Development of Morphea Following Treatment with an ADA Biosimilar: A Case Report.

BACKGROUND: Tumor necrosis factor alpha (TNFα) is a pivotal cytokine involved in the pathogenesis of certain inflammatory diseases, such as rheumatoid arthritis (RA), spondyloarthropathies, and inflammatory bowel diseases. In the last two decades, TNFα inhibitors (TNFi) have revolutionized the treatment and outcome of the above disorders. However, the use of TNFi has been associated with the development of many autoimmune phenomena and paradoxical skin manifestations that may present as the same type of clinical indications for which the TNFi effectively used. Thus, they may display as arthritis, uveitis, colitis, psoriasis, and several other cutaneous clinical manifestations, among them the development of morphea, a localized scleroderma skin lesion. CASE PRESENTATION: We describe a 58-year-old woman with seronegative RA, refractory to methotrexate, who was treated with ABP-501 (Hefiya), an adalimumab (ADA) biosimilar and developed an oval-shaped, deep skin lesion of approximately 3.5cm in size, affecting the left part of her back compatible with morphea 3 months after the initiation of therapy. ADA biosimilar was discontinued and two months later, she had substantial skin improvement. CONCLUSION: This is the first report of morphea manifestation during TNFi biosimilar since the patient had no other trigger factors for morphea development like trauma and infections. Physicians dealing with patients treated with TNFi biosimilars should be aware of paradoxical skin reactions, among them morphea; thus, close monitoring, a minute and careful clinical examination, and a follow- up check are required.

Morphea-like discoid lupus erythematosus in a patient with a history of polyacrylamide gel injection: A case report.

BACKGROUND: Discoid lupus erythematosus (DLE) is an autoimmune disease with multifactor etiology which develops in genetically susceptible patients. Rarely, DLE lesions can mimic other connective tissue disorders such as morphea. The growing application of soft tissue fillers is associated with increasing complications. Some substances used for soft tissue augmentation such as silicon implants may trigger lupus erythematosus diseases. CASE REPORT: Here we report a case of morphea-like discoid lupus erythematosus developed several years after polyacrylamide dermal filler (PAAG) injection for facial rejuvenation. CONCLUSION: As noninvasive procedures like dermal filler injections are increasing worldwide, physicians may consider the long-term probable side effects of these compounds.

Platelet-Rich Plasma Combined Fat Transplantation for the Treatment of Bleomycin-Induced Murine Scleroderma.

BACKGROUND: Low-fat retention induced by inflammation limits the clinical application of fat grafting for treating localized scleroderma (LS) patients. Novel methods to improve the therapeutic outcome are needed. OBJECTIVE: The aim of the study is to investigate the effect of platelet-rich plasma (PRP)-assisted fat transplantation on skin fibrosis and adipose survival in the LS model. METHODS: The LS model was established by the injection of bleomycin into BALB/C nude mice, which were randomly divided into the following 4 groups: healthy control, LS disease group model, fat transplantation group, and PRP+ fat transplantation group. The mice received a subcutaneous injection at back with phosphate-buffered saline, fat, or 20% PRP+ fat. Factors of immunoregulation, angiogenesis and adipogenesis were measured. RESULTS: Platelet-rich plasma-combined fat transplantation significantly attenuated dermis fibrosis by reducing the production of type III collagen. The fat retention in the PRP+ fat transplantation group was 43 ± 4 mg, significantly higher than 22 ± 15 mg in the fat transplantation group (P = 0.0416). The level of tumor necrosis factor α and interleukin 2 showed no significant difference between the groups. The expression of angiogenesis factors, vascular endothelial growth factor, hepatocyte growth factor, platelet-derived growth factor, and CD31, significantly increased in the PRP+ fat transplantation group. The expression of adipogenesis factors, insulin-like growth factor 1 receptor, extracellular signal-regulated kinase, anti-CCAAT-enhancer-binding proteins, and peroxisome proliferator-activated receptor γ, also significantly increased in the PRP+ fat transplantation group. CONCLUSIONS: The results demonstrated that PRP-combined fat transplantation attenuated dermis fibrosis and raised fat survival in the LS model by promoting angiogenesis and adipogenesis through insulin-like growth factor 1 receptor/extracellular signal-regulated kinase signaling pathway.

Morphea after initiation of dupilumab in two pediatric atopic dermatitis patients.

Morphea is a rare multifactorial autoimmune disorder characterized by a complex and dynamic interplay between Th1 and Th2 signaling. Active clinical trials are currently investigating the safety and efficacy of dupilumab for the treatment of primary morphea. Here, we present two cases of morphea that developed in pediatric atopic dermatitis patients treated with dupilumab. These findings may support a causal relationship between IL-4 receptor blockade and the development of the early inflammatory phase of morphea.

