Upcoming treatments for morphea

Abstract Morphea (localized scleroderma) is a rare autoimmune connective tissue disease with variable clinical presentations, with an annual incidence of 0.4–2.7 cases per 100,000. Morphea occurs most frequently in children aged 2–14 years, and the disease exhibits a female predominance. Insights into morphea pathogenesis are often extrapolated from studies of systemic sclerosis due to their similar skin histopathologic features; however, clinically they are two distinct diseases as evidenced by different demographics, clinical features, disease course and prognosis. An interplay between genetic factors, epigenetic modifications, immune and vascular dysfunction, along with environmental hits are considered as the main contributors to morphea pathogenesis. In this review, we describe potential new therapies for morphea based on both preclinical evidence and ongoing clinical trials. We focus on different classes of therapeutics, including antifibrotic, anti‐inflammatory, cellular and gene therapy, and antisenolytic approaches, and how these target different aspects of disease pathogenesis.


| INTRODUCTION
Morphea (localized scleroderma) is a rare autoimmune connective tissue disease with variable clinical presentations, with an annual incidence of 0.4-2.7 cases per 100,000. Morphea occurs most frequently in children aged 2-14 years, and the disease exhibits a female predominance. 1 Morphea is typically found in patches and bands with thickened skin on the head, extremities, and trunk. Although morphea is considered a skin-limited disease, depending on the subtype and the affected anatomical location, it can cause significant disfigurement (hyperpigmentation and skin atrophy) and physical impairment (joint contracture). In addition, patients with morphea on head are at risk of ocular and neurological complications. There are currently efforts underway to update and improve the disease classification but morphea is generally classified into five groups of plaque, generalized, bullous, linear, and deep. The theories on its pathogenesis are often extrapolated from studies of systemic sclerosis (SSc) due to their similar skin histopathologic features; however, clinically they are two distinct diseases as evidenced by different demographics, clinical features, disease course, and prognosis. [2][3][4][5][6][7][8][9][10][11] An interplay between genetic factors, epigenetic modifications, immune and vascular dysfunction, along with environmental hits are considered as the main contributors to morphea pathogenesis. 12 No cure for morphea exists, but advances in our understanding of the mediators and cellular pathways underlying fibrosis have revealed potential therapeutic targets to prevent permanent damage. Current treatment recommendations for morphea are limited, with a combination of systemic corticosteroids and methotrexate as the most common treatment option. 5,9,10 However, these are not disease-specific treatments and their long-term use is associated with many side effects. 13,14 Thus, there are unmet needs in both understanding morphea pathogenesis and identifying targeted therapies. Here, we review the new emerging treatments for morphea (Table 1) focusing on potential novel treatments based on preclinical studies or early-phase clinical trials for both morphea and cutaneous manifestations of SSc (Table 2). We discuss the rationale of investigations, including potential mechanisms of action and efficacy for specific clinical subtypes of morphea.

| ANTIFIBROTIC DRUGS
The histopathological hallmark of morphea is excessive deposition of extracellular matrix (ECM) in the skin, which is mainly composed of fibrillar collagens along with fibronectin, elastin, and tenascin C. This occurs as the result of inflammation-triggered fibroproliferation and differentiation of fibroblasts into myofibroblasts ( Figure 1).
Transforming growth factor-β (TGFβ) is one of the most well-studied profibrotic mediators in the skin. 12 Fresolimumab, a humanized antibody targeting TGFβ, is well-tolerated and had promising results in early stages of diffuse cutaneous SSc, 15 making it a possible treatment for morphea. Intracellular TGFβ signaling involves both SMAD-dependent and -independent pathways. The latter involves several tyrosine kinases, including ABL1, SRC kinase EGR1, signal transducer and activator of transcription 3 (STAT3), MRTFA, MRTFB, and FAK. 12 Imatinib, an ABL1-selective tyrosine kinase inhibitor, was not well-tolerated and did not show satisfying anti-fibrotic results in a clinical trial for treatment of SSc (Table 2). There is a trial of Imatinib ongoing for morphea patients (Table 1) with results pending.
