bFGF could be a biomarker of malignancy in RS3PE syndrome: an ambispective single-center cohort analysis of 51 patients

Objectives Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) is a rare inflammatory arthritis, with a higher incidence of malignancy. The aim of this study is to identify biomarkers for predicting malignancy in RS3PE. Methods A total of 51 patients with RS3PE from September 2007 to May 2019 were retrospectively reviewed and followed for up to 5 years, with 15 patients with osteoarthritis (OA) and 14 patients with elderly-onset rheumatoid arthritis (EORA) as disease controls. Serum levels of angiogenesis cytokines were measured by electrochemiluminescent immunoassay and Luminex Human Magnetic Assay. Clinical data and laboratory parameters were analyzed to identify risk factors for malignancy. Results A total of forty-eight RS3PE patients (94.1%) were available with follow-up data; 8 patients (16.7%) were diagnosed with malignancy, of which 6 patients were hematological tumor; and 2 patients were solid tumors. Serum levels of basic fibroblast growth factor (bFGF) were exclusively higher in RS3PE patients with malignancy [14.21 (7.52, 23.18) ng/mL] than RS3PE patients without malignancy [4.32 (2.88, 7.42) ng/mL], OA [3.20 (2.20, 5.30) ng/mL], and EORA [3.20 (2.20, 5.30) ng/mL]. The optimal cut-off value of bFGF for malignancy was 10ng/mL in RS3PE. Logistic regression analysis indicated that elevation of bFGF was a risk factor for malignancy in RS3PE. Conclusions This study indicated that bFGF was elevated in RS3PE patients with malignancy and could serve as a biomarker for predicting paraneoplastic RS3PE.

bFGF could be a Biomarker of Malignancy in RS3PE Syndrome: an Ambispective Single Center Cohort Analysis of 51 Patients

ObjectivesRemitting seronegative symmetrical synovitis with pitting edema (RS3PE) is a rare inflammatory arthritis, with a higher incidence of malignancy. The aim of this study is to identify biomarkers for predicting malignancy in RS3PE.MethodsA total of 51 patients with RS3PE from September 2007 to May 2019 were retrospectively reviewed and followed for up to 5 years, with 15 patients with osteoarthritis (OA) and 14 patients with elderly-onset rheumatoid arthritis (EORA) as disease controls. Serum levels of angiogenesis cytokines were measured by electrochemiluminescent immunoassay and Luminex Human Magnetic Assay. Clinical data and laboratory parameters were analyzed to identify risk factors for malignancy.ResultsA total of forty-eight RS3PE patients (94.1%) were available with follow-up data, 8 patients (16.7%) were diagnosed with malignancy, of which 6 patients were hematological tumor, and 2 patients were solid tumor. Serum levels of basic fibroblast growth factor (bFGF) were exclusively higher in RS3PE patients with malignancy [14.21 (7.52, 23.18) ng/mL] than RS3PE patients without malignancy [4.32 (2.88, 7.42) ng/mL], OA [3.20 (2.20, 5.30) ng/mL] and EORA [3.20 (2.20, 5.30) ng/mL]. The optimal cut-off value of bFGF for malignancy was 10ng/mL in RS3PE. Logistic regression analysis indicated that elevation of bFGF was a risk factor for malignancy in RS3PE.ConclusionsThis study indicated that bFGF was elevated in RS3PE patients with malignancy and could serve as a biomarker for predicting paraneoplastic RS3PE.

POS1355 THE REMITTING SERONEGATIVE SYMMETRICAL SYNOVITIS WITH PITTING EDEMA SYNDROME (RS3PE): REVIEW OF TEN YEARS AT A REFERENCE HOSPITAL