TRPA1 as a potential factor and drug target in scleroderma: dermal fibrosis and alternative macrophage activation are attenuated in TRPA1-deficient mice in bleomycin-induced experimental model of scleroderma.

BACKGROUND: Systemic sclerosis is a rheumatoid disease best known for its fibrotic skin manifestations called scleroderma. Alternatively activated (M2-type) macrophages are normally involved in the resolution of inflammation and wound healing but also in fibrosing diseases such as scleroderma. TRPA1 is a non-selective cation channel, activation of which causes pain and neurogenic inflammation. In the present study, we investigated the role of TRPA1 in bleomycin-induced skin fibrosis mimicking scleroderma. METHODS: Wild type and TRPA1-deficient mice were challenged with intradermal bleomycin injections to induce a scleroderma-mimicking disease. Macrophages were investigated in vitro to evaluate the underlying mechanisms. RESULTS: Bleomycin induced dermal thickening and collagen accumulation in wild type mice and that was significantly attenuated in TRPA1-deficient animals. Accordingly, the expression of collagens 1A1, 1A2, and 3A1 as well as pro-fibrotic factors TGF-beta, CTGF, fibronectin-1 and YKL-40, and M2 macrophage markers Arg1 and MRC1 were lower in TRPA1-deficient than wild type mice. Furthermore, bleomycin was discovered to significantly enhance M2-marker expression particularly in the presence of IL-4 in wild type macrophages in vitro, but not in macrophages harvested from TRPA1-deficient mice. IL-4-induced PPARγ-expression in macrophages was increased by bleomycin, providing a possible mechanism behind the phenomenon. CONCLUSIONS: In conclusion, the results indicate that interfering TRPA1 attenuates fibrotic and inflammatory responses in bleomycin-induced scleroderma. Therefore, TRPA1-blocking treatment could potentially alleviate M2 macrophage driven diseases like systemic sclerosis and scleroderma.

Tocilizumab for Corticosteroid-Refractory Immune Checkpoint Inhibitor-Induced Generalized Morphea.

This case report describes a 78-year old woman with a stage IIA BRAF wild-type melanoma on the left leg who experienced a grade 2 vitiligo, a marked skin thickening, and painful swelling of the limbs.

Paclitaxel-induced diffuse scleroderma with possible scleroderma-renal crisis: a case report and literature review of taxanes-induced scleroderma.

INTRODUCTION/OBJECTIVES: Scleroderma is a rare complication in taxanes therapy. Although individual cases of taxanes-induced scleroderma have been reported, the clinical manifestation and treatment outcomes were reviewed and summarized rarely. This study reported a patient who developed diffuse scleroderma and possible scleroderma renal crisis after paclitaxel therapy for ureter cancer. METHOD: A PubMed literature review on published cases of taxanes-induced scleroderma up until April 2022 was included for analysis. RESULTS: The search identified 27 patients with adequate information for analysis. Of the 28 patients, including the one presented here, 22 were female. Peripheral edema was the most common symptom in all but one patient, and often accompanied by erythema in 11. Symptoms usually occurred in half of the patients within the 4th course of treatment. Skin lesions gradually progressed to skin fibrosis, and extended proximally. Internal organ involvements were uncommon. Antinuclear antibody tests were positive occasionally, but anti-Scl70 and anti-centromere usually were negative. Taxanes therapy was discontinued, continued and unavailable in 21, 3, and 4 patients, respectively. Corticosteroids for skin lesions with or without immunosuppressive drugs were given to 15 patients. Of 25 patients with available skin outcomes, 19 improved. There was no significant skin improvement between those who did or did not receive skin treatment (62.5% vs. 75.0%, p = 0.37). Skin usually improved after discontinuing taxanes. CONCLUSION: Taxanes-induced scleroderma is different from idiopathic scleroderma. Physicians should be aware of this condition in order to provide early diagnosis and apply appropriate management in order to avoid serious complications from severe skin sclerosis. Key Points • Scleroderma is a rare but unique and serious complication of taxanes therapy • Skin manifestations and distribution are similar to idiopathic scleroderma, but vascular phenomenon, internal organ involvement and scleroderma-associated auto-antibodies are presented rarely. Skin improvement usually occurs shortly after discontinuing taxanes • The role of immunosuppressive therapy in treating taxanes-induced scleroderma is not clear.

Generalized morphea following the COVID vaccine: A series of two patients and a bibliographic review.

