Central players in these processes are the myofibroblasts, which are activated early and characterized by a high amount of a-smooth muscle actin, high extracellular matrix production and contractile properties. These fibroblasts also produce and secrete growth factors and cytokines (TGF-ß, CTGF, PDGF, FGF-2, IL-6, IL-11 etc.), which act in an autocrine and paracrine mode and are involved in the regulation of many inflammatory processes [9]. A small percentage of these activated myofibroblasts may come from fibrocytes from the circulation, some are generated via epithelial and endothelial transition (see above) or are recruited from the fascia and the subcutaneous fat. Others are dermal resident cells, which are activated by cellular interactions and by cytokines and growth factors, released by macrophages and other inflammatory cells. Recently, it became clear that skin fibroblasts represent a highly diverse population of different subsets, which have specific functions. In localized scleroderma and systemic sclerosis, several of these populations have been characterized; they demonstrate different stages of activation, with some characteristics of the previously described myofibroblasts.

B-cells play a central role in initiating the inflammatory phase; they regulate T-cells in a complex network, secrete cytokines, and produce autoantibodies against cellular antigens. Their role in fibrotic reactions has been discussed for a long time. B-cells have more recently been used as targets of B-cell specific therapeutic monoclonal antibodies and of CAR T cell therapy to achieve B-cell depletion (see below). The results of the trials underline the role of B-cells in the control of some of the severe autoimmune diseases [10, 11].

T-cells are subdivided into a large number of different subsets, which can have profibrotic but also antifibrotic activities. Th1-cells produce IFN-γ, which is a well-known cytokine, regulated in many inflammatory diseases, leading to fibrosis. Th2-cytokines include IL-4, -5, -13 and have been associated with the development of fibrosis in many studies [12]. Also, Th17- and Th22-cells were found to be induced in several fibrotic processes, although IL-17 has also shown antifibrotic activities. Regulatory T-cells (Tregs) produce IL-10 and TGF-ß and are directly and indirectly involved in several pathways regulating the tissue response during fibrotic conditions. IL-11 belongs to the IL-6 family and has been shown to play an important role in myocardial fibrosis by regulating macrophage activity [13].

Macrophages are key players in the control of repair, scar formation and fibrosis. They exist in several subsets and have a high plasticity with either pro-inflammatory and pro-fibrotic activities or anti-inflammatory and pro-regenerative functions. They are major producers of the master cytokine TGF-ß, respond to Th2 signals and closely interact with fibroblasts [8, 14–18]. By modulating fibroblast functions, they can also regulate ECM deposition and its macromolecular arrangement, and they are considered to be crucial target cells for novel therapeutic approaches [17].

Occurrence of autoantibodies has been described in several of the fibrosing and sclerosing diseases. In lichen sclerosus, autoantibodies against the extracellular matrix protein 1 and against BP 180 (Collagen XVII) have been detected [19]. Both proteins are located close to the epidermal-dermal junction, which agrees with the inflammatory reaction in lichen sclerosus in the superficial papillary layer of the dermis. In localized/circumscribed scleroderma, mainly in patients with the linear and the generalized subsets, circulating antinuclear autoantibodies can be detected. In most patients with systemic sclerosis circulating autoantibodies directed against different cellular antigens are found; here these antibodies represent a crucial diagnostic feature and are characteristic for distinct subsets of the disease (see below). However, evidence for a pathophysiological role of most of these antibodies is still missing and they are thought to be secondary to the inflammation and tissue damage. In contrast, more recently other autoantibodies have been detected in patients with SSc, which are directed against extracellular antigens (cellular receptors or ECM constituents). These autoantibodies are thought to initiate cellular responses and may therefore be involved in the initiation and/or the perpetuation of the inflammatory/fibrosing response [20–23].

Following the initial injury with a damage of the vessel wall and the release of platelets, the different inflammatory cells form a close network and interact directly or indirectly with the tissue resident cells, the endothelial cells, the epithelial cells, pericytes and different subsets of fibroblasts. They are crucial for the activation and formation of myofibroblasts and specific fibroblast subsets in the fibrotic processes of the skin. They determine the expression of the specific disease, the clinical symptoms and the prognosis. These complex cellular interactions involving many cytokines and other mediators are summarized in Fig. 2. They also provide the opportunity for very specific therapeutic approaches, which have already today changed the treatment and management of patients in the daily practice.

