• RS3PE
• arthritis
• edema
• polymyalgia rheumatica
• seronegative arthritis
• synovitis

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.

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.

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.

This study indicated that bFGF was elevated in RS₃PE patients with malignancy and could serve as a biomarker for predicting paraneoplastic RS₃PE.

• Malignancy
• RS3PE
• bFGF

• MMP-3
• RS3PE
• VEGF
• matrix metalloproteinase 3
• remitting seronegative symmetrical synovitis with pitting edema
• vascular endothelial growth factor

• Edema
• Humans
• Matrix Metalloproteinase 3
• Pneumonia
• Synovitis
• Vascular Endothelial Growth Factor A

• Adenocarcinomal
• Lung cancer
• Rheumatic syndrome
• Systemic lupus erythematosus

We report a case of remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome in a 71-year-old woman. She referred to our hospital with finger stiffness, edema of both hands and feet, pain of bilateral shoulder, wrist, metacarpophalangeal, proximal interphalangeal, and ankle joints. Rheumatoid factor was negative, human leukocyte antigen -B7 antigen was positive. Moreover, matrix metalloproteinase 3 (MMP-3) was high. She was diagnosed with RS3PE syndrome, and treatment with prednisolone (15 mg/d) was started. One week after prednisolone treatment initiation, CRP decreased to negative, and joint pain was almost completely resolved. However, hand stiffness persisted, and MMP-3 level was still high. Thus, prednisolone dose was increased to 20 mg/d, and the stiffness resolved. Twenty days after treatment initiation, MMP-3 was normalized. MMP-3 was more indicative of RS3PE syndrome symptoms than CRP. Thus, MMP-3 seems to be more sensitive to RS3PE syndrome symptoms.

• Serum matrix metalloproteinase 3
• Remitting seronegative symmetrical synovitis with pitting edema syndrome

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.

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.

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.

• Case report
• RS3PE syndrome
• Toxic shock syndrome
• VEGF

• Adverse effects
• Immune checkpoint inhibitor
• Nivolumab
• RS3PE
• Remitting seronegative symmetrical synovitis with pitting edema

• Administration, Oral
• Aged
• Antibodies, Monoclonal/adverse effects
• Antineoplastic Agents/adverse effects
• Edema/chemically induced
• Edema/drug therapy
• Glucocorticoids/administration & dosage
• Hand/diagnostic imaging
• Humans
• Immunotherapy/adverse effects
• Male
• Melanoma/drug therapy
• Nivolumab
• Prednisone/administration & dosage
• Radiography
• Synovitis/chemically induced
• Synovitis/diagnostic imaging
• Synovitis/drug therapy

The patient was a 69-year-old male who had started experiencing acute-onset pain in both shoulder joints and edema of both hands and feet. His symptoms progressively worsened within 1 month. Laboratory data indicated elevated CRP and erythrocyte sedimentation rate despite the normal range of antinuclear antibodies and rheumatoid factor and normal organ function. Furthermore, imaging data of the hand indicated synovitis without bone erosions. Meanwhile, chest CT revealed a lung tumor, leading to a diagnosis of primary lung adenocarcinoma with EGFR mutation (cT2aN3M0, stage IIIB). Based on these findings, he was diagnosed as suffering from paraneoplastic remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome. Thereafter, his symptoms disappeared as the tumor size was rapidly decreased by gefitinib therapy for lung adenocarcinoma. Currently, RS3PE syndrome can be classified as a vascular endothelial growth factor (VEGF)-associated disorder. Given that his symptoms improved by chemotherapy, the present case further supported the possible hypothesis that paraneoplastic RS3PE syndrome might be caused by tumor-induced VEGF. Therefore, the present case suggested that the symptoms of acute-onset joint pain accompanied by pitting edema in elderly patients should be considered suspicious for a malignant tumor, thereby warranting a detailed full-body examination.

• Lung cancer
• Paraneoplastic syndrome
• Remitting seronegative symmetrical synovitis with pitting edema

• EML4-ALK
• Lung cancer
• Matrix metalloproteinase-3
• Paraneoplastic syndrome
• Remitting seronegative symmetrical synovitis with pitting edema syndrome