Identification and characteristics of patients with potential difficult-to-treat Psoriatic Arthritis: exploratory analyses of the Greek PsA registry.

OBJECTIVE: To present the characteristics of patients with potential difficult-to-treat (D2T) psoriatic arthritis (PsA). METHODS: We used data from the Greek multicentre registry of PsA patients. D2T-PsA was defined as follows: patients with at least 6-months disease duration, who have failed to at least 1 csDMARD and at least 2 bDMARDs/tsDMARDs with a different mechanism of action and have either at least moderate disease activity (MODA) defined as DAPSA > 14, and/or are not at minimal disease activity (MDA). Demographic and clinical characteristics were compared between D2T and non-D2T PsA patients. In two sensitivity analyses, patients classified as D2T solely according to the MODA or MDA criterion were examined separately. RESULTS: Among 467 patients included, 77 (16.5%) were considered D2T and 390 non-D2T PsA. Compared with non-D2T, patients with D2T PsA presented more commonly with extensive psoriasis (p< 0.0001) and were more likely to have higher BMI (p= 0.023) and a history of inflammatory bowel disease (p= 0.026). In the MODA and MDA sensitivity analyses, 7.5% and 12.5% of patients were considered D2T, respectively. In both sensitivity analyses, extensive psoriasis was again identified as an independent variable for D2T PsA (p= 0.001 and p= 0.008, respectively). Moreover, female gender (p= 0.034) in the MODA analysis and axial disease (p= 0.040) in the MDA analysis were independent variables for D2T PsA. CONCLUSION: Despite the availability of therapies, D2T PsA is common in real-life cohorts of patients with PsA and extensive psoriasis. High BMI, female gender, axial-disease, and history of IBD were also associated with D2T PsA.

Anti-TNF-α induced paradoxical psoriasis in patients with ankylosing spondylitis: a systematic review.

OBJECTIVES: The approval of TNF-a inhibitors (TNFi) was a breakthrough in the treatment of ankylosing spondylitis (AS). Although also effective in psoriasis, drug-related adverse events of onset of psoriasiform skin lesions - paradoxical psoriasis (PP) under TNFi have been reported. METHODS: We performed an electronic data search in MEDLINE via Pubmed and Cochrane library scientific databases from inception to January 2023, following the PRISMA guidelines. We assessed the distinct characteristics and frequency of risks for PP appearance in AS patients treated with different TNFi. RESULTS: PP was found in 0.5-1% of TNFi-treated AS patients and the latency period was 2-11 months. The safest TNFi in terms of PP induction was certolizumab, whereas the one most commonly associated with PP was infliximab. CONCLUSIONS: PP is an uncommon adverse reaction to TNFi treatment in AS patients and responds well to drug withdrawal. More large data studies need to be conducted though, to shed light on PP nature and management.

Low cognitive functioning and depressive symptoms in patients with rheumatoid arthritis and systemic sclerosis: a clinical study.

BACKGROUND: Recently, cognitive deficits occurring in rheumatic diseases have attracted scientific attention. Cognitive symptoms in patients with Rheumatoid Arthritis (RA) and Systemic Sclerosis (SSc) have not been thoroughly studied. This study aimed to assess cognitive function and its relationship with depressive symptoms in RA and SSc and compare it to mild neurocognitive disorder due to Alzheimer's disease (MiND) and to individuals without cognitive impairment. METHODS: Cognitive function and depressive symptoms were tapped with the Cognitive Telephone Screening Instrument plus (COGTEL+), the Serial Seven Test (SST), the Mini-Mental State Examination (MMSE) and the Geriatric Depression scale-15 (GDS), respectively. Statistical analyses included between groups-, correlation- and regression analyses. Demographic characteristics were considered in the regression models. RESULTS: The study included 30 individuals with RA, 24 with SSc, 26 adults without cognitive impairment and 33 individuals with MiND. Lower performance in verbal short-term memory, concentration/attention, verbal fluency and MMSE in patients with RA compared to individuals without cognitive impairment was detected. Of note, performance on verbal fluency, concentration/attention, inductive reasoning and MMSE was lower in RA compared to MiND. Individuals with SSc performed worse in verbal fluency and in MMSE in comparison to adults without cognitive deficits. Verbal fluency deficits in SSc exceeded that in MiND. Performance on MMSE, COGTEL+, prospective memory, working memory, verbal fluency and concentration/attention was related to GDS scores, which did not vary across the groups. CONCLUSIONS: Patients with RA and SSc encountered cognitive dysfunction, which partially pertains to depressive symptoms. Of note, the severity of cognitive dysfunction in many cases exceeded that of MiND.