Most of the novel therapies focus on endothelial cell damage, pro-inflammatory cytokines, the regulation of immunocompetent cells, the control of antibody synthesis. However, a direct influence of the fibrotic process itself is still not sufficiently developed. This article will address the main skin disorders that are associated and defined by marked cutaneous sclerosis, lichen sclerosus, the sclerodermiform Graft versus host disease (GvHD), metabolic fibrosing skin diseases, and localized scleroderma as well as systemic sclerosis.

We will discuss the classical therapeutic approaches for the daily clinical practice but also highlight new specific therapeutic developments.

Lichen sclerosus is a chronic inflammatory disease, affecting the skin and the mucous membranes across all age groups [24, 25]. It occurs in males and females, with a marked female predominance, similar to several other chronic inflammatory connective tissue diseases. Especially in young children and in elderly women the genital involvement with severe pruritus, pain/soreness and the development of strictures, results in a considerable reduction of the quality of life with sexual and urinary dysfunction [26]. Therefore, early diagnosis and early initiation of therapies is required. Skin lesions present as characteristic white, porcelain-like, often oval plaques with follicular hyperkeratosis. These plaques are sometimes surrounded by an inflammatory reaction, preceding the central fibrosis and atrophy. Disruption of the epidermal-dermal junction zone, due to the inflammatory reaction in the papillary layer of the dermis may result in blister formation.

Rarely lichen sclerosus can also spread over large areas of the integument and leads to severe burning and itching as well as to dermatogenous contractures. Differentiation from some subsets of localized scleroderma (e.g., lichen sclerosus like localized scleroderma) can be difficult but histological analysis of a biopsy is helpful. There are a number of reports highlighting a genetic background in some patients [27]. The pathophysiology is similar to localized scleroderma, but the disease remains limited to the dermo-epidermal zone and the papillary dermis [27]. Interestingly, autoantibodies against the extracellular matrix protein 1 have been described some time ago, however it remains unclear, whether these are pathogenic, represent an initial or secondary event. Lichen sclerosus represents a facultative precancerous condition. Given its potential to progress to a vulvar or penile carcinoma, early diagnosis and early therapy are crucial together with regular check-ups [28, 29]. In children, however, prognosis of Lichen sclerosus is good [30].

Therapy remains symptomatic, with highly potent corticosteroids (Class III or IV), mainly in the inflammatory initial phase of the disease and reduction of the dosages depending on the disease development. Also, calcineurin inhibitors may be used as a maintenance therapy or if topical corticosteroids are contraindicated or insufficient (off-label) [25]. These approaches have to be supported by careful skin care (co-treatment with topical ointments instead of creams/gels and avoidance of trigger factors) and sometimes also surgical interventions (e.g. circumcision in male patients). UV therapy (UVA1) is recommended only as a second-choice option in women with genital LS, in adults with extragenital LS, while considering carcinogenic potential and practical feasibility. This therapy is not recommended for genital lichen sclerosus in male patients or in pediatric populations [25].

There is currently not sufficient evidence for systemic immunosuppressive therapeutic options. However, several reports describe the use of systemic or topical JAK inhibitors (off-label) [31]. In addition, acitretin or methotrexate are suggested by current guidelines as off-label options, when systemic treatment is required in adults with genital and/or extragenital LS (off-label) [25]. Potential therapeutic options have been recently reviewed and European guidelines have been published [25].