Acting downstream of TGFβ, connective tissue growth factor (CTGF) works to stimulate fibrotic processes and is another potential therapeutic target for morphea. 16 Elevated levels of CTGF messenger RNA (mRNA) has been reported in morphea patients. 17 Iloprost, a prostacyclin analogue, has been found to temporarily suppress secretion of CTGF by fibroblasts. 16 FG-3013 (pamrevlumab), a fully recombinant human monoclonal antibody against CTGF was found to significantly attenuate peritoneal fibrosis in mouse models even below levels of fibrosis in CTGF knockout mice. 18 FG-3013 also inhibited recruitment of inflammatory cells, reduced vascular injury, and mitigated fibroblast migration. Numerous studies cite FG-3013's ability to attenuate different models of induced fibrosis, 19,20 and a randomized controlled trial (RCT) of patients with interstitial lung fibrosis who were randomized to either FG-3013 or placebo is awaiting trial results. 21 These data warrant a clinical trial of pamrevlumab for morphea patients.
Lidocaine, is another intriguing treatment for scleroderma and is associated with an improvement in cutaneous fibrosis. 22 Lidocaine reduces the activity of prolyl hydroxylase, an essential enzyme for the biosynthesis of collagen. 22 It could be beneficial in treating morphea, especially considering topical delivery for localized disease.
Lipophosphatidic acid (LPA) is generated at sites of cell injury and induces various cellular responses including ECM production through LPA1 and LPA6 receptors. 23,24 SAR100842, a LPA1 receptor antagonist, reversed dermal thickening in a mouse model of skin fibrosis. 24 A study of 15 patients with dcSSc who received SAR100842 showed a nonsignificant reduction in modified Rodnan skin score (mRSS), though the expression of LPA target genes were reduced in the active treatment group. 24 Future studies of SAR100842 are warranted based on these results for SSc and morphea. &Pirefenidone (PFD) is another agent that inhibits differentiation and proliferation of fibroblasts in animal models and in vitro studies. 25,26 A RCT is ongoing to examine PFD in SSc, and it could be of benefit for morphea patients.

| ANTI-INFLAMMATORY DRUGS
Both the innate and adaptive immune systems are involved in the inflammatory response in SSc as well as morphea. Various cytokines, chemokines, and inflammatory cell types are implicated in the cascade of events that lead to inflammation and release of profibrotic mediators. In the early stages of SSc and morphea, accumulation of monocytes, macrophages, T cells, B cells, mast cells, and eosinophils are observed histologically. 27,28 Here, we will breakdown different antiinflammatory targets for morphea based on their proposed mechanisms of action.    | 1133 F I G U R E 1 Potential drug targets for the treatment of morphea (created with Biorender.com). An unknown stimulus leading to tissue damage causes secretion of chemokines to recruit leukocytes to the dermis. Recruited leukocytes release cytokines including TGFβ and IL-1, and IL-6, in addition to IL-4, 8, 13 (not shown), leading to differentiation of progenitor cells (fibroblasts, pericytes, and endothelial cells) into myofibroblasts. Abnormally activated myofibroblasts lead to excess production of collagen, fibronectin, and tenascin-C, which act as DAMP and can activate undifferentiated fibroblasts into myofibroblasts. This self-fibrotic process leads to uncontrolled proliferation of myofibroblasts. Here we have highlighted potential treatments for both morphea and scleroderma in yellow, and treatments used previously for scleroderma in pink. Antifibrotic targets for treatments include: TGFβ, tyrosine-protein kinase, ABL-1 inhibitor, anti-CTGF, CB2 receptor agonist, PPAR-γ and pan-PPAR agonists, direct thrombin inhibitors. No current clinical trials for vascular targets exist for