RS3PE syndrome: Autoinflammatory features of a rare disorder.

Remitting seronegative symmetrical synovitis with pitting oedema (RS3PE) syndrome was first described by McCarty in 1985 and is characterized by pitting oedema and an acute symmetrical synovitis of small joints. Self-directed inflammation in autoimmune disorders is caused by an abnormal activation of the adaptive immune system, while in autoinflammatory disorders, it is due to aberrant activation of the innate immune system without autoantibodies or autoreactive T cells. The role of autoimmunity in the pathogenesis of RS3PE syndrome is suggested by possible associations with some autoimmune diseases and human leukocyte antigen (HLA) haplotypes. However, several other features point to a possible role of autoinflammation in RS3PE syndrome. In this review, the relative contributions of both innate and adaptive immune systems to the pathogenesis of RS3PE syndrome are discussed.

[RS3PE syndrome with angioimmunoblastic T-cell lymphoma early after the start of immunosuppressive therapy].

A 75-year-old man visited our Collagen Disease Department because of a fever, edema in the lower legs, and arthralgia. He presented with peripheral arthritis of the extremities and was negative for rheumatoid factor, leading to a diagnosis of RS3PE syndrome. A search for malignancy was performed, but no obvious malignant findings were found. After starting treatment with steroid, methotrexate, and tacrolimus, the patient's joint symptoms improved, but after five months, enlarged lymph nodes throughout the body were observed. A lymph node biopsy revealed a diagnosis of other iatrogenic immunodeficiency-associated lymphoproliferative disorders/angioimmunoblastic T-cell lymphoma (OI-LPD/AITL). After discontinuation of methotrexate and follow-up, no lymph node shrinkage was observed, and the patient had strong general malaise, so chemotherapy was started for AITL. After the start of chemotherapy, the patient's general symptoms improved quickly. RS3PE syndrome is a polyarticular, rheumatoid factor-negative, polyarticular synovitis with symmetric dorsolateral hand-palmar symmetric indentation edema that occurs mainly in elderly patients. It is also noted as a paraneoplastic syndrome, with 10%-40% of patients having malignant tumors. When our patient was diagnosed with RS3PE syndrome, a search for malignancy was performed, but there were no findings suggestive of malignant disease. However, after methotrexate and tacrolimus administration was started, the patient developed rapid lymph node enlargement, and the pathology showed AITL. The possibility of AITL as an underlying disease and RS3PE syndrome as a paraneoplastic syndrome, or conversely, OI-LPD/AITL associated with immunosuppressive therapy for RS3PE syndrome is considered. We herein report this case, as sufficient recognition is required for a proper diagnosis to be made and treatment of RS3PE syndrome to be performed.

Remitting Seronegative Symmetrical Synovitis with Pitting Edema Syndrome Worsen after the Administration of Dulaglutide.

Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome is characterized by symmetrical polyarthritis and limb pitting edema. Although the detailed mechanisms of this syndrome have not been clearly understood, some agents including dipeptidyl peptidase-4 inhibitors have been reported to induce RS3PE syndrome. However, glucagon-like peptide-1 (GLP-1) analogues have not been reported to be associated with this syndrome. A 91-year-old woman was admitted to our hospital with complaints of severe polyarthritis and limb edema. She was diagnosed with RS3PE syndrome. Oral prednisolone improved her symptoms. However, her symptoms worsened after the administration of dulaglutide, with elevated serum inflammatory markers. Discontinuation of dulaglutide without additional treatment improved her symptoms and laboratory findings. This case might indicate the possibility of development and worsening of RS3PE syndrome caused after GLP-1 analogue.

RS3PE syndrome developing during the course of probable toxic shock syndrome: a case report.