The role of anti-eosinophilic therapies in eosinophilic granulomatosis with polyangiitis: a systematic review.

Eosinophilic granulomatosis with polyangiitis (EGPA) is an antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, mostly affecting small-sized arteries and usually occurring in patients with an allergic background. Eosinophils seem to play a significant role in the pathogenesis of the disease and, therefore, biologics targeting interleukin 5 (IL5), a cytokine tightly linked to eosinophils, have emerged as a promising therapeutic tool. A systematic review of Medline was conducted from 2007 to 2022 to search for data regarding the use of anti-IL5 therapies in patients with EGPA. Ongoing or unpublished trials were also searched in ClinicalTrials.gov and the World Health Organization trials portal. The efficacy and safety of mepolizumab, an anti-IL5 monoclonal antibody (mAb), was confirmed by a randomized controlled trial (RCT), although a significant proportion of patients did not respond to this treatment. Other studies showed that both doses of 100 mg and 300 mg of mepolizumab are almost equally effective in EGPA. Benralizumab, an anti-IL5 receptor mAb has preliminary promising results and an RCT is planned to be conducted. Apart from their clinical efficacy in EGPA, anti-IL5 therapies may have steroid-sparing properties. Anti-IL5 therapies seem to be effective and safe in patients with refractory/relapsing EGPA and can be used as a steroid-sparing treatment. Nevertheless, more research is needed to clarify the pathophysiology of the disease; this may potentially lead to the identification of biomarkers to pinpoint patients most likely to respond to anti-IL5-blockade.

Treatment of digital ulcers in systemic sclerosis: recent developments and future perspectives.

Digital ulcers (DUs) comprise the main manifestation of vasculopathy and are a major cause of disability in patients with systemic sclerosis (SSc). A literature search in Web of Science, PubMed and Directory of Open Access Journals was performed in December 2022 to identify articles published in the last decade regarding the management of DUs. Prostacyclin analogues, endothelin antagonists and phosphodiesterase 5 inhibitors have shown promising results both as a stand-alone treatment and in combination for the treatment of existing and prevention of new DUs. Moreover, autologous fat grafting and botulinum toxin injections, although not readily available, can be of use in recalcitrant cases. Many investigational treatments with promising results could pave the way for a paradigm shift in the treatment of DUs in the future. Despite these recent advances, challenges remain. Better-designed trials are of paramount importance to optimise DU treatment in the years to come. Key Points • DUs are a major cause of pain and reduced quality of life in patients with SSc. • Prostacyclin analogues and endothelin antagonists have shown promising results both as a stand-alone treatment and in combination for the treatment of existing and prevention of new DUs. • In the future, a combination of more powerful vasodilatory drugs, perhaps in conjunction with topical approaches, may improve outcomes.

The role of B cells in the pathogenesis of systemic sclerosis: an update.

The pathogenesis of SSc is incompletely understood, but several lines of evidence suggest that B cells are involved. Effector B (Beff) cells are hyperactivated and produce autoantibodies (autoAbs), and regulatory B cells (Bregs) are decreased, although a recent study reported a defect in central B cell tolerance. AutoAbs appear before fibrosis, and some have direct profibrotic effects, while others also induce microvasculopathy. Recently, a study found that B cells reactive to topo I with high affinity produce IL-6 and cause fibrosis in mice, whereas B cells with low affinity for topo I produce IL-10 and inhibit fibrosis. Ibrutinib, a Bruton's tyrosine kinase inhibitor, promoted B cells with low affinity for topo I and decreased fibrosis. These findings provide a rationale for innovative B cell-directed strategies for managing SSc, such as ibrutinib or chimeric antigen receptor T cells, particularly in the early inflammatory stage of the disease.

Identification of outcome domains in immune checkpoint inhibitor-induced inflammatory arthritis and polymyalgia rheumatica: A scoping review by the OMERACT irAE working group.