Background:The Remitting Seronegative Symmetrical Synovitis with Pitting Edema Syndrome (RS3PE) is a rare rheumatological disease, considered a benign process.Objectives:This study aims to describe its clinical features and serological markers, and also to analyze its possible association with neoplasms.Methods:An observational retrospective study was performed to assess demographic and clinical characteristics of patients diagnosed from RS3PE at a reference hospital amongst the Rheumatology and Internal Medicine departments, from 2010 to 2021.Results:Twenty-seven patients were included, with a mean age of 82.74 y.o. (IC95% 80.45-85.04; range 66 to 93), and a 51.85% proportion of males. Only 22.22% were from rural areas.All patients presented bilateral hand edema although some associated feet edema (40.74%) or morning stiffness (70.37%). Blood tests demonstrated anemia in 44.44% of patients. Inflammatory markers were elevated, such as C-Reactive Protein (29.23 mg/L, IC95% 18.17-40.29), erythrocyte-sedimentation rate (33.74 mm/hour, IC95% 24.22-43.26) and fibrinogen (531.6 mg/dL, IC95% 482.91-580.30). Only a few patients presented any autoimmune serological marker such as antinuclear antibodies (18.18%) or rheumatoid factor (8.70%).X-ray screening was realized to 22 patients. 14 showed of osteoarthritis radiologic presentation, 4 had radiological findings of chondrocalcinosis and one of them presented both. Only one patient had bone erosion.Malignancy screening was performed at diagnosis in only 29.63% of patients (all negative). During follow-up only two tumors were detected (mean accumulated follow-up: 40.37 months, IC95% 26.70-54.04; range 1 to 122) and there were adenocarcinoma primary neoplasms.All but one patient received low-dose corticosteroids, with a good and rapid response in all cases. Three patients received treatment with methotrexate (2) or leflunomide (1).Conclusion:RS3PE must be contemplated in elderly patients presenting with bilateral hand pitting edema and articular symptoms. No specific biomarkers have been described, but inflammatory reaction is often found in the absence of rheumatoid arthritis biomarkers. Rapid response to corticosteroids is prevalent. Only two neoplasms were detected during follow-up.References:[1]Paira S, Graf C, Roverano S, Rossini J. Remitting seronegative symmetrical synovitis with pitting oedema: a study of 12 cases. Clin Rheumatol. 2002 May;21(2):146-9. doi: 10.1007/pl00011218. PMID: 12086166.[2]Cobeta García JC, Martínez Burgui J. RS3PE syndrome or benign edematous polysynovitis in the elderly. Study of 8 cases. Rev Clin Esp. 1999 Dec;199(12):785-9. Spanish. PMID: 10687410.[3]Moreno Obregón F, Del Castillo Madrigal M, Díaz Narváez F, Pérez Delgado FJ. RS3PE syndrome with positive rheumatoid factor. Reumatol Clin. 2019 Nov-Dec;15(6):e168-e169. English, Spanish. doi: 10.1016/j.reuma.2017.11.009. Epub 2017 Dec 15. PMID: 29254743Disclosure of Interests:None declared

Remitting Seronegative Symmetrical Synovitis With Subsequent IgA Hypergammaglobulinemia. A Case of Chronic Inflammation Causing Macroprolactinemia and a Misdiagnosis

Prolactin is a pituitary hormone that functions in breast development and milk production in women and also plays an important role in immunoregulation and human immune responses, including autoimmune diseases. Macroprolactin, known as “big-big prolactin”, is due to the presence of marked hyperprolactinemia associated with evidence of prolactin-Ig (typically IgG4 or less frequently IgA) circulating complexes. We describes a case of 51 year-old female, with more than a 4 year history of reported hyperprolcatinemia who was treated with Cabergoline 0.5 mg weekly. Prior to treatment, she reported menses every 30-40 days, but denied galactorrhea or symptoms of sellar mass effect. Our patient had mildly elevated prolactin levels of 40-50 ng/dl. Her Thyroid function test were within normal limits. Patient had two pituitary MRIs in 2017 and 2019 which did not show sellar abnormalities. Prior to cabergolibe initiation, she was diagnosed with RS3PE syndrome (Remitting seronegative symmetrical synovitis with pitting edema) due to bilateral swelling in the dorsum of her hands. She was found to have hypergammaglobulinemia which was related to IgA elevation from chronic inflammation. Further investigation showed actual bio-active monomeric prolactin level was normal (4.8 ng/dl) and macroprolactin elevation from hypergammagolbulinemia. Before diagnosing her paraproteinemia and her macroprolactin predominance, she had received years of dopamine agonist therapy which was discontinued after diagnosis. We report a novel association of IgA predominant hypergammaglobulinemia from a chronic rheumatologic condition, leading to a misdiagnosed hyperprolcatinemia. Care should be taken to determine monomeric Prolactin levels prior to treatment, specially when symptoms are equivocal and/or imaging studies are negative.

Ischemic Bowel Mimicking a Colonic Mass in RS3PE Syndrome

Remitting seronegative symmetrical synovitis with pitting edema syndrome is characterized by symmetrical synovitis involving wrists and flexor digitorum tendon sheaths associated with marked pitting edema of the dorsum of hands. It is considered a paraneoplastic syndrome. Here we describe a middle-aged patient with this syndrome presenting with acute abdomen and ischemic bowel mimicking a colonic mass. Rheumatologists and surgeons should consider mesenteric vascular events in patients with remitting seronegative symmetrical synovitis with pitting edema who present with acute abdomen, even in patients younger than 50 years. Our case is the first case in the literature reporting the association between ischemic infarction of colon and remitting seronegative symmetrical synovitis with pitting edema. Remitting seronegative symmetrical synovitis with pitting edema needs to be listed among other rheumatologic diseases associated with mesenteric vascular occlusion.