The appearance of morphea after vaccination has been reported to date as single and deep lesions that appear exactly at the site of the skin puncture. It was therefore postulated that the origin could be the trauma related to the injection. The aim of this article is to review the various hypotheses offered in the published literature about generalized morphea following vaccination. We present two cases of generalized morphea after COVID-19 vaccination and review the published literature on immune-related cutaneous reactions. As previously reported, antigenic cross-reactivity between vaccine spike proteins and human tissues could cause certain immune-mediated diseases, including generalized morphea. Herein we report two cases of generalized morphea probably induced by the COVID-19 vaccine, given the temporal relationship with its administration. In summary, environmental factors such as vaccination against SARS-COV-2 could induce an immune system dysregulation, which would have an important role in the pathogenesis of morphea. We present two cases of generalized morphea probably induced by the COVID-19 vaccine, given the time elapsed between vaccination and the onset of the skin lesions.

Drug-induced scleroderma-like lesion.

Drug-induced scleroderma-like lesion is a condition in which administration of a drug induces skin sclerotic lesions similar to systemic sclerosis or morphea. The clinical manifestations of drug-induced scleroderma-like lesion can be divided into two types: scleroderma-like lesions and morphea-like plaques. A wide variety of drugs can cause drug-induced scleroderma-like lesion. Bleomycin, L-tryptophan, vinyl chloride, and phytonadione (vitamin K1) have been reported, but in recent years, cases due to chemotherapeutic agents, such as taxane-based agents, gemcitabine, and tegafur-uracil, and immune checkpoint inhibitors have increased. Drug-induced scleroderma-like lesion differs from systemic sclerosis in that it does not include Raynaud's phenomenon, nail-fold capillary abnormality, organ involvement, such as reflux esophagitis, interstitial pneumonia, renal crisis, or anti-nuclear Abs. On the other hand, there are reports of cases in which Raynaud's phenomenon, positive conversion of anti-nuclear Abs, and development of skin sclerosis from the fingers developed after initiation of the drug. Whether the skin sclerosis improves after discontinuation of the drug depends on the patient. In patients with severe skin sclerosis, functional impairment, such as flexion contracture of the fingers, may occur, and systemic therapy, such as steroids, may be necessary. When treating patients with skin sclerosis, it is important to keep in mind the possibility that the sclerotic lesion may be induced by a drug.

Atezolizumab-induced scleroderma: a rare complication.

Few cases of programmed death-ligand 1 inhibitor-induced scleroderma have been reported and their clinical features remain unpublished. Optimal management is, therefore, unknown and an autoantibody association has yet to be identified. We present the case of a female in her 60s who developed skin thickening after starting atezolizumab for metastatic non-small cell lung cancer. Skin biopsy 7 months after symptom onset showed histological changes consistent with scleroderma. Anti-PM/SCL-75 antibody was positive. Atezolizumab was discontinued and treatment was started with mycophenolate mofetil. After 5 months, she experienced mild improvement in skin thickening. Earlier identification of this complication may limit morbidity in this disease process, which otherwise has limited treatment options. In suspected cases, obtaining scleroderma-associated autoantibodies may help with earlier diagnosis.

Morphea following treatment with pembrolizumab for melanoma with metastatic lymph nodes: case report and review of literature.

Pembrolizumab is a humanized IgG4 isotype mAb that the targets and blocks the programmed cell death protein 1 receptor on lymphocytes. Its use in treating metastatic melanoma is associated with increased overall survival compared to other older immunotherapies. Several adverse effects have been noted including both systemic and cutaneous manifestations. As a relatively novel treatment option, many new cutaneous manifestations are still being observed, occurring at various times after initiation of therapy. Previously noted cutaneous adverse effects include sarcoid-like reactions, rash, and changes in preexisting lesions or scars. Here we present a case in which biopsy-proven morphea developed after completion of pembrolizumab therapy.

Nivolumab-induced plaque morphea in a malign melanoma patient.

BACKGROUND: Nivolumab is one of the targeted cancer therapy agent that acts to increase the immune responses by inhibition of antiprogrammed-death-receptor 1, which is one of the check points of the immune response. Nivolumab can be used to treat malign melanoma, lung, renal, head and neck, colorectal, hepatocellular cancers, and special cases of Hodgkin lymphoma. AIMS: We aimed to report a rarer cutaneous side effect of nivolumab because of the increasing uses of this agent in various cancer treatments. METHODS: We present a 48-year-old female, metastatic melanoma patient who developed plaque morphea lesion without any systemic involvement during nivolumab treatment. Plaque lesion responded well to use of topical corticosteroid and calcipotriol. RESULTS: Numerous cutaneous side effects associated with nivolumab have been reported in the literature. The most common cutaneous side effects are maculopapular rash, pruritus, and vitiligo. Morphea and disorders from this spectrum reported due to PD-1 inhibitors in the literature are; morphea, sclerodermoid changes, eosinophilic fasciitis, and lichen sclerosis. CONCLUSION: Patients who are treated by PD-1 inhibitors may be examined carefully in terms of morphea and scleroderma-like conditions although they are not as common as other cutaneous side effects.