INTRODUCTION: Immune checkpoint inhibitors (ICI), increasingly used cancer therapeutics, can cause off-target inflammatory effects called immune-related adverse events (irAEs), including ICI-induced inflammatory arthritis (ICI-induced IA) and polymyalgia rheumatica (ICI-induced PMR). There are no validated classification criteria or outcome measures for these conditions, and adaptation of treatment recommendations from corresponding rheumatic diseases may not be appropriate. We summarized clinical descriptors of ICI-induced IA and ICI-induced PMR and aggregated domains used for these conditions in order to inform the development of a core set of outcome domains. METHODS: As the initial step of the core domain set generation process, we systemically searched Medline (Pubmed), EMBASE, Cochrane, and CINHL through March 2021 to identify all studies that provide both clinical descriptions and domains relevant to ICI-induced IA and ICI-induced PMR. Domains were mapped to core areas, such as pathophysiological manifestations, life impact, resource use, and longevity/survival, as suggested by the OMERACT 2.1 Filter. RESULTS: We identified 69 publications, over a third of which utilized non-specific diagnoses of "arthritis," "arthralgia," and/or "PMR". Other publications provided the number, the distribution and/or names of specific joints affected, while others labeled the irAE as the corresponding rheumatic disease, such as rheumatoid arthritis or spondyloarthritis. Most distinct domains mapped to the pathophysiology/manifestations core area (24 domains), such as signs/symptoms (13 domains), labs (6 domains), and imaging (5 domains), with harm domains of adverse effects from irAE treatment and fear of irAE treatment decreasing ICI efficacy. Forty-three publications also referenced irAE treatment and 35 subsequent response, as well as 32 tumor response. CONCLUSION: There is considerable heterogeneity in the domains used to clinically characterize ICI-induced IA and ICI-induced PMR. There were several domains mapped to the pathophysiologic manifestations core area, although several publications highlighted domains evenly distributed among the other core areas of life impact, longevity/survival and resource use.

Is there a Role for Anti-IL-5 Therapies in Eosinophilic Fasciitis?

Introduction: Eosinophilic Fasciitis (EF) is a rare disease, originally proposed as "diffuse fasciitis with eosinophilia" by Shulman in 1974. Symptoms of EF include peripheral eosinophilia accompanied by symmetrical inflammation of the subcutaneous fascia and muscle, usually locating in the upper arms or thighs. There is no approved standard of care treatment. Methods: Taking into account that eosinophils may be pathogenetically involved in EF, we performed a review on Medline focusing on anti-Interleukin-5 (IL-5) therapies in EF. Results: Only one case of a patient with EF has been reported who was successfully treated with reslizumab, an anti-IL-5 therapy. The patient had EF refractory to the commonly used immunosuppressive treatment but when reslizumab was added, the patient experienced remission of her symptoms. Discussion: The exact aetiology of EF is still unclear, and many therapeutic approaches have been tested. Commonly used immunosuppressive agents, such as corticosteroids are not always effective and associate with significant side effects. Eosinophils seem to have a role in the pathogenesis of the disease; anti-eosinophilic therapies targeting IL-5/IL-5 Receptor could be an attractive alternative for the treatment of the disease.

Disease Profile and Achievement of Therapeutic Goals in a Modern, Nationwide Cohort of 923 Patients with Psoriatic Arthritis.

Background: Psoriatic arthritis (PsA) is a heterogenous chronic inflammatory disease affecting skin, joints, entheses, and spine with various extra-musculoskeletal manifestations and comorbidities. The reported patient, disease and treatment characteristics in the modern therapeutic era are limited. Methods: In this cross-sectional, multi-centre, nationwide study, we recorded the demographic, clinical, and therapeutic characteristics as well as the comorbidities of patients with PsA seen for 1 year (1/1/2022-31/12/2022). Results: 923 patients (55% females) with a median (IQR) age of 57 (48-65) years and a mean disease duration of 9.5 years were enrolled. Family history of psoriasis and PsA was noted in 28.3% and 6.3%, respectively. Most patients had limited psoriasis (BSA<3: 83%) while enthesitis, dactylitis, nail and axial involvement reported in 48.3%, 33.2%, 43% and 25.9% of patients, respectively. Regarding comorbidities, approximately half of patients had dyslipidaemia (42%) or hypertension (45.4%), 36.8% were obese and 17% had diabetes while 22.7% had a depressive disorder. Overall, 60.1% received biologics and among them more patients treated with anti-IL-17 or -12/23 agents were on monotherapy (64.2%) compared to those on TNFi monotherapy (49.4%, p=0.0001). The median PsA activity as assessed by the DAPSA score was 6 (IQR: 2.3 - 13.1) with 46% of patients reaching minimal disease activity status (MDA). Conclusion: In this large, real life, modern cohort of patients with PsA with frequent comorbidities who were treated mainly with biologics, almost half achieved minimal disease activity. These results show the value of existing therapeutic approaches while at the same time highlight the existing unmet needs.

Molecular Mechanisms of New Bone Formation in Axial Spondyloarthritis.

