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.

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.

Case Report: Resolution of remitting seronegative symmetrical synovitis with pitting edema during nivolumab therapy for gastric cancer.

The anti-programmed cell death-1 (PD-1) antibody nivolumab has been shown to significantly prolong the survival of patients with unresectable advanced or recurrent gastric cancer (AGC). However, immune-related adverse events (irAEs), which show different profiles from those of cytotoxic agents or conventional molecular-targeted drugs including tyrosine kinase inhibitors, have been reported. Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) is a rare autoimmune disorder with acute-onset, rheumatoid factor-negative, symmetric synovitis associated with limb edema observed in elderly persons. A case of RS3PE syndrome that developed after administration of nivolumab for advanced gastric cancer is reported. This is the first report of a case of RS3PE syndrome as an irAE caused by nivolumab in a patient with gastric cancer.

Remitting seronegative symmetrical synovitis with pitting edema syndrome postsecond COVID-19 vaccination: a case report.

Coronavirus disease 19 (COVID-19) has become the most serious public health crisis of our generation, and vaccines are effective in preventing its infection. Remitting seronegative symmetrical synovitis with pitting edema is an idiopathic rare benign syndrome, but it could be secondary to aautoimmune diseases. Here, the authors reported the first case of this syndrome's development after COVID-19 vaccination. Case presentation: A 52-year-old woman presented with hand edema, arthralgia, and morning stiffness, after receiving the second dose of m RNA COVID-19 vaccination. Examination revealed edema in the dorsum of both hands and symmetrical tenderness of the shoulders, elbows, wrists, knees, and ankles. Blood test results were normal except for elevated levels of C-reactive protein. The immune profile and the tuberculin test were also negative. A hand radiograph showed soft tissue edema. Ultrasonography of the extremities has shown tenosynovitis. Remitting seronegative symmetrical synovitis with pitting edema syndrome was diagnosed according to the diagnostic criteria. She was treated with 30 mg/day prednisolone, with a complete disappearance of edema and arthralgia after 10 days, and the C-reactive protein level was decreased. Clinical discussion: Vaccines are still the most effective and protective method against COVID-19 infection, but it may trigger an immunological response. Remitting seronegative symmetrical synovitis with pitting edema (or sometimes RS 3 PE) is a rare nonunderstood syndrome identified by symmetric polyarthritis, synovitis, acute pitting edema of hands and/or feet, and a negative serum rheumatoid factor, with an excellent prognosis to treatment with steroid. Usually occurred in the old aged population, young patients' cases were mentioned. As the authors did not find any data about our subject, this is the first case of this syndrome development after the second dose of COVID-19 vaccination. Conclusion: The occurrence of acute symmetrical seronegative polysynovitis with extremities edema, in the elderly, should guide toward the diagnosis of this syndrome.

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.

Remitting Seronegative Symmetrical Synovitis with Pitting Oedema Following Administration of the Chadox1-S/NCOV-19 Coronavirus Vaccine.

Introduction: We describe a case of remitting seronegative symmetrical synovitis with pitting oedema (RS3PE) syndrome following administration of the ChAdOx1-S/nCoV-19 [recombinant] vaccine, suggesting a possible causal link. Case Description: A 72-year-old man presented to his general practitioner with swollen, oedematous hands and legs 2 weeks after receiving a coronavirus vaccine. He had raised inflammatory markers but remained systemically well. He was initially presumed to have cellulitis, but his symptoms persisted despite several courses of antibiotics. Deep vein thromboses, cardiac failure, renal failure and hypoalbuminaemia were ruled out. Upon Rheumatology review, he was diagnosed as having RS3PE syndrome with the Covid vaccine suspected of being an immunogenic trigger. Following initiation of steroid therapy, his symptoms improved dramatically, as is characteristic of RS3PE syndrome. Discussion: The pathophysiology of RS3PE is unclear. It is known to have various triggers and associations including infections, certain vaccines and malignancy. This case highlights that a coronavirus vaccine (ChAdOx1-S/nCoV-19 [recombinant] vaccine) is also a possible trigger. Factors that make the diagnosis likely include an acute onset of symptoms including pitting oedema in a typical distribution, age above 50, and unremarkable autoimmune serology. Other learning points from this case include the importance of antibiotic stewardship and the need to explore non-infectious causes of illness when antibiotics do not improve symptoms. Conclusion: The ChAdOx1-S/nCoV-19 [recombinant] vaccine is a possible trigger of RS3PE. However, the benefits of vaccines against coronavirus outweigh the risks in the majority of patients. LEARNING POINTS: This case demonstrates a possible link between the ChAdOx1-S/nCoV-19 [recombinant] vaccine and autoimmune conditions such as RS3PE.It is important to consider alternative diagnoses when antibiotic regimes fail to work.A barrier to accurate diagnosis includes an episodic approach, where a patient presents to multiple clinicians acutely rather than having a long-term, continuous relationship with a single multi-disciplinary team, where response to treatment can be monitored.