BACKGROUND: Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) is a rare syndrome characterized by "remitting," "seronegative" (namely rheumatoid factor-negative), and "symmetrical" synovitis with pitting edema on the dorsum of the hands and feet. Recently, there have been reports that serum vascular endothelial growth factor (VEGF) is elevated in this condition. CASE PRESENTATION: An 85-year-old man visited our department with a rash that had appeared 2 days earlier and a fever that had developed on the day of his visit. Based on clinical findings of fever, erythema exudativum multiforme, transitory hypotension, conjunctiva hyperemia, elevated creatine kinase, and desquamation, we suspected toxic shock syndrome (TSS). Therefore, we started treatment with vancomycin (1 g/day) and clindamycin (600 mg/day), after which his fever rapidly remitted. However, pitting edema on the dorsum of his hands and feet appeared on day 7, and the patient also had painful wrist and ankle joints. Additional tests were negative for rheumatoid factor, and anti-cyclic citrullinated protein antibodies were < 0.2 U/mL. Further, serum matrix metalloproteinase-3 (199.6 ng/mL; reference value ≤123.8 ng/mL) and serum VEGF (191 pg/mL; reference value ≤38.3 pg/mL) levels were elevated, and human leukocyte antigen-A2 was detected. The patient was thus diagnosed with RS3PE syndrome, for which he satisfied all four diagnostic criteria: 1) pitting edema in the limbs, 2) acute onset, 3) age ≥ 50 years, and 4) rheumatoid factor negativity. He was treated with oral prednisolone, resulting in the normalization of his serum VEGF level to 34.5 pg/mL 1 month after starting treatment. It is currently 1 year since disease onset, and although the patient has stopped taking prednisolone, there has been no recurrence of RS3PE syndrome. CONCLUSIONS: To the best of our knowledge, this is the first reported case of a patient developing RS3PE syndrome during the clinical course of TSS. We propose that the onset mechanism involved an increase in blood VEGF due to TSS, which induced RS3PE syndrome. As serum VEGF becomes elevated with both severe infections associated with shock and RS3PE syndrome, awareness that these conditions can occur concurrently is essential.

Clinical outcomes in the first year of remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome.

OBJECTIVE: We investigated clinical outcomes in patients with remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome. METHODS: This is a retrospective multicenter study conducted in Nagasaki, Japan. We consecutively diagnosed a total of 41 patients with RS3PE syndrome between October 2003 and September 2012 and evaluated their outcomes from medical records from the first year of follow-up. RESULTS: Although an excellent initial response to corticosteroids was noted in all 41 patients, 34 (82.9%) were still receiving corticosteroids and 13 (31.7%) showed elevated C-reactive protein (CRP) at one year. Multivariate analysis demonstrated that male gender and high CRP level at entry were independent variables associated with patients' one-year CRP level being ≥0.5 mg/dL. Odds ratios were 17.05 ([95% CI 2.41-370.12], p < 0.026) and 12.99 ([95% CI 1.78-269.62], p < 0.0096), respectively. Twenty-four patients (58.5%) were still receiving prednisolone (PSL) ≥ 5 mg/day at one year. Disease-modifying anti-rheumatic drugs including methotrexate were required in three patients (10.3%). Neoplasms were found in 14 patients (34.1%) and 1 of these had died due to lung cancer at one year. CONCLUSIONS: RS3PE syndrome initially responds well to corticosteroids with remission of symptoms. However, outcomes of RS3PE syndrome appear to be worse than expected, and may be influenced by gender and initial CRP level.

A Case Report of Remitting Seronegative Symmetrical Synovitis With Pitting Edema Causing Severe Anemia, Acute Progressive Dementia, and Chronic Eczema in an Older Female.

Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome is a type of seronegative arthritis characterized by a favorable prognosis (Remitting), absence of rheumatoid factor (Seronegative), symmetry (Symmetrical), and synovitis with pitting edema on the backs of the hands and feet. The cause of RS3PE syndrome remains unknown, but involvement of the immune system is suspected, and steroids are highly effective. Here, we present a case of an 86-year-old woman with severe anemia and bilateral lower limb edema accompanied by chronic eczema, considered to be caused by RS3PE syndrome. The patient's symptoms included bilateral lower limb edema, allergic rash, cognitive decline, and difficulty in moving, all of which were attributed to RS3PE syndrome. Given the variety of systemic symptoms associated with RS3PE syndrome, which can significantly impair the activities of daily living (ADLs) in the elderly, early detection and treatment are crucial.

Comparison of therapeutic responses between polymyalgia rheumatica and remitting seronegative symmetrical synovitis with pitting edema syndrome.

Polymyalgia rheumatica (PMR) and remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome are common inflammatory rheumatic diseases in the elderly. In this study, we investigated the difference of the therapeutic responses between patients with PMR and RS3PE syndrome. Twenty-four patients with PMR and 12 patients with RS3PE syndrome were treated with initial dosages of 10-20 mg per day oral prednisolone, and the dosages were then tapered. Percentages of patients with negative c-reactive protein (CRP) after 8-week treatment were significantly more in RS3PE syndrome than in PMR. Percentages of patients with relapse during one-year treatment were less likely to be in RS3PE syndrome than in PMR. These differences observed between the two disorders were not associated with the level of initial CRP. There was no significant difference in percentages of patients with prednisolone-free remission after two-year treatment between PMR and RS3PE syndrome. These results indicate that the early response to the treatment is greater in RS3PE syndrome than in PMR. J. Med. Invest. 70 : 145-149, February, 2023.