The sclerodermiform GvHD is a fibrosing subtype of the chronic graft-versus-host disease, representing a prevalent immune-mediated complication among patients following allogeneic hematopoietic stem cell transplantation (HSCT) [32]. Chronic GVHD occurs in 30–70% of patients after HSCT and increases the risk of morbidity and mortality [33].It commonly presents with lichenoid and/or sclerotic lesions, leading to dermatogenous contractures, pruritus, and/or pain, and sometimes ulcerations, caused by fibrotic change in skin, subcutaneous tissue, and joint/fascia. Additional clinical signs include pigmentary changes, poikiloderma, cutaneous xerosis, and lichen sclerosus-like plaques, which may present in an asymmetric or patchy pattern, but can also occur in a generalized distribution. It is driven by a chronic immune dysregulation following allogeneic stem cell transplantation, leading to donor T-cell-mediated tissue injury, which promotes fibroblast and myofibroblast activation, ultimately resulting in excessive cutaneous ECM deposition [34].

Systemic corticosteroids remain the standard first-line therapy for chronic GVHD, but at least one-third of affected patients do not respond and require additional treatment. Extracorporeal photopheresis is widely used for corticosteroid-refractory cases [35]. Recently, several agents have been approved for treatment-refractory chronic GVHD. Ibrutinib and ruxolitinib are now established options following the failure of first-line therapy [36–38]. Belumosudil and axatilimab are indicated after at least two prior lines of treatment failure. Emerging options include ivarmacitinib, TDI-01, rovadicitinib, and pimicotinib, which target distinct inflammatory and fibrotic pathways [33, 35, 39, 40].

Scleroedema adultorum is characterized by a diffuse hardening of the skin, mainly in the face, the neck and the upper arms but sometimes also the trunk. The palpation of the skin, however, differs from typical sclerotic diseases. There are prominent follicular openings and the skin appears to be tight and swollen. This is due to an excessive deposition of acid mucopolysaccharides. There are not many fibroblasts in the dermis and the collagen fibers as well as the elastic network appear to be unchanged. It is postulated that circulating factors lead to a specific reprogramming of fibroblasts to induce synthesis of hyaluronic acid but direct evidence is still lacking. Several subsets of scleroedema adultorum can be differentiated (see Table 1). The disease can occur in young children, probably associated with a post infectious reaction and later in life in the course of diabetes mellitus. The prognosis in patients with a streptococcal infection is usually good and after antibiotic therapy it slowly disappears. In scleroedema associated with diabetes there is usually a prolonged duration even if diabetes is treated. In some patients scleroedema of Buschke is associated with paraproteinemia (Table 1). Some patients respond to UVA therapy or also high dose of intravenous immunoglobulins and radiotherapy have been used with some success. Limited response has been reported for glucocorticoid and immunosuppressive approaches. More specific therapies are not yet available and a better understanding of the molecular mechanisms involved in the disease is urgently required [3].

Scleromyxoedema, is a rare cutaneous mucinosis, which affects the skin but may also present with extracutaneous manifestations and usually occurs in association with a monoclonal gammopathy. It affects middle-aged adults with no ethnicity or gender predominance. Typical clinical signs are numerous waxy, firm papules/plaques, which represent the mucin and ECM deposition. Extracutaneous manifestations can involve the heart, the gastrointestinal tract, the lungs, the musculoskeletal system as well as the renal, ocular and nervous system. This disease can lead to significant morbidity and mortality in case of systemic involvement. The pathogenesis is still not fully understood, but the impact of the associated monoclonal gammopathy and the underlying plasma cell clone continues to be debated. Circulating cytokines (such as IL-1, IL-4, IL-17, TNF-alpha and TGF-ß) are suspected to initiate glycosaminoglycan synthesis and fibroblast proliferation within the skin. Up to now, no randomized clinical trials have identified drugs to improve the course of the disease of affected patients. Intravenous immunoglobulins (IVIG) is recommended as first-line treatment option. Alternative options are systemic corticosteroids and immunomodulatory drugs, such as thalidomide or lenalidomide [3].

Localized scleroderma (LoS, morphea or circumscribed scleroderma), represents a very heterogeneous spectrum of fibrotic skin diseases, which has led to classification systems comprising three to five different major categories with further subgroups, depending on regional guidelines [4, 41]. These classification systems differentiate limited, linear, generalized localized scleroderma, along with mixed presentations, superficial and deep variants, and the eosinophilic fasciitis [4, 41]. The European Dermatology Forum (EDF) guidelines differentiate into the limited, linear, generalized, deep and mixed form of localized scleroderma, including the eosinophilic fasciitis as a separate subtype within localized scleroderma [4].