Axial spondyloarthritis (axSpA) is a disease characterised by new bone formation. Biologic agents targeting TNFα or IL-17 are used widely and are very effective in controlling symptoms and improving quality of life in these patients. However, the effect of biologics on radiographic progression is still not entirely known. The most crucial question to be addressed is whether new bone formation in the context of axSpA is linked to the inflammatory process. If new bone formation and inflammation are interconnected, then long-term suppression of inflammation with biologic agents may eventually lead to inhibition of ankylosis. On the other hand, if these processes are totally uncoupled then biologics may not have an obvious effect on radiographic progression. In this case, targeting pathways that control new bone formation may be a more feasible approach to retard radiographic progression in axSpA. The molecular mechanisms involved in new bone formation in axSpA have been extensively investigated throughout the last years. In this narrative review we summarise the data regarding the mechanisms of new bone formation in axSpA.

Pathogenetic Aspects of Systemic Sclerosis: A View Through the Prism of B Cells.

Systemic sclerosis (SSc) is a rare fibrotic rheumatic disease, associated with psychological distress and increased morbidity and mortality due to skin involvement and internal organ damage. The current understanding of the complex pathogenesis is yet incomplete and disease therapeutic algorithms are far from optimal. Immunologic aberrations are considered key factors for the disease, along with vascular involvement and excess fibrosis. Adaptive immunity and its specialized responses are an attractive research target and both T and B cells have been extensively studied in recent years. In the present review, the focus is placed on B cells in SSc. B cell homeostasis is deranged and B cell subsets exhibit an activated phenotype and abnormal receptor signaling. Autoantibodies are a hallmark of the disease and the current perception of their diagnostic and pathogenetic role is analyzed. In addition, B cell cytokine release and its effect on immunity and fibrosis are examined, together with B cell tissue infiltration of the skin and lung. These data support the concept of targeting B cells as part of the therapeutic plan for SSc through well designed clinical trials.

DKK-1 Is Underexpressed in Mesenchymal Stem Cells from Patients with Ankylosing Spondylitis and Further Downregulated by IL-17.

Dickkopf-1 (Dkk-1) is a key regulator of bone remodeling in spondyloarthropathies. Nevertheless, data regarding its expression in cells of pathophysiologic relevance, such as mesenchymal stem cells (MSCs), are lacking. Herein, we aimed to address DKK1 gene expression and Wnt pathway activation in MSCs from patients with ankylosing spondylitis (AS) and explore the effect of IL-17 on MSCs with respect to DKK-1 expression and Wnt pathway activation. Primary MSCs were isolated from the bone marrow of the femoral head of two patients with AS and two healthy controls undergoing orthopedic surgery. MSCs were cultured for 7 days in expansion medium and for 21 days in osteogenic medium in the presence or absence of IL-17A. Gene expression of DKK-1 and osteoblastic markers was determined by RT-PCR. Alkaline phosphatase activity, alizarin red and Van Kossa staining were used to assess osteoblastic function and mineralization capacity. DKK-1 was significantly downregulated in MSCs and osteoblasts from patients with AS compared to controls. Moreover, MSCs and osteoblasts from AS patients displayed increased Wnt pathway activation and enhanced osteoblastic activity, as indicated by increased expression of osteoblast marker genes and alkaline phosphatase activity. IL-17 downregulated DKK-1 expression and increased osteoblastic activity and mineralization capacity. DKK-1 is underexpressed in MSCs from AS patients compared to controls, whereas IL-17 has an inhibitory effect on DKK-1 expression and stimulates osteoblastic function. These data may have pathogenetic and clinical implications in AS.

Vision loss in giant cell arteritis: case-based review.

Prompt initiation of pulse glucocorticoid treatment is recommended in case of visual symptoms and suspected or proven giant cell arteritis (GCA). Pulse treatment in most cases prevents involvement of an initially unaffected fellow eye. We present the case of a biopsy-proven GCA in a 79-year-old man, complicated by sequential bilateral blindness. Initial unilateral vision loss was treated by 1 g methylprednisolone intravenously for 3 days, followed by 1 g/kg prednisone daily. Despite treatment, the second eye went completely blind 11 days after the initial vision loss. We performed a systematic search on Medline and Scopus aiming at identifying all cases of GCA complicated with loss of vision in a previously unaffected eye under pulse treatment for initially monocular vision loss. We identified 11 articles reporting 21 patients that met our inclusion criteria. Contralateral vision loss occurred 1-12 days following treatment initiation, with a median of 2 days. Treatment initiation was delayed up to 8 days since the initial vision loss, with a median delay of 2 days. Anterior ischemic optic neuropathy was the dominant mechanism of vision loss. Sequential involvement of the fellow eye in case of unilateral vision loss in GCA is rare. With 12-day interval being the longest reported, we conclude that even though the first 2 days are the most critical for the visual outcome, blindness in the initially unaffected eye may rarely occur later. Nonetheless, immediate initiation of pulse treatment remains of vital importance to preserve vision in the contralateral eye.

