RS3PE in Association With Dipeptidyl Peptidase-4 Inhibitor: Report of Two Cases

R emitting seronegative symmetrical sy-novitis with pitting edema (RS3PE), first described by McCarty (1), is characterized by symmetrical pitting edema of the hands and feet; tenderness, swelling, and/or limited motion of the joints; fatigue; and fever (1,2). It commonly occurs in elderly people (1,2). We have recently encountered two cases of RS3PE that developed shortly after the initiation of a dipeptidyl peptidase-4 (DPP4) inhibitor and resolved markedly upon cessation of it. Case 1 was a 74-year-old woman with a 30-year history of type 2 diabetes who presented with edema of the hands, low grade fever, and malaise, which developed 5 weeks after switching from 20 mg gliclazide to 50 mg sitagliptin. Physical examination revealed severe pitting edema at the dorsum of the hands and mild ede-ma at the fingers of both hands and the dorsum of the feet. Mild arthralgia was also present at the wrists and knees. Glyco-hemoglobin A1C (HbA 1c) was 7.2% (National Glycohemoglobin Standardization Program equivalent). Case 2 was a 71-year-old man with a 1-year history of type 2 diabetes who noticed pitting edema of the dorsum of the hands and the feet 8 weeks after starting 100 mg vildagliptin. HbA 1c was 5.7%. In cases 1 and 2, C-reactive protein (CRP; reference range ,9.5 nmol/L) was 1,313 and 13 nmol/L, respectively, and erythrocyte sedimentation rate was 86 and 23 mm/hour, respectively. Rheuma-toid factor, anticyclic citrullinated protein antibody, antinuclear factor, and anti-DNA antibody were negative in both cases. Neither patient had a history of drug allergy and collagen vascular disorders. In case 1, expression of CD26, a lymphocyte membrane protease with DPP4 activity, was found in 38% of the peripheral lympho-cytes, which was within the normal range (3). The symptoms and signs, and the laboratory data established diagnosis of RS3PE (1,2). Under a presumptive judgment that DPP4 inhibitor use was related to RS3PE, the DPP4 inhibitor was discontinued in both cases. In case 1, the symptoms and signs ameliorated markedly after 7 days, and CRP was 837 nmol/L. Because edema had not completely disappeared, 20 mg prednisolone was initiated 25 days after cessation of sitagliptin, which was followed by complete resolution of edema and the near-normalization of CRP at 76 nmol/L. In case 2, striking improvement of symptoms and signs and normalization of CRP (8 nmol/L) had occurred within 10 days of cessation of vildagliptin. DPP4 inhibitors are relatively new oral hypoglycemic agents that elevate plasma active …