The updated German guidelines again modified the classification system [41]. These guidelines included the plaque-type morphea, guttate morphea, atrophoderma of Pasini and Pierini, and also the deep morphea within the limited subtype of localized scleroderma [41].

Although affecting primarily the skin, some subsets of localized scleroderma can also involve deeper tissues (see Table 2). In these cases, affected subcutaneous tissue, including the fat, the fascia, the muscles, the joints and the bones. This can cause severe dermatogenous contractures, leading to growth/length differences of the affected extremity. Linear localized scleroderma of the face (en coup de sabre and Parry-Romberg syndrome) may also involve subcutaneous structures, leading to atrophy of fat, muscle, and bone. In these specific subtypes, involvement of the central nervous system (CNS), ocular abnormalities (such as uveitis and scleritis), jaw involvement with dental malalignment, and significant cosmetic disfigurement may also occur.

The pathogenesis of morphea is incompletely understood and likely multifactorial. Multiple external trigger factors, including Borelia bugdorferi infections have been discussed but convincing data are missing. Specific HLA class I and II alleles are associated with LoS and overlap with other autoimmune diseases, such as rheumatoid arthritis, autoimmune thyroid disease, type 1 diabetes, and multiple sclerosis [2, 42, 43]. Early LoS is characterized by increased Th1/Th17 responses, while later stages show a Th2-dominant profile. Key cytokines such as TGF-β, PDGF, and CTGF drive fibroblast activation and proliferation, resulting in increased collagen and extracellular matrix deposition [2].

Depending on the depth of skin involvement (superficial vs deep) and the degree of functional impairment (e.g., joint contractures or facial involvement): topical corticosteroids or topical calcineurin inhibitors/calcipotriol ointment are advised for superficial lesions (see Fig. 3). Also phototherapy with UVA1 or PUVA has shown anti-inflammatory and anti-fibrotic effects in patients with early superficial inflammatory stages of LoS.

More extensive and severe disease requires systemic therapy, typically with methotrexate as the first-line option. In highly active and inflammatory cases, systemic corticosteroids can be added within the first 3–6 months. Other treatment options have been reported in LoS, comprising MMF as second-line and abatacept as third-line treatment options. Other immunosuppressive or immune modulating drugs have been reported in case reports and case series of LoS, including rituximab, tocilizumab, JAK inhibitors, IVIG, azathioprine, apremilast [4].

SSc is a complex autoimmune connective tissue disease. It is initiated by an interplay of vascular damage, immune dysbalance, and progressive fibrosis.

Endothelial cell damage reduces nitric oxide production and promotes vasoconstriction, platelet activation, and abnormal angiogenesis and leads to the synthesis of proinflammatory cytokines (Endothelin-1, TNF-α, IL-6, IL-1β), chemokines (CXCL4, CCL2, CXCL8), and growth factors (VEGF, PDGF, endothelin-1, TGF-β) together with an increased expression of adhesion molecules and platelet activation. This vascular dysfunction causes clinical features such as Raynaud’s phenomenon, digital ulcers, pulmonary arterial hypertension and erectile dysfunction. This complex interplay between immune cells and tissue resident cells perpetuates not only the vascular dysfunction, but also induces the recruitment of other immune cells (Th2 T cells), which secrete transforming growth factor-ß (TGF-ß), interleukins (IL-13, IL-4, Il-10, Il-6) and activate fibroblasts to myofibroblasts and induce vasculopathy [44, 45]. Concurrently, the immune system becomes dysregulated – autoreactive T cells, B cells, and macrophages infiltrate the tissues, which release profibrotic cytokines such as transforming growth factor-β (TGF-β), interleukin-6, -1 (IL-6, -1), and platelet-derived growth factor (PDGF) while dendritic cells secrete type 1 interferon (IFN). All this together activates fibroblasts to excessive deposition of extracellular matrix, leading to fibrosis of the skin and affected organs. Clinically, this process manifests as progressive skin thickening, esophageal dysmotility, interstitial lung disease, myocardial fibrosis, and scleroderma renal crisis, which has a major impact on the quality of life of affected patients.