A Remitting Seronegative Symmetrical Synovitis With Pitting Edema (RS3PE) Syndrome Patient With High-Grade Serous Ovarian Cancer: A Possible Pathogenesis of Tumor-Derived Vascular Endothelial Growth Factor.

A 65-year-old female was previously diagnosed with remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome by internal doctors in our hospital nine years ago. Computed tomography revealed the presence of multiple disseminated peritoneal nodules with a large tumor mass. Histological analysis of the tumor and peritoneal nodules confirmed the diagnosis of high-grade serous ovarian cancer. The serum vascular endothelial growth factor (VEGF) level was highly elevated (1,223.9 pg/mL) (normal range: <38.3 pg/mL). One month after the first administration of docetaxel and cyclophosphamide chemotherapy, her peripheral edema decreased with a parallel reduction of serum VEGF (675.2 pg/mL). These findings suggest the correlation of VEGF with both RS3PE and ovarian cancer in this case.

RS3PE Syndrome with Subsequent PMR Caused by Long-Term DPP-4 Inhibitor Use.

Remitting seronegative symmetrical synovitis with pitting oedema (RS3PE) syndrome has been reported in patients treated with dipeptidyl peptidase-4 inhibitors (DPP-4i). We experienced a case of RS3PE syndrome in a 73-year-old man with a history of type 2 diabetes, who developed RS3PE as a side effect of vildagliptin. Further to this, the patient developed polymyalgia rheumatica (PMR), the first such case associated with long-term DPP-4i use. LEARNING POINTS: RS3PE syndrome and PMR are rare diseases that cause painful extremities in adults. We need to know if it occurs by DPP-4i.RS3PE syndrome and PMR can be complicated with malignancy or giant cell arteritis. However, we must rule out side effects of drugs at first from the standpoint of medical resources.

A patient with Castleman's disease initially manifesting symmetrical synovitis with pitting oedema.

Castleman's disease (CD), especially multicentric CD (MCD) has been known to manifest a variety of clinical features such as fatigue, anaemia, fever, and hypergammaglobulinaemia. Here, we report a 72-year-old female patient who had complicated severe synovitis, as an initial manifestation of the disease, lastly diagnosed as MCD. Initially, she had been diagnosed as remitting seronegative symmetrical synovitis with pitting oedema (RS3PE) syndrome because of bilateral leg pitting oedema with significant C-reactive protein and matrix metalloproteinase-3 elevation but no disease-specific autoantibodies. Promptly, corticosteroid and additionally weekly methotrexate were introduced, but her leg oedema and inflammatory findings did not adequately come to be a remission. A lymph node biopsy from the groin region was performed because multiple lymph node swelling in ultrasound examination appeared even after introducing treatments, which revealed mixed-type CD. Multiple lymphadenopathies were observed in the axilla and inguinal region; finally, we diagnosed her as idiopathic MCD and introduced tocilizumab, which significantly improved leg oedema as well as inflammatory findings. As is shown in this case, manifestations included in RS3PE syndrome could be one of the clinical phenotypes in MCD, which should be considered as a differential diagnosis of MCD.

Acute progressive bilateral carpal tunnel syndrome associated with remitting seronegative symmetrical synovitis with pitting edema syndrome: A case report.

The association between carpal tunnel syndrome (CTS) and remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome, an elderly onset rheumatic disease, is not fully understood. Here, we describe a case of acute CTS caused by RS3PE syndrome. An 84-year-old man visited the hospital with sudden onset of severe neuralgia in the median nerve and pitting edema in both hands. Computed tomography showed low-density areas around the flexor tendons and median nerve compression in the carpal tunnel. Rapidly progressing intolerable neuralgia and paralysis required urgent carpal tunnel release in the left hand. After surgery, we considered the possibility of RS3PE syndrome and started the administration of prednisolone. The pitting edema and neuralgia improved. In this case, imaging and intraoperative findings suggest that the effusion generated from flexor tenosynovitis associated with RS3PE syndrome increased the internal pressure in the carpal tunnel rapidly, which led to acute CTS and urgent surgery.

Remitting seronegative symmetrical synovitis with pitting edema syndrome in maintenance hemodialysis.