ACTH vs steroids for the treatment of acute gout in hospitalized patients: a randomized, open label, comparative study.

The management of acute gout in the hospital setting may be challenging since most patients are elderly with multiple unstable comorbidities. However, there are no prospective clinical trials for hospitalized patients with gout to guide optimal management. Evidence indicates that steroids or adrenocorticotropic hormone (ACTH) may be effective and safe therapeutic options for these patients. This study aimed at directly comparing the efficacy and safety of ACTH vs betamethasone for the treatment of gout in hospitalized patients. This is the first prospective clinical trial for hospitalized patients with gout. We designed a randomized, open label study to assess the efficacy and safety of a single intramuscular injection of either ACTH or betamethasone in hospitalized patients with acute gout. Primary efficacy endpoints were the change in intensity of pain as recorded using a Visual Analogue Scale (VAS) at baseline compared to 24 h (ΔVAS24h), and 48 h. Moreover, we assessed safety and effects on the hypothalamic-pituitary-adrenal (HPA) axis, glucose and lipid homeostasis, bone metabolism, electrolytes and renal function. 38 patients were recruited. Both treatments were highly effective. The mean ± SE ΔVAS24h and ΔVAS48h for ACTH was 4.48 ± 0.29 and 5.58 ± 0.26, respectively. The mean ± SE ΔVAS24h and ΔVAS48h for betamethasone was 4.67 ± 0.32 and 5.67 ± 0.28, respectively. Direct comparison between the two groups at 24 h and 48 h did not show statistically significant differences. Both treatments were well tolerated and safe. The effects on all metabolic parameters were mostly minimal and transient for both treatments. However, ACTH may affect less the HPA axis and bone metabolism compared to betamethasone, thus leading to the conclusion that. ACTH and betamethasone are effective and safe for the management of acute gout in hospitalized patients but that ACTH may associate with less disturbance of the HPA axis and bone metabolism. Our data support the use of both drugs as first line treatments for hospitalized patients with gout.Clinical trial registration: ClinicalTrials.gov NCT04306653.

Differences in thyroid function tests after administration of a single supraphysiological dose of ACTH or a high dose of a synthetic steroid.

OBJECTIVE: Although the suppressive action of synthetic steroids on the hypothalamus-pituitary-thyroid (HPT) axis is established, little is known regarding the effect of the administration of synthetic adrenocorticotropic hormone (ACTH). DESIGN: In the context of a randomized, open label, comparative study assessing the efficacy and safety of ACTH and betamethasone in the treatment of hospitalized patients with acute gout, we compared the effects of these agents on thyroid function tests. METHODS: Serum TSH, total T4 and T3 and cortisol were measured before and at 24 and 48 h after a single intramuscular dose of synthetic ACTH (1 mg) or betamethasone (6 mg), in 38 hospitalized patients with acute gout and normal thyroid function. RESULTS: The final analysis included 32 patients, due to missing data. The ACTH and betamethasone groups did not differ regarding the mean age, gender, severity of gout attack, and baseline thyroid parameters. In the ACTH group TSH and T4 were significantly decreased at 24 and at 48 h compared to baseline, while T3 was decreased at 24 but not at 48 h. In the betamethasone group T3 remained stable; TSH and T4 decreased significantly from baseline levels at 24 h; at 48 h, TSH had returned to and T4 showed a partial rebound towards pre-treatment values. CONCLUSIONS: A single IM administration of 1 mg of synthetic ACTH has more profound and prolonged effects on the HPT axis, lasting for at least 48 h, compared to a single IM dose of 6 mg betamethasone.

Real-world safety and efficacy data of immunotherapy in patients with cancer and autoimmune disease: the experience of the Hellenic Cooperative Oncology Group.