SSc occurs significantly more frequently in female patients, usually between 40 and 60 years.

SSc is classified into several subgroups – the diffuse cutaneous SSc (dcSSc), the limited cutaneous SSc (lcSSc), the SSc overlap syndrome, an undifferentiated or “very early” SSc, and systemic sclerosis sine scleroderma (see Table 3). These subtypes differ considerably with respect to organ manifestations, extent of skin involvement, autoantibody profiles, and disease course [46].

B-cells play a key role in the pathogenesis of several autoimmune processes including fibrosing skin diseases. They have been investigated in detail especially in scleroderma. They are thought to lead to disease progression by producing pathogenic autoantibodies and cytokines, and to interact with fibroblasts, endothelial cells, T cells, dendritic cells, and other immune cells. Therapeutic strategies targeting B-cells appear promising, through depletion, inhibition of their cytokines, or blockade of costimulatory signals. Inhibitors targeting CD20, CD19, and B-cell activating factor (BAFF), along with novel strategies such as CAR-T cell therapy, represent highly promising approaches for early disease intervention and sustained long-term remission [58].

Chimeric antigen receptor (CAR) T-cell therapy, originally developed for hematologic malignancies, has recently been discussed as a promising game changer for different multisystemic autoimmune diseases, including systemic sclerosis (SSc). This approach involves CD19-targeted CAR T-cells, which selectively deplete CD 19+B cell populations. This offers a potentially long-lasting “immune-reset” effect, in SSc. Recent studies have shown already promising results, with improvements in skin thickening, pulmonary function, and patient-reported outcomes in refractory SSc. A positive effect on skin with a reduction of the mRSS of 31% within the first 100 days of treatment [53, 66], an improvement of the ACR-CRISS score and an improvement of ground-glass opacities in the HR-CT scan with an increase of FVC, showing also a potential effect on lung involvement was noted in these studies [53].

Very recently, additional studies have been published [67] and several others are still running.

Although this therapeutic option seems to be powerful and innovative, it also carries significant risks that are highly relevant when considering to use it in autoimmune diseases. One of the main acute risks of CAR T-cell therapy are cytokine release syndromes (CRS) and neurotoxicity, while long-term risks include B-cell aplasia, infections, and cytopenias. Further clinical studies and careful patient selection, monitoring, and standardized management protocols are very important, to lower the risk of life-threatening side effects.

Inebilizumab, an afucosylated IgG1 monoclonal anti-CD19 antibody, depletes B-cells in a broader range than CD20 antibodies. It has been investigated in a phase I, randomized, placebo-controlled, escalating, single dose study, and has shown a potential effect on skin sclerosis, but not on pulmonary function [68, 69].

In a phase II, proof-of-concept, single center, open-label, single-arm trial, eleven dcSSc patients with severe skin involvement, have been treated with brentuximab vedotin, an anti-CD30 antibody, which is approved for the treatment of non-Hodgkin lymphoma. It helped to improve the mRSS in patients with severe skin thickening as well as the lung function (FVC) and the patient-reported outcomes [70, 71].

Abatacept is a recombinant, fusion protein comprising cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) linked to an immunoglobulin Fc fragment that inhibits T-cell co-stimulation by blocking CD28 by binding to CD80/CD86. In a phase 2, placebo-controlled trial, abatacept failed to demonstrate a significant improvement in mRSS. However, a subsequent subgroup analysis based on gene expression profiling suggested that mRSS improvement may occur only in patients with an inflammatory or normal-like molecular signature [72, 73]. However, it has also to be considered that Abatacept may increase the risk of infections and has been associated with potentially serious exacerbations of chronic obstructive pulmonary disease (COPD) [74].