INTRODUCTION: The remitting seronegative symmetrical synovitis with pitting edema syndrome primarily occurs in elderly individuals to represent symptoms of edema, pain, and joint swelling. It could be misdiagnosed in elderly maintenance hemodialysis patients, as hemodialysis patients often present with pain and joint swelling induced by hypervolemia, inflammation, amyloidosis, and/or chronic kidney disease. Here, we describe a maintenance hemodialysis patient with remitting seronegative symmetrical synovitis with pitting edema syndrome. CASE PRESENTATION: A 71-year-old man on maintenance hemodialysis who complained of continuous pain and swelling of joints was diagnosed with remitting seronegative symmetrical synovitis with pitting edema syndrome on his clinical findings that revealed tenosynovitis at the joint without joint erosions and no elevation of anti-cyclic citrullinated peptide antibody and rheumatoid factor. After administration of prednisolone, systemic edema, and pain improved in 2 days. CONCLUSION: Remitting seronegative symmetrical synovitis with pitting edema syndrome should be considered as a differential diagnosis in hemodialysis patients with edema and/or arthralgia.

Differences in musculoskeletal ultrasound findings between RS3PE syndrome and elderly-onset rheumatoid arthritis.

OBJECTIVE: To retrospectively analyze the differences in musculoskeletal ultrasound (MSUS) findings to distinguish patients with remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome and patients with elderly-onset rheumatoid arthritis (EORA). METHODS: We consecutively recruited patients with RS3PE syndrome (n = 7) and EORA (n = 22) who underwent pre-treatment MSUS of both hands. Synovial hypertrophy and vascularity of articular synovitis and those of tenosynovitis of the digital flexor tendons and the carpal extensor tendon were evaluated by gray-scale and power Doppler, respectively on a semi-quantitative scale (0-3). The presence/absence of intra-articular synovial effusion, bone erosion, peritendinitis of the digital extensor tendon, and subcutaneous edema were noted. RESULTS: Compared to the EORA group, mild articular synovitis was observed more extensively, and the frequency of intra-articular synovial effusion was significantly higher in the RS3PE syndrome group. Severe articular synovial hypertrophy was more frequent in the EORA group compared to the RS3PE syndrome group, and bone erosion was observed in some EORA cases. Tenosynovitis of the digital flexor tendon was more frequent and severe in the RS3PE syndrome group compared to the EORA group. Although the frequency and severity of tenosynovitis of the carpal extensor tendon were similar in the two groups, digital extensor tendon peritendinitis was more frequent in the RS3PE syndrome group. CONCLUSION: To distinguish patients with RS3PE syndrome from those with EORA, it is important to evaluate not only intra-articular lesions but also extra-articular lesions by MSUS.

Synchronous Occurrence of Bazex Syndrome and Remitting Seronegative Symmetrical Synovitis with Pitting Edema Syndrome in a Patient with Lung Cancer.

A 69-year-old man developed bilateral polyarthritis, edematous extremities, and skin desquamation on the fingers and ears. He did not meet the criteria for any connective tissue disease, including rheumatoid arthritis. An examination revealed advanced lung cancer. His systemic manifestations were attributed to paraneoplastic Bazex syndrome and remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome. Treatment with pembrolizumab (an anti-programmed death-1 antibody) for lung cancer relieved his symptoms and shrank the lung tumor. Bazex and RS3PE syndromes are rare paraneoplastic diseases. We herein report this unique case of synchronous development of these two paraneoplastic syndromes in the presence of advanced lung cancer.

[Seronegative symmetrical synovitis with edema in both hands in patient with central cord injury]. / Sinovitis simétrica seronegativa con edema en ambas manos en paciente con lesión centromedular.

A 55-year-old man with post-traumatic central cord injury, diagnosed with remitting seronegative symmetrical synovitis with pitting edema (RS3PE syndrome). The clinical picture begins with an acute pain in hands, swelling and stiffness. The physical examination revealed edema with fovea on the back of both hands, with pain and swelling in the metacarpophalangeal joints. Given this, different analytical tests and radiography of hands were requested. We started treatment with 30mg of prednisone, showing significant clinical improvement, disappearing arthritis and edema, and normalization of the analytical values. The peculiarity of presentation of RS3PE syndrome in a patient with a central cord injury is due to the difficulty of identifying it due to the superposition of clinical manifestations together with the lack of knowledge of it, being in the absence of this lesion, an easily diagnosable pathology, do not require excessive complementary tests, and with an excellent prognosis after the appropriate early treatment.

[Glucocorticoid sensitive bilateral leg swelling in an 85-year-old woman presenting with polymyalgia rheumatica: A case report]. / Œdèmes des membres inférieurs cortico-sensibles chez une patiente âgée de 85 ans présentant une pseudopolyarthrite rhizomélique.