Morphea, but the 2017 EULAR treatment guidelines and current clinical trials for vascular agents targeting cutaneous manifestations of SSc are indicated. Anti-inflammatory targets for treatments include: MMF, cyclophosphamide, CB2 receptor agonist, anti-BAFF/BLyS (belimumab), anti-CD20, thalidomide, IL-6R blockade, abatacept, TGFβ inhibitor, PPAR agonist, UVA1 and UVB. CB2, cannabinoid-2; CTGF, connective tissue growth factor; DAMP, damage associated molecular patterns; EULAR, European League Against Rheumatism; IL, interleukin; PPAR-γ, peroxisome proliferator-activated receptor γ; SSc, systemic sclerosis; TGFβ, transforming growth factor-β

| Agents targeting cytokines
IL-6 and oncostatin M (OSM) are soluble mediators found in the serum of SSc patients and correlate with skin involvement. 12 Both signal through the IL-6 receptor (IL-6R) heterodimer and utilize the Janus kinase (JAK)-STAT pathway (see below). 29 OSM mediates both fibrosis and inflammation via STAT3, which has been linked to endothelial cell activation and increased expression of adhesion molecules. 30,31 Targeting IL-6 and its receptor had promising results in preclinical studies. 32 Tocilizumab, an IL-6 receptor antibody, showed modest effect on skin scores in SSc 12 in a RCT. There are active clinical trials investigating the effect of another IL-6R antibody, sarilumab, and GSK2330811, a humanized monoclonal antibody against OSM, on progression of morphea (NCT03679845) and dcSSc (NCT03041025), respectively. 33 In a study of mRNA gene expressions from skin biopsies taken from patients with diffuse cutaneous SSc and localized SSc showed significantly elevated levels of IL-7, IL-13, and interferon γ (IFNγ), 34 which seem to be potential targets. IL-7 is a modulator of T and B cell development, with antifibrotic effects in SSc patients presumably through inhibition of TGFβ secretion from fibroblasts. 35 IL-13 has an important role in B cell function, monocyte modulation, and seemingly has the ability to suppress production of TNF, IL-1, IL-8, and chemokine (C-C motif) ligand 3 (CCL3) from macrophages and monocytes. 36,37 Elevation of IL-13 correlates with a profibrotic response, whereas IL-7 and IFNγ worked to balance this response. 34 IL-1β, a member of the IL-1 family, has associations with the pathogenesis of SSc. 38 However, a recently completed RCT of rilonacept (IL-1β inhibitor) ( Table 2) showed no significant impact on cutaneous manifestations. Clinical trials targeting the other cytokines have not yet been conducted.
Polydeoxyribonucleotide (PDRN) exerts antiinflammatory responses by reducing TNF-α, IL-6, and high-mobility group box protein-1 (HMGB1), 39 which have been positively correlated with skin thickness in SSc. 40 The intramuscular form of PDRN, PLACENTEX, is currently being evaluated in SSc and could therefore be translated to morphea (NCT03388255). 41

| Chemokine targets
The selectivity of chemokines has been well-studied, and their ability to recruit specific leukocytes has been the target of many pharmaceutical interventions. Monocyte chemoattractant protein 1 (MCP1, or CCL2) is produced by numerous immune cells and acts as the predominant chemoattractant and activator of monocytes and T-cells. 42 Elevated expression of CCL2 mRNA has been found in SSc fibroblasts. 42 CCL3 also participates in the recruitment of monocytes and T helper lymphocytes, upregulates the expression of adhesion molecules, and correlates with a profibrotic response. 34,43 Interferon-inducible T cell (I-TAC, or CXCL11), a chemoattractant, has been found to attenuate bleomycininduced mouse model lung fibrosis with systemic treatment by inhibiting vascular remodeling. 44 Inhibition of CCL24, a chemokine that regulates inflammatory and fibrotic activities through its receptor, CCR3, was shown to decrease liver fibrosis in patients 45 and decrease activation of fibroblasts in bleomycin-induced mouse model fibrosis. 