BACKGROUND: Data on the safety and efficacy of immune checkpoint inhibitors (ICI) in patients with concurrent autoimmune diseases (AID) are limited. METHODS: We performed a retrospective multicenter review of medical records of patients with cancer and underlying AID who received ICI. The primary endpoint was progression-free survival (PFS). RESULTS: Among 123 patients with pre-existing AID who received ICI, the majority had been diagnosed with non-small cell lung cancer (NSCLC, 68.3%) and melanoma (14.6%). Most patients had a rheumatologic (43.9%), or an endocrine disorder (21.1%). Overall, 74 (60.2%) patients experienced an immune-related adverse event (irAE) after ICI initiation, AID flare (25.2%), or new irAE (35%). Frequent irAEs included thyroiditis, dermatitis and colitis. ICI was permanently discontinued due to unacceptable (8.1%) or fatal (0.8%) toxicity. In patients with NSCLC, corticosteroid treatment at the initiation of immunotherapy was associated with poor PFS (HR = 2.78, 95% CI 1.40-5.50, p = 0.003). The occurrence of irAE was associated with increased PFS (HR = 0.48, 95% CI 0.25-0.92, p = 0.026). Both parameters maintained their independent prognostic significance. CONCLUSIONS: ICI in patients with cancer and pre-existing AID is associated with manageable toxicity that infrequently requires treatment discontinuation. However, since severe AID flare might occur, expected ICI efficacy and toxicity must be balanced. CLINICAL TRIAL IDENTIFIER: NCT04805099.

The impact of osteoporosis and vertebral compression fractures on mortality and association with pulmonary function in COPD: A meta-analysis.

OBJECTIVE: Osteoporosis is highly prevalent among patients with chronic obstructive pulmonary disease (COPD) and most commonly presents as a vertebral compression fracture (VCF). Our objective was to quantify the effect of osteoporosis and VCFs on the mortality and pulmonary function tests (PFTs), such as forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC), of patients with COPD. METHODS: A PubMed/Medline search was conducted using the search terms "chronic obstructive pulmonary disease", "osteoporosis" and "vertebral compression fracture". Meta-analyses were conducted to evaluate the differences in mortality and PFTs between patients with COPD with and without osteoporosis or VCFs, according to PRISMA guidelines. PROSPERO registration: CRD42019120335. RESULTS: Of the 896 abstracts identified, 27 studies describing 7662 patients with COPD of which 1883 (24.6%) had osteoporosis or VCFs, were included. Random effects model analysis demonstrated that patients with COPD and osteoporosis or VCFs had an increased OR for mortality of 2.40 (95% CI: 1.24; 4.64, I2=89%, P<0.01), decreased FEV1/FVC with a mean difference of -4.80% (95% CI: -6.69; -2.90, I2=83%, P<0.01) and decreased FEV1, with a mean difference of -4.91% (95% CI: -6.51; -3.31, I2=95%, P<0.01) and -0.41 L (95% CI: -0.59; -0.24, I2=97%, P<0.01), compared to control subjects. Apart from FEV1 (liters) in subgroup 1 (P=0.06), all subgroup analyses found significant differences between groups, as did sensitivity analysis of low risk of bias studies. CONCLUSION: Osteoporosis and VCFs are associated with a significant reduction in survival and pulmonary function among patients with COPD.

Serotonin and systemic sclerosis. An emerging player in pathogenesis.

OBJECTIVES: Systemic sclerosis (SSc) is a complex, autoimmune disease characterized by multiple organ fibrosis and vasculopathy. Experimental and clinical evidence indicates that serotonin is crucially involved in the fibrotic process and mediates vascular manifestations such as Raynaud's phenomenon (RP) or pulmonary arterial hypertension (PAH), all key features of SSc. In this review, we summarize the current knowledge on the potential contribution of serotonin in SSc pathogenesis and provide a rationale for further investigation of this molecule as a therapeutic target. METHODS: Medline and Cochrane databases were searched from inception to April 2021 using the search terms (systemic sclerosis OR scleroderma OR Raynaud OR Pulmonary arterial hypertension) AND serotonin. RESULTS: Serotonin, a key molecule in an array of central and peripheral functions, has a multifaceted role in regulating fibrosis and vasculopathy. Experimental data suggest that serotonin drives fibrosis in the skin and visceral organs, promotes platelet aggregation, induces vasoconstriction and increases pulmonary vascular resistance. Earlier human trials regarding drugs that inhibit serotonin signaling produced mixed results. However, recent advances in the understanding of the underlying molecular mechanisms could help identify novel therapeutics targeting the serotonin pathway and inform future clinical trials. CONCLUSIONS: Serotonin may be a mediator in both fibrosis and vasculopathy. Further exploration of the potential role of serotonin in SSc is justified.