FRI0488 CLINICAL AND LABORATORY FEATURES OF PATIENTS WITH REMITTING SERONEGATIVE SYMMETRICAL SYNOVITIS WITH PITTING EDEMA COMPARED TO PATIENTS WITH SERONEGATIVE RHEUMATOID ARTHRITIS

Background:In the case of seronegative arthritis, it was difficult to make a differential diagnosis between remitting seronegative symmetrical synovitis with pitting edema syndrome (RS3PE) and seronegative rheumatoid arthritis (seronegative RA) because the distribution of affected joints was similar and the patients with RS3PE or seronegative RA may have edema.Objectives:To compare the clinical characteristics of RS3PE and seronegative RAMethods:We retrospectively examine consecutive patients diagnosed with RS3PE or seronegative RA in our hospital from 2007 to 2019. Patients in whom both ACPA and RF were negative were included. The patients with RS3PE met the criteria of McCarty et al.: (1) pitting edema of the dorsum of both hands and both feet, (2) sudden onset of polyarthritis, (3) seronegative for ACPA and RF. (4)no radiologically evident erosions developed. The patients with seronegative RA met the EULAR/ACR 2010 criteria. The patients who were diagnosed with RS3PE at first and then diagnosed with seronegative RA afterward were included in seronegative RA group. The first analysis was performed on the affected joints, CRP, ESR, Hb, LDH, edema, the history of malignancy 2 years before and after the diagnosis, treatment, and the history of infection requiring hospitalization after the start of treatment. The affected joints were shoulders, elbows, wrists, finger joints (the MCP, and PIP joints), hips, knees, ankles, and toe joints (the MTP and PIP joints). The secondary analysis was performed on the above evaluations with a propensity score (PS) matching for age.Results:In the first analysis, 20 patients with RS3PE and 122 patients with seronegative RA were enrolled. The mean ages (RS3PE, seronegative RA) were 81.1, 67.4 years old. Females were 60.0%, 63.1%. The mean observation period was 25.4, 63.6 months. The proportion of affected joints were shoulders (25.0%, 42.6%), elbows (10.0%, 29.5%: p=0.06), wrists (85.0%, 73.8%), finger joints (80.0%, 95.1%: p=0.01), hips (0%, 9.8%), knees (40.0%, 37.7%), ankles (65.0%, 39.3%: p=0.03) and toe joints (40.0%, 32.8%). Edema at diganosis was observed in 100%, 17.21% (p <0.0001). The mean levels of the following blood tests at diagnosis were noted: CRP, 9.0 and 4.8 mg/dL (p=0.02); ESR, 87.6 and 60.7 mm/1h (p=0.003); Hb, 10.4 and 11.8 mg/dl (p=0.001); LDH, 198.3 and 177.9 U/L (p = 0.12); MMP-3, 742.5 and 633.8 ng/mL (p = 0.14). The proportion of patients with high LDH levels (>222 U/L) was 13.6% and 9.0% (p=0.0269). The proportion of patients having the history of malignancy was 20.0%, 8.2% (p=0.10). The patient treated with prednisolone as the initial treatment was 100% and 41.0%; the mean dose was 14.3 and 9.9 mg/d. After the start of treatment, the proportion of infection requiring hospitalization was 20.0 and 3.28% (p=0.002).In the secondary analysis with PS, 17 patients with RS3PE and 17 patients with seronegative RA were enrolled. The mean ages were 80.4, 78.9 years old. Females were 52.9, 76.4%. The affected joints with difference were elbows (11.8, 35.3%: p=0.10), wrists (82.4, 100%: p=0.06), and finger joints (82.4, 100%: p=0.06). The mean levels of Hb at diagnosis was 10.4, 11.4 mg/dL (p=0.01). The proportion of patients having the history of malignancy was 23.5% and 0% (p=0.03). After the start of treatment, the proportion of infection requiring hospitalization was 23.5% and 0% (p=0.03).Conclusion:When the ankles are affected and edema is observed, RS3PE is more likely than seronegative RA. RS3PE had higher levels of CRP, ESR, and LDH. The proportion of anemia was higher in RS3PE. The proportions of infection requiring hospitalization and the history of malignancy were higher in RS3PE.References:[1]McCarty DJ, O’Duffy JD et al. Remitting Seronegative Symmetrical Synovitis with Pitting Edema (RS3PE Syndrome). JAMA 1985; 254: 2763–2767. DOI:10.1001/jama.1985.03360190069027Disclosure of Interests:Misako Higashida-Konishi: None declared, Keisuke Izumi Grant/research support from: Asahi Kasei Pharma, Takeda Pharmaceutical Co., Ltd., Speakers bureau: Asahi Kasei Pharma Corp, Astellas Pharma Inc., Bristol Myers Squibb, Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Mitsubishi Tanabe Pharma Co., Satoshi Hama: None declared, Yutaro Hayashi: None declared, Yutaka Okano: None declared, Hisaji Oshima: None declared