46 Fractalkine (CX3CL1), a chemokine expressed on proinflammatory cytokine activated endothelial cells and interacts with the receptor, CX3CR1, has been found to be strongly expressed in TGFβ-cultured skin fibroblasts. 47 CXCL4 was proposed to be an SSc biomarker that associates with progressive fibrosis in SSc patients, 48 and correlates strongly with worsening pulmonary and skin involvement. 49 CXCL4 is mostly secreted by plasmacytoid dendritic cells (pDCs), suggesting pDCs play a central pathological role in organ fibrosis. 49 CXCL4 is widely accepted as one of the most antiangiogenic chemokines, which we have previously discussed as an early event in SSc. 49 CXCL4 inhibits IFNγ, while increasing production of IL-13 and IL-4. 50 CXCL4 also promotes monocyte survival, 51 enhances monocyte binding to endothelial cell walls, 52 and, when used to differentiate monocytes invitro, strongly induces a specific macrophage subtype that is commonly seen in atherosclerotic plaques. 53 Kroef et al. 54 demonstrated that CXCL4 drives the release of PDGF, in mice bleomycin-induced fibrosis models. PDGF release led to TNF-α-induced cytokine release 55 and strongly activated fibroblasts. 48 As our understanding of the pathological timeline in cutaneous SSc and morphea grows, the CXCL4-PDGF mechanism will likely be a valid target for future clinical trials in homogenous subsets of patients.
There are currently no clinical trials targeted at inhibiting one or more chemokines or their receptors to our knowledge. These downstream mechanisms may play important roles in control of fibrosis in the future.

| Agents targeting immune-related receptors
Nuclear receptors, such as peroxisome proliferatoractivated receptors (PPARs), are another target implicating in the fibrogenesis in scleroderma. [56][57][58] PPARγ, has a role in numerous cellular functions including regulation of cell growth, innate immunity, and connective tissue biology 59 as it was shown to be a negative regulator of fibrosis both in vitro and in vivo. [60][61][62][63][64][65] PPARα is another target expressed in skin 66 which participates in skin homeostasis, repair, and morphogenesis. Stimulating PPARα attenuates fibrogenesis in different organs. 67,68 Fenofibrate, a PPARα agonist, as well as rosiglitazone and pioglitazone, both PPARγ agonists, have shown promising results in reducing inflammation and skin fibrosis. It must be noted these medications have brought about safety concerns, which are suspected to be due to their strong agonistic activity. 58,69,70 A novel pan PPAR-agonist with moderate activity, IVA337 (lanifibranor), is currently being studied in a proof-of-concept clinical trial. IVA337 was developed to mediate some of the safety concerns, as well as to synergistically reduce profibrotic responses ( Table 2). In vitro and in vivo preclinical studies have shown that IVA337 prevents, as well as induces regression of, fibrotic damage of skin. 71,72 If IVA337 continues to show efficacy and safety in its proofof-concept trial, morphea patients could benefit from pan-PPAR agonist drugs.
Cannabinoids exert anti-inflammatory and antifibrotic properties. 73 They activate G-protein-coupled cannabinoid 1 and 2 (CB-1 and CB-2) receptors. CB-2 found in skin and circulating immune cells. 56 The CB-2 agonist ajulemic acid (synthetic) has been found to block IL-6 release, and moderate the response of fibroblasts through the generation of prostaglandin J2 and lipoxin A4 at low doses and direct stimulation of PPARγ at higher doses (see below). 57,58 A phase II clinical trial of Lenabasum (ajulemic acid) showed efficacy in patients with SSc 69 ; however, another more recent trial did not show significant efficacy from Lenabasum versus placebo with preliminary data ( Table 2).