Idiopathic remitting seronegative symmetrical synovitis with pitting edema syndrome with underlying history of malignancy.

Key Clinical Message: By reporting this case, we hope to emphasize the importance of maintaining a high index of clinical suspicion for the early recognition of RS3PE in patients presenting with atypical symptoms of PMR and underlying history of malignancy. Abstract: Remitting seronegative symmetrical synovitis with pitting edema is a rare rheumatic syndrome of unknown etiology. It shares qualities with many other common rheumatological disorders such as rheumatoid arthritis and polymyalgia rheumatica, making diagnosis especially challenging. RS3PE has been speculated to be a paraneoplastic syndrome, and those cases associated with underlying malignancy have shown to respond poorly to conventional treatment. Therefore, it is advisable to routinely screen patients with malignancy and presenting with RS3PE for cancer recurrence, even if in remission.

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.

[Remitting seronegative symetrical synovitis with pitting edema. One case report]. / Sinovitis simétrica seronegativa remitente con edema y fóvea. Presentación de un caso.

Background: RS3PE (remitting seronegative symmetrical synovitis with edema and pitting) is a rare entity of unknown etiology that has been related to genetic predisposition due to the presence of HLA-A2 in 50% of cases and less frequently HLA-B7. Its pathogenesis is unknown, but it has been related to growth factors, and some mediators (TNF, IL-6). It is common in elderly people and the course of this illness presents with acute symmetrical polyarthritis, accompanied by edema in hands and feet. The diagnosis requires a high index of suspicion and to differentiate it from other entities such as rheumatoid arthritis, complex regional pain syndrome, rheumatic polymyalgia, in addition to ruling out malignant neoplasms, since there are many reports of its association with both solid and hematological neoplasms, being of bad prognosis when there is association. When there is no association with cancer, it responds well to the use of low doses of steroids and its prognosis is usually favorable. Clinical case: 80-year-old woman with an acute onset with polyarthralgia, functional limitation associated with pitting edema in hands and feet. After approaching the patient and ruling out associated neoplasms, it was diagnosed RS3PE. It was managed with prednisone, observing a good response, with remission of the manifestations at 6 weeks and subsequent suspension of the steroid. Conclusions: RS3PE is a rare entity, and a high index of suspicion is required for the diagnosis. A complete approach is important to rule out cancer in patients affected with this syndrome. Prednisone continues to be the best therapeutic option.

Introducción: la RS3PE (sinovitis simétrica seronegativa remitente con edema y fóvea) es una entidad rara de etiología desconocida que se ha relacionado con predisposición genética por la presencia de HLA-A2 en el 50% de los casos y con menor frecuencia HLA-B7. Se desconoce su patogenia, pero se ha relacionado con factores de crecimiento y algunos mediadores (TNF, IL-6). Se presenta en personas de edad avanzada, cursa con poliartritis aguda simétrica, acompañada de edema en manos y pies. El diagnóstico requiere de un alto índice de sospecha y diferenciarlo de otras entidades como artritis reumatoide, síndrome de dolor regional complejo, polimialgia reumática, además de descartar neoplasias malignas, ya que existen muchos reportes de su asociación con neoplasias tanto sólidas como hematológicas y es de mal pronóstico cuando existe asociación. Cuando no existe asociación con cáncer tiene buena respuesta al uso de dosis bajas de esteroides y su pronóstico suele ser favorable. Caso clínico: mujer de 80 años con un cuadro de inicio agudo con poliartralgias, limitación funcional asociada a edema de manos y pies con fóvea. Después del abordaje y de descartar neoplasias asociadas, se diagnosticó RS3PE. Se manejó con prednisona y hubo buena respuesta, con remisión de las manifestaciones a las 6 semanas y suspensión posterior del esteroide. Conclusiones: la RS3PE es una entidad rara y para diagnosticarla se requiere un alto índice de sospecha. Es importante el abordaje completo para descartar cáncer en los pacientes afectados con este síndrome. La prednisona continúa siendo la mejor opción terapéutica.