Belimumab is an anti-BAFF human monoclonal antibody, which is already approved for the treatment of systemic lupus erythematosus. It blocks B-cell activating factor (BAFF), which has been shown to be increased in skin biopsies of the tight skin mouse model as well as in serum of patients with SSc [75, 76]. In a randomized, double-blind, placebo-controlled pilot study with 20 early dcSSc patients on mycophenolate treatment, additional belimumab showed a greater median improvement in skin fibrosis/mRSS compared to placebo, but did not reach statistical significance [77]. Interestingly, responders to belimumab demonstrated significant suppression of B-cell signaling and profibrotic gene pathways [77], which may increase the risk for adverse events [58]. Further studies might consider to use this approach together with a combination therapy.

Bruton’s tyrosine kinase (BTK) is an intracellular kinase, which plays an important role in the B-cell receptor (BCR) signaling pathway, supporting B-cell activation, proliferation, and survival. It offers an option to modulate disease relevant signaling processes, but not fully deplete B-cells [78].

Ibrutinib, an oral BTK inhibitor, has shown in preclinical studies in SSc the ability to modulate immune responses, attenuate fibrosis by interfering with profibrotic pathways, and exert anti-inflammatory effects, making it a promising therapeutic candidate [58].

Increasing evidence of type I interferon (IFN-I) pathway dysregulation, known as the “interferon signature” in SSc and in localized scleroderma provide the therapeutic rationale for Anifrolumab, targeting one of the key mediators for autoimmunity and fibrosis [79, 80]. Up to now, the type I interferon pathway represents a promising therapeutic target, but its efficacy in patients has not yet been proven, but it is used currently in clinical trials [81].

An interesting novel approach is the modulation of macrophage activation and their interaction with fibroblasts. This is based on several in vitro and mouse studies demonstrating that macrophages can directly modulate fibroblast activities [82, 83]. It has also been shown that this involves the activation of IL-4/IL-13 receptors. In addition, IL-4 and IL-13 have been reported to be overexpressed in scleroderma. Therefore, inhibition of the IL-4/IL-13 pathway has been thought to be a promising target. Based on this, romilkimab, a humanized, bispecific IgG4 monoclonal antibody targeting and neutralizing IL-4 and IL-13, demonstrated a statistically significant reduction in mRSS at 24 weeks in patients with diffuse cutaneous systemic sclerosis (dcSSc) in a randomized, placebo-controlled trial conducted on a background of stable immunosuppressive therapy [84] and dupilumab was successfully used in the treatment of keloids [85, 86]. Similar studies have been more recently initiated with localized scleroderma. Modulation of macrophage activity can also be achieved by a broad inhibition of cytokine pathways e.g. by JAK inhibitors [87].

Since TGF-ß has been identified as a master regulator in the induction of fibrosis, its inhibition has been considered a highly promising therapeutic strategy. However, TGF-ß has a variety of additional biological functions and is subject to complex regulatory mechanisms. It also interacts with several other cytokines, e.g. IL-17.

TGF-ß is present in 3 isoforms, which differ in their expression patterns and biological activities. Moreover, TGF-ß is secreted in an inactive form bound to latent TGF-ß-binding protein. Within tissues, this complex is anchored to extracellular matrix proteins, which on the one hand ensures a tight and complex regulation of this highly potent cytokine, and on the other hand also allows for rapid bioavailability of TGF-ß when required. Following an initial small study with a monoclonal antibody against TGF-ß1 (CAT-192/Metelimumab) [88], Fresolimumab, a neutralizing human monoclonal antibody against all three isoforms of TGF-ß, already showed in 2015 that it can rapidly inhibit TGF-ß regulated genes and improved mRSS in a small study of 15 patients [89]. Adverse events were anemia and bleeding [89]. In small studies also a TGF-ß 1/3 ligand trap has been used without convincing effects. As an alternative approach, monoclonal antibodies against avß6, an integrin involved in the activation of TGF-ß, have been used in Idiopathic pulmonary fibrosis (IPF) and inhibitors of the TGF-ß dependent signaling pathway have been investigated. More recently a clinical trial using antibodies specific for TGF-ß3 has been initiated [90]. It has also to be noted that TGF-ß leads to induction of Connective Tissue Growth Factor. (CTGF), which represents another potential antifibrotic target.