| Innate immune system targets
Toll-like receptors (TLRs) are transmembrane receptors expressed on both innate immune and stromal cells that are important for sensing foreign compounds known as pathogen-associated molecular patterns (PAMPs) as well as endogenous danger-associated molecular patterns (DAMPs). 74,75 DAMPs are released after cellular stress and initial vascular injury in SSc and morphea and are the source of the subsequent inflammatory cascade. 76 There is likely a propagation of DAMPs throughout the continuation of the disease, as they are released during ECM remodeling. Innumerable PAMPs and DAMPs trigger different TLRs and many have been found in increased levels in SSc patient serum and skin biopsies including S100A7 and the Epstein-Barr virus. [77][78][79][80][81][82] Abnormal TLR signaling has been observed in SSc, [83][84][85] but the related data for morphea patients has not been generated. TLR2 contributes to myofibroblast activation and differentiation. 86 TLR2 recognizes its ligands by forming a heterodimer with TLR1 or TLR6. Deletion of TLR2 in bleomycin-induced lung fibrosis mouse model, 87 or blocking its downstream pathway by ablation of the adaptor protein MyD88 in human and mouse pericytes, is associated with reduced inflammation and fibrosis. 88 A TLR2 blocking antibody, OPN-305, has been also found to be safe and tolerable and may be useful in SSc. 86,89 TLR3 has been successfully blocked with CNTO 3157, a monoclonal antibody that inhibits dsRNA-induced activation of NF-κB response pathways, though no studies have used it in fibrosis models. 90 A small subset of SSc patient biopsies showed significantly elevated levels of TLR3 in fibrotic skin lesions. 91 Endothelin-1 (ET-1), a profibrotic molecule, that is activated by TLR3 is associated with enhanced pulmonary fibrosis in preclinical and clinical studies as well as skin fibrosis in mice. 92 ET-1 levels are increased in skin of SSc patients. 93 Although there is no data on ET1 expression in morphea, it seems to be an auspicious target for skin fibrosis. 78 TLR4 induces fibrosis via TGFβ signaling, 94 and blocking its activity reversed fibrosis in various preclinical disease models. Expression of TLR4 and its ligands (HMGB1, heat-shock protein 90, tenascin C, and fibronectin) is also increased in the skin of SSc patients, highlighting the therapeutic benefit of blocking TLR4. TLR8 has been recently proposed as a future target for SSc. [95][96][97] TLR9 has strong association with TGFβ pathway and fibroblast activation in rapidly progressing idiopathic pulmonary fibrosis, suggesting a role in fibrosis. 98 TLR inhibition may have greater effects earlier in the disease course due to the prevention of fibroblast transition as well as TGFβ secretion. While systemic inhibition of TLRs carries an increased risk of infection, topical application, or cell-specific targeting, may prove a safer alternative for morphea patients.
A potential innate cell target in morphea is the dendritic cell (DC). DCs colocalize with fibroblasts and modulate their function and activity while expressing TGFβ1. 99,100 DCs express abnormally high levels of IL-10 in SSc pathology. 101,102 Preclinical trials are being conducted to target DCs. Abatacept binds the costimulatory molecule CD86 on DCs and may work in part by blocking APC interactions with T-cells (see below section on T cells). 103 Existing therapies that block DCs such as Anti-BDCA-2 antibodies targeting pDCs and nanobodies may have clinical significance in morphea. 104 Macrophages are one of the most abundant cells histologically in morphea lesions. They release proinflammatory and profibrotic mediators including TGFβ, PDGF, and IL-6. 73,105 The early phases of skin sclerosis involve infiltration of leukocytes and macrophages. 106 In patients with lSSc, Higashi-Kuwata et al. 107 showed an increased number of cells expressing CD204, which is expressed by M2 macrophages. Cyclic adenosine monophosphate (cAMP) is a ubiquitous second messenger molecule that is associated with numerous physiological responses including inflammation. 108 The activation of cAMP has been well studied and is mediated by PDE-4, which has been found to be expressed exclusively within inflammatory cells. 109 In a study by Maier et al., 73 PDE-4 inhibition was found to reduce skin fibrosis in different mice models of skin fibrosis. Inhibition of PDE4 resulted in decreased leukocytic infiltration in skin and decreased differentiation of M2 macrophages and their profibrotic cytokines. 73 A Phase 2, pilot study is ongoing to assess the safety and efficacy of a topical PDE4 inhibitor, crisaborole 2% ointment for adult patients with morphea (Table 1).