[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.

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.

Remitting Seronegative Symmetrical Synovitis with Pitting Edema (RS3PE) Syndrome Precedes the Development of Hepatocellular Carcinoma.

Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome is characterized by bilateral synovitis and marked pitting edema of the hands and/or feet. Despite the unknown etiology of RS3PE, several reports have described the putative association of this disease with malignant tumors. We herein report the findings of a 76-year-old man with RS3PE syndrome who developed hepatocellular carcinoma 3 years after achieving clinical remission of RS3PE using corticosteroid treatment; high vascular endothelial growth factor and tumor necrosis factor-alpha levels were considered to have contributed to carcinogenesis in this patient. The sequence of clinical events in this case strongly suggests that careful follow-up, even after clinical remission, is necessary for patients with RS3PE syndrome whose malignancy is not confirmed at diagnosis.

Idiopathic remitting seronegative symmetrical synovitis with pitting edema syndrome mimicking symptoms of polymyalgia rheumatica: a case report.

BACKGROUND: Remitting seronegative symmetrical synovitis with pitting edema is a rare rheumatic condition of the elderly population that is well described but whose mechanisms remain little studied. This syndrome is characterized by symmetrical swelling located mainly on the dorsal part of the hands and the feet. Because of possible heterogeneous clinical presentation, it can easily mimic the onset of other rheumatic diseases or appear associated with them. Here we report a case of a patient who developed remitting seronegative symmetrical synovitis with pitting edema with preexisting shoulder and hip girdle pain associated with progressive fatigue, indicating a possible differential diagnosis of polymyalgia rheumatica. We reviewed and compared classification for remitting seronegative symmetrical synovitis with pitting edema and polymyalgia rheumatica and discussed other differential diagnoses. CASE PRESENTATION: An 84-year-old Caucasian woman presented to our General Medicine Unit with acute onset of symmetrical hands and feet edema, leading to functional limitation due to pain and stiffness. Additionally, she was complaining about neck, shoulder, and pelvic girdle pain present for about 2 months associated with worsening asthenia. Blood tests showed an elevated level of C-reactive protein and erythrocyte sedimentation rate, as well as absence of anti-cyclic citrullinated peptide antibodies and rheumatoid factor. As all criteria of remitting seronegative symmetrical synovitis with pitting edema syndrome were present, the patient was treated with low-dose prednisone, with a rapid and complete resolution of symptoms. She remains asymptomatic without treatment 2 years after the onset of symptoms, without any evident oncologic etiology. CONCLUSIONS: This case is an example of a classic representation of remitting seronegative symmetrical synovitis with pitting edema syndrome with clinical elements suggesting a concomitant existing early stage of polymyalgia rheumatica. These two entities, classified in the group of seronegative arthritis, can coexist (up to 10% of cases), with remitting seronegative symmetrical synovitis with pitting edema appearing as an initial or late manifestation of polymyalgia rheumatica. It is essential to remind that remitting seronegative symmetrical synovitis with pitting edema is associated with a higher risk of cancer (30%). A proper diagnosis allows the clinician to precisely define the appropriate therapy duration to limit its side effects in the elderly and remain aware of the potential risk of underlying malignancy.

Acute Onset of Remitting Seronegative Symmetrical Synovitis With Pitting Edema (RS3PE) Two Weeks After COVID-19 Vaccination With mRNA-1273 With Possible Activation of Parvovirus B19: A Case Report With Literature Review.

Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) is a rare clinical entity characterized by "remitting," "seronegative," and "symmetrical" synovitis with pitting edema on the dorsum of the hands and feet. Although rheumatic or malignant diseases are diseases that are known to coexist with RS3PE, other factors such as medication, infection, and vaccination have been reported to be associated with RS3PE. Here, we present a case of RS3PE syndrome that satisfied all four diagnostic criteria of RS3PE (pitting edema in the limbs, acute onset, age ≥ 50 years, and/or rheumatoid factor negativity) after mRNA-1273 SARS-CoV-2 vaccination.

Comparison of complications during 1-year follow-up between remitting seronegative symmetrical synovitis with pitting edema syndrome and elderly-onset rheumatoid arthritis.

Remitting seronegative symmetrical synovitis with pitting edema syndrome (RS3PE), a rheumatic disease affecting the elderly, responds well to corticosteroids; however, our RS3PE patients' corticosteroid therapy is longer than expected. Elderly-onset rheumatoid arthritis (EORA) patients are reported to be at a significantly increased risk for steroid-related side effects including cardiovascular diseases (CVDs). To clarify the complications during a 1-year follow-up in corticosteroid-treated RS3PE patients compared to EORA patients. We retrospectively analyzed the records of 47 RS3PE patients (28 men, 19 women, age 78.4 ± 7.5 years) and 46 EORA patients (10 men, 36 women; 77.0 ± 6.8 yrs) to compare the complications over a 1-year follow-up. The RS3PE and EORA groups' average initial PSL doses were 16.5 ± 7.2 mg/day and 7.3 ± 4.6 mg/day, respectively. During the 1-year follow-up after treatment, there was no significant increase in CVDs in both groups. However, infections occurred in nine RS3PE patients, which is a significantly higher incidence compared to the EORA patients with infections (n = 3). The initial PSL dose was the independent variable associated with the incidence of infection. Infections were significantly increased during elderly RS3PE patients' steroid therapy. The initial corticosteroid dose was an infection-risk factor.Key messagesInfections are increased during steroid therapy in elderly patients with RS3PE syndrome.The initial dose of corticosteroids was one of the risk factors for infections.

Remitting seronegative symmetrical synovitis with pitting edema: a case report.

BACKGROUND: Edema occurs in various disorders. One of those is remitting seronegative symmetrical synovitis with pitting edema, a rare syndrome whose pathophysiology is not clearly understood. We report herein a case of refractory edema diagnosed as remitting seronegative symmetrical synovitis with pitting edema. CASE PRESENTATION: A 82-year-old Asian male was admitted to the Department of General Internal Medicine with a 2-month history of symmetrical swelling of both hands. Despite treatment with loop diuretic furosemide 40 mg daily, his condition did not respond to the medication and his quality of life deteriorated. An examination of the joints showed tenderness suggestive of synovitis with restricted movements in bilateral proximal interphalangeal joint. Laboratory findings revealed hyperglycemia, elevated erythrocyte sedimentation rate 118 mm/hour, and elevated C-reactive protein 6.58 mg/dL. Plain radiographs of both hands showed soft tissue swelling, changes consistent with osteoarthritis, and no erosions. The diagnosis of bilateral remitting seronegative symmetrical synovitis with pitting edema was made. Treatment with prednisolone 15 mg daily was instituted. CONCLUSIONS: Although remitting seronegative symmetrical synovitis with pitting edema is rare, it should be remembered as a disease that causes edema in the elderly.

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.

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.

Case Report: Syndrome of Remitting Seronegative Symmetrical Synovitis with Pitting Edema-A Rare but Treatable Condition in Palliative Medicine.

The syndrome of remitting seronegative symmetrical synovitis with pitting edema (RS3PE) is a rare diagnosis that is often missed due to lack of both definitive diagnostic criteria and awareness of the disease. This case report describes a patient with chronic lymphocytic leukemia whose diagnosis of RS3PE was possibly delayed due to concomitant treatment-related arthralgias. The pathophysiology, presentation, and treatment of RS3PE are discussed. Greater awareness of malignancy-related RS3PE is crucial from a palliative care perspective as typical opioid pain management will prove ineffective and delay appropriate treatment.