INTRODUCTION: Polymyalgia rheumatica (PMR) can be associated with distal swelling indicating an associated RS3PE syndrome. We report a case of PMR associated with oedema of the lower limbs, which resolved rapidly under glucocorticoid therapy. CASE REPORT: A 85-year-old woman presented with a 4 month history of PMR responding to the 2012 EULAR/ACR classification criteria. Examination of the lower limbs revealed pitting oedema bilaterally up to the knees, with mild erythema and warmth. Hypoalbuminemia (30g/L) was present. There was no cardiac, renal or hepatic cause to explain leg swelling. FDG-PET/CT demonstrated increased metabolism in the periarticular area of shoulders and hips. There was no sign of aortitis or neoplasia. Under treatment with prednisone 10mg/day leg swelling disappeared concomitantly to a weight loss of 8kg within 8days. CONCLUSION: This case, the first to report leg swelling of inflammatory origin in the context of PMR, could indicate an increased vascular permeability caused by inflammation in the elderly.

Idiopathic remitting seronegative symmetrical synovitis with pitting edema syndrome associated with bilateral pleural and pericardial effusions: a case report.

BACKGROUND: Remitting seronegative symmetrical synovitis with pitting edema syndrome is characterized by symmetrical synovitis with pitting edema in the dorsum of the hands or feet. Most cases of remitting seronegative symmetrical synovitis with pitting edema syndrome are idiopathic, but some are secondary to malignancy, autoimmune disease, or neurodegenerative disorders. Pleural and pericardial effusions are unusual complications in idiopathic remitting seronegative symmetrical synovitis with pitting edema syndrome. CASE PRESENTATION: A 74-year-old Japanese woman presented to our hospital with arthralgia and pitting edema in her feet. She had pain in multiple joints, peripheral edema, and a markedly elevated erythrocyte sedimentation rate. Enhanced computed tomography and laboratory data showed no evidence of malignancy. These findings suggested that she had idiopathic remitting seronegative symmetrical synovitis with pitting edema syndrome. She also developed respiratory distress because of bilateral pleural and pericardial effusions. Laboratory data showed that serum vascular endothelial growth factor and interleukin-6 were significantly elevated. After administration of steroids, her pleural and pericardial effusions decreased and finally disappeared. Furthermore, vascular endothelial growth factor and interleukin-6 decreased when the pleural and pericardial effusions disappeared. CONCLUSIONS: Here we report the case of a patient with idiopathic remitting seronegative symmetrical synovitis with pitting edema syndrome associated with life-threatening complications, including bilateral pleural and pericardial effusions during the course of the illness, which led to respiratory failure and atrial fibrillation. Elevated vascular endothelial growth factor and interleukin-6 may be associated with the cause of pleural and pericardial effusions in idiopathic remitting seronegative symmetrical synovitis with pitting edema syndrome.

Vascular endothelial growth factor levels and rheumatic diseases of the elderly.

BACKGROUND: Increasing vascular endothelial growth factor (VEGF) has been reported in remitting symmetrical seronegative synovitis with pitting edema (RS3PE) syndrome, rheumatoid arthritis (RA), polymyalgia rheumatica (PMR) and giant cell arteritis (GCA). The aim of this study was to compare VEGF levels in patients over 60 years of age who have RS3PE, RA, PMR or GCA so as to determine whether elevated VEGF is specific for a rheumatic disease, the inflammation or edema that occurs with these pathological conditions. METHODS: In this retrospective, multicentric study we assessed serum and plasma levels of VEGF in patients over 60 years of age with rheumatic diseases that were either de novo or of recent onset according to the initial clinical presentation, and we compared these patients with a control group. RESULTS: Serum and plasma VEGF levels were determined in 80 patients (5 with RS3PE, 13 with RA, 44 with PMR, and 18 with GCA) and 37 controls. Edema occurred in five patients with RS3PE, four with RA, and one with PMR, but not patients with GCA. Serum VEGF levels were significantly higher in individuals with rheumatic diseases (849 (405.5-1235.5) pg/ml) relative to the controls (484 (302-555) pg/ml) (p < 0.001). There were no significant differences between patients with RS3PE, RA, PMR, or GCA in terms of the VEGF serum levels (p = 0.60) or plasma levels (p = 0.57). Similarly, the occurrence of edema did not correlate with VEGF levels. CONCLUSION: VEGF increases in rheumatic diseases compared to a control group. This was not associated with specific rheumatic diseases or with edematous rheumatic diseases.