| Adaptive immune system
3.5.1 | Selective T cell-targeted therapies CD3 + and CD4 + T lymphocytes are the most abundant inflammatory cellular infiltrate in morphea. 110 The first signal in T cell activation is antigen-specific and is introduced via the T cell receptor and peptide-MHC molecules on the APC membrane. 111 The second signal is antigen nonspecific and is achieved via costimulatory molecules such as transmembrane protein CD28. 112,113 T cells that are activated without costimulation are susceptible to anergy, deletion, and dysregulated immune tolerance. 114 CTLA4 is homologous to CD28, and both interact with CD80/CD86 on APCs. 115 Preclinical data show that abatacept, a soluble recombinant fusion protein fused to the extracellular domain of CTLA-4 and CD80/86, reduces skin fibrosis and cutaneous monocytes, B-and T-cells in mice and circulating fibrocytes in an in vitro assay. 116,117 In early dcSSc, abatacept failed to improve skin score, though it showed a trend toward significance as well as manageable AEs. 118 In contrast, numerous published cases exist for the use of abatacept in patients with morphea and show promise for future potential large-scale trials. [119][120][121] A retrospective compilation of eight cases of juvenile morphea showed no progression of disease after 30 months treatment with abatacept, and some cases had improvements in preexisting lesions. 122 Blocking inducible T cell costimulator (ICOS), another member of the CD28-superfamily, has shown promising antifibrotic activity in preclinical models of skin fibrosis. 123 ICOS + T cells are study was terminated elevated in the skin of patients with SSc. 123 Further research is needed to identify safety and efficacy of anti-ICOS agents in humans.
Cyclophosphamide is a traditional immunosuppressive alkylating agent that cross-links cellular DNA and interferes with cell division. 124 It is a welltolerated and approved drug for treatment of progressive skin disease and lung fibrosis. 12 A recent clinical trial ( Table 2) of patients with diffuse cutaneous SSc showed a significant improvement in mRSS with high dose cyclophosphamide (50 mg/kg). Cyclophosphamide might be a favorable agent for severe cases of diffuse morphea.
Basiliximab, a chimeric monoclonal antibody targeting CD25 (IL-2Rα)-positive lymphocytes, significantly reduced skin thickness in SSc patients. 125 CD25 is expressed on activated T and B-lymphocytes and morphea patients have elevated serum interleukin-2 receptor levels. Of note, regulatory T cells (Tregs) also express high levels of CD25 and a few studies reported decrease in their number and activity in morphea 126 ; thus, it is not clear what the net outcome of targeting CD25 in the disease activity would be. There is accumulating evidence that suggests Tregs are important for maintenance of self-tolerance and prevention of autoimmunity. Frantz et al. 127 raises the question that the paradoxical increase in Tregs seen later in SSc compared with the low number seen early in the disease suggests an over-compensatory mechanism. Inhibition of Tregs later in the disease may prevent pathologic transition into effector T cells (Th17 and Th2). The immunosuppressive agent mycophenolate mofetil (MMF) works by inhibiting de novo synthesis of purines and suppresses T and B-lymphocyte proliferation. 128 Promising results have been seen (Table 2) in an RCT comparing MMF to placebo (plus cyclophosphamide) in terms of skin involvement.
Thalidomide, an immune modulator that works via suppressing Th1 cells, showed positive changes in skin fibrosis and number of infiltrated dermal CD8+ T-cells in SSc patients. 129 Pomalidomide is 100 times more potent than thalidomide. 130 A previously active pomalidomide study was terminated due to not meeting the primary endpoints (Table 2). Overall, pomalidomide is a powerful immunomodulatory agent with numerous mechanisms including TNFα inhibition, while its use would be limited to severe cases of morphea due to the severe side effects including significant birth defects and sensorimotor peripheral neuropathy.

