEO Pharma, MSD, Novartis, Pfizer, Samsung, and UCB. C. Schlapbach has received honoraria for serving as an adviser or speaker for AbbVie, Almirall, BMS, Incyte, LEO Pharma, Lilly, Kiowa Kirin, Novartis, Pfizer, and Sanofi and has received research funding from PPM Services. Single-cell profiling of prurigo nodularis demonstrates immune-stromal crosstalk driving profibrotic responses and reversal with nemolizumabJournal of Allergy and Clinical ImmunologyVol. 153Issue 1PreviewPrurigo nodularis (PN) is a chronic neuroimmune skin disease characterized by bilaterally distributed pruritic hyperkeratotic nodules on extremities and trunk. Neuroimmune dysregulation and chronic scratching are believed to both induce and maintain the characteristic lesions. Full-Text PDF Open Access