Brodalumab is a monoclonal antibody targeting the IL-17 receptor A (IL-17RA), which blocks the signaling pathway of multiple IL-17 cytokine family members. The IL-23/IL-17 axis is implicated in autoimmune and fibrotic diseases and in SSc, IL-17 and its receptor are upregulated in skin and fibrotic tissues in preclinical models, suggesting a pathogenic role in systemic sclerosis [91]. In a phase 1, open-label, single-arm study with 8 patients, brodalumab significantly reduced the mRSS [92], a finding that requires confirmation in larger, controlled clinical trials.

Since IL-23 is known to maintain the differentiation of TH-17 cells and induces secretion of other inflammatory cytokines such as IL-6 and IL-17, guselkumab, an anti-IL-23 antibody, appears to be a promising therapeutic option and has been used already in 3 SSc patients, who had SSc together with psoriasis vulgaris. These patients have shown a decrease of the modified Rodnan Skin Score, an improvement of the combined response index for SSc and a significant increase in the number of nailfold capillaries [93]. A multicenter, randomized, placebo-controlled, double-blind, proof-of-concept study of guselkumab in patients with SSc is completed in Japan, but no results are yet available.

IL-31 levels are shown to be elevated in plasma and fibrotic skin and lung tissue of a subset of systemic sclerosis patients, with overexpression of its receptor (IL-31RA) in fibroblasts of the skin and the lung. In skin fibroblasts, IL-31 promotes proliferation, collagen release, and profibrotic activation via pSTAT3 signaling. In vivo, IL-31 induces skin and lung fibrosis in mice. These findings identify the IL-31/IL-31RA axis as a potential profibrotic pathway contributing to fibrosis in systemic sclerosis, supporting nemolizumab as a promising therapeutic candidate [94].

JAK inhibitors are small-molecule agents that interfere with the JAK/STAT signaling pathway and thereby reduce cytokine and growth factor mediated signaling. They are orally available and can interfere with cytokine signaling pathways implicated in inflammation and fibrosis (for review see [95]). It has already shown a significant improvement in mRSS in SSc, with an acceptable safety profile [96]. It has also been used in several uncontrolled studies in patients with localized scleroderma. Although JAK inhibitors (e.g. baricitinib, upadacitinib und tofacitinib) represent promising therapeutic options for several fibrotic skin diseases exerting anti-inflammatory and anti-fibrotic properties the level of evidence is still low, due to the lack of randomized, placebo-controlled trials [97].

Ziritaxestat is a small, selective molecule that inhibits autotaxin, which is an extracellular lysophospholipase D enzyme responsible for the hydrolysis of lysophosphatidylcholine to form lysophosphatidic acid (LPA), a bioactive lipid mediator involved in inflammation and fibrosis [98]. In a randomized, placebo-controlled phase 2a study, in which patients with early dcSSc received standard immunosuppressants, an improvement in mRSS could be shown for patients treated with Ziritaxestat, compared to those with placebo [98]. The drug was generally well tolerated. Further large-scale, well-controlled studies are warranted to confirm these findings and define the therapeutic window for autotaxin inhibition in systemic sclerosis.

Another approach to modulate inflammatory and fibrotic activities is the activation of the Melanocortin receptors (MCRs), G-protein-coupled receptors, expressed on many different cell types. MCR-signaling reduces the activity of many proinflammatory cytokines. Whether this approach can be successfully used in fibrotic skin diseases, remains to be established [99].

Intravenous immunoglobulins (IVIg) are human polyspecific IgG, developed from the plasma of healthy individuals, increasingly used since decades for a wide range of autoimmune and inflammatory diseases. Its exact mechanism is still unclear but it is likely that it is involved in modulation of B- and T-cell receptor interactions and neutralization of pathogenic antibodies. In systemic sclerosis, preclinical and clinical studies have shown reductions in skin fibrosis and improved mRSS, particularly after repeated treatment courses [74, 100, 101]. It is also often used successfully in the therapy of patients with scleroedema adultorum and scleromyxoedema [3].