| Selective B cell-targeted therapies
B-cells have been implicated in SSc pathogenesis. 131 Significant correlations have been found between both memory B cell phenotypes and autoantibodies with SSc severity, the specific antibodies are discussed elsewhere. 132 B lymphocyte stimulator (BlyS), a B cell stimulating cytokine, has been also correlated with worsening skin fibrosis in patients with morphea. 133 However, whether B cells and autoantibodies also play a role in morphea pathogenesis is less clear. Belimumab, a BlyS inhibitor, is currently being investigated in a single center placebo controlled RCT in patients with SSc (Table 2). However, it failed to show a significant reduction in cutaneous outcomes in a previous pilot trial. 134 Depletion of B cells with rituximab (RTX), an anti-CD20 monoclonal antibody, improved skin manifestations of SSc. 135-137 A 5-year open-label trial evaluating B cell depletion therapy with RTX in morphea patients (Table 1) is still awaiting results. B cell depletion therapy has been shown to be effective in mouse model skin thickening and shows a promising therapy for human trials. 138

| DUAL ANTI-INFLAMMATION AND ANTIFIBROTIC ACTIVITY
Phototherapy is the standard treatment for morphea, and it inhibits both fibrosis and inflammation. Current clinical trials include UVA-1 versus placebo, medium versus high dose UVA-1, UVB, and fractional carbon dioxide laser versus UVA-1 phototherapy (Table 1).
JAK-STAT pathways play key roles in inflammationdriven fibrosis (Figure 2). JAK/STAT pathways are activated by profibrotic cytokines and growth factors, IFNs, 139 numerous interleukins 140 and OSM (see above). STAT3 has a central role in TGFβ-induced myofibroblast differentiation and collagen production, and selective STAT3 inhibitors are in development. 141,142 STAT4 deficient mice exhibited reduced fibrosis following bleomycin administration. 143 Ruxolitinb, a JAK1 and JAK2 inhibitor, exerts anti-fibrotic effects and was initially developed for myelofibrosis. 144 Ruxolitinib has shown minimal responses in children with pan-sclerotic morphea; however, one study found ruxolitinib was able to decrease scleroderma fibroblast activity downstream of TGFβ. 145 In animal models, TGFβ-induced fibrosis is JAK2 dependent. 145,146 JAK inhibition was seen to decrease inflammation in humans with morphea, some showing reversal of fibrosis as well. 147 Baricitinib, another JAK1 and JAK2 inhibitor, had positive effects on skin fibrosis in one morphea patient 148 while tofacitinib, a JAK1 and JAK3 inhibitor, showed substantial success in numerous morphea cases. 146,149,150 A recently completed safety trial of tofacitinib showed a trend in improvement of skin fibrosis and no significant side effects over six months (Table 2). No JAK/STAT inhibitor has been examined at a large scale in morphea, though these case studies highlight their therapeutic potential.

| CELLULAR AND GENE THERAPY
Cellular therapies including autologous hematopoietic stem cell transplantation have been effective in improving skin scores in selected SSc patients, and in a case report of two pediatric pansclerotic morphea patients. [70][71][72]151 Some clinical trials have begun to implement utilization of autologous cells in combination with gene editing therapy.
FCX-013 is an autologous fibroblast, which is genetically modified using lentivirus and encoded for matrix metalloproteinase 1 (MMP-1) that breaks down collagen. FCX-013 is injected locally into fibrotic skin lesions, and the patient ingests an oral compound (Veledimex), which facilitates the MMP-1 protein expression. A current trial has been fasttracked for the treatment of moderate to severe SSc (Table 2). Gene editing technologies such as the clustered regularly interspaced sort palindromic repeats (CRISPR) system, have recently been used for manipulating the human genome and are effective for cutaneous diseases with a genetic component in preliminary research. 152 Future advances may facilitate the use of CRISPR in morphea.
6 | AGENTS TARGETING CELLULAR SENESCENCE, AGEING, AND DEATH: SENOLYTICS Evidence suggests that premature activation of agingassociated molecular mechanisms contribute to decreased self-tolerance 153 and the pathology of SSc 154 and bleomycin-induced models. 155 Cellular senescence is a term used to describe a state in which there is irreversible growth arrest. 156 A detectable phenotype for senescent cells, the senescenceassociated secretory phenotype (SASP), has been utilized in research to detect cellular senescence. In senescent fibroblasts, SASP has been associated with anti-fibrotic effects in liver fibrosis mouse models. 157 In a bleomycininduced lung fibrosis model, accumulation of senescentresistant myofibroblasts led to increased fibrosis. 158 Dasatinib is a selective BCR-Abl and Src family tyrosine kinase inhibitor. A recent analysis of a clinical trial of patients with SSc-related-interstitial lung disease showed decreased skin expression of SASP following dasatinib treatment correlated with clinical improvement. 159 Additionally, patients with higher levels of SASP at baseline showed greater improvement after senolytic treatment, 160 suggesting that clearance of pathogenic senescent cells in lesional tissue could be a measurable method of treatment response in future trials.
NADPH oxidase 4 (NOX4), a TGFβ responsive gene which is stimulated during the production of collagen, is another senolytic target. 12 Activation of NOX4 leads to creation of reactive oxygen species, and expression of various genes required for collagen processing (LOX, LOXL1-LOXL4, P4Ha3, SERPINH1, FKBP10, PLOD2), secretion, and ECM tissue deposition. 161 GKT-137831 (setanaxib), a NOX1/NOX4 inhibitor showed significant reduction in profibrotic TGFβ mediated effects on fibroblasts from sclerotic lesional tissue. Setanaxib is currently in a clinical trial for IPF patients, 162 and shows promise as another senolytic pathway of potential utilization for morphea.
Mitochondrial priming, 163,164 a term used to describe the proximity of the cell's mitochondria to apoptotic activation, is driven by the detection of increased matrix stiffness in myofibroblasts, and is further mediated by the balance of pro-and antiapoptotic BCL-2 family proteins. 165 Increases in BCL-2 family member expression leads to rapid elimination of myofibroblasts. This mechanism provides a model for resolution of tissue repair. In this model, cell survival becomes dependent entirely on BCL-X L . It is hypothesized that this "stiffness activated" myofibroblast model is dependent on mechanotransduction (continued stimulation of myofibroblasts via ECM stiffness). ABT-263 (navitoclax), a drug that displaces BCL-X L from proapoptotic BH3 homology BCL-2 protein (BIM), successfully treats well-established fibrosis in mouse models via induction of apoptosis. 166 Bleomycinchallenged mice have also been observed to have elevated levels of BCL-2 versus controls. No clinical trials for navitoclax or other BH3 mimetics exist for SSc or morphea patients. A new therapeutic strategy of BH3 profiling to determine an individual's mitochondrial priming would allow researchers to stratify groups of patients.

| MAJOR OPEN QUESTIONS
Questions remain in how morphea should be treated or managed, including: how can we safely test novel treatment approaches in clinical trials, if the goal is to limit inflammation early so as to prevent more extensive fibrosis? Testing novel therapeutics may require deviation from standard-of-care. Are there combination therapies or approaches that could prove better than standard of care? Ideally, halting inflammation and/or blocking immunefibroblast crosstalk would be combined with tissue remodeling to promote full homeostasis. How efficacious or translatable will senolytics be for morphea? Clinical trials specifically for morphea would need to be conducted.

| CONCLUSIONS AND PERSPECTIVES
Though morphea can cause significant morbidity due to physical disfigurement and decreased quality of life, most clinical and translational research studies have focused on cutaneous manifestations of SSc. With recent advancements in our understanding inflammation, fibrosis, cellular senescence, advanced cellular aging, and dysregulated mechanisms of cellular control in morphea, we hope that successful morphea treatment research continues to look at ways in which we can halt and reverse inflammatory-fibrotic processes. This will most likely be achieved through combination therapies that inhibit inflammation and reverse fibrosis. Ideal treatment regimens for morphea patients will