Polymyalgia Rheumatica in Association with Remitting Seronegative Sinovitis with Pitting Edema: a Neoplastic Warning

Polymyalgia rheumatica (PMR) is considered the commonest inflammatory rheumatological disease in adults aged greater than 65 years.(1-3) Classic symptoms are bilateral pain, aching and stiffness in the shoulders, pelvic girdle and neck, usually with sudden onset. In most cases the patient remembers the exact day when these symptoms appeared.(4,5) As opposed to the symptoms of osteoarthritis, the stiffness and pain tend to be bilateral or symmetric and improve with activity. They are greater in the morning and improve during the day. The dramatic response to low-dose corticosteroid treatment (15 mg/day prednisone or prednisone equivalent, on average) is characteristic and represents an important diagnostic criterion, despite the recent classification criteria proposed by European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR) collaborative group.(6) In some patients, it is necessary to change the initially used glucocorticoid with a different one at equivalent dosage to obtain an effective response.(4) The management of PMR is generally possible in a rheumatologic outpatient clinic without hospitalization.(7,8) The relationship between PMR and cancer is still uncertain, and the data available in the literature are contradictory. Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) is an uncommon elderly-onset rheumatic condition, described for the first time by McCarty et al.(9) in 1985. RS3PE syndrome is characterized by tenosynovitis of extensor tendons at the wrist and (less frequently) at the feet that characteristically respond to low-dosages of corticosteroids. Its removal occurs rapidly and relapse is extremely rare in the “benign” forms.(10,11) Since 1985, cancer and benign tumors have been described in association with RS3PE. RS3PE can represent a neoplastic marker in elderly patients with rheumatic diseases in up to 20% of cases.(12) The levels of vascular endothelial growth factor (VEGF), a cytokine able to increase vascular permeability and dilation, are significantly higher in RS3PE patients than in controls, and the levels decreased after glucocorticoid treatment.(13) The importance of VEGF in the neoplastic spreading is well-known,(14) but the real importance of VEGF in the paraneoplastic potentiality of RS3PE remains speculative until today. RS3PE can be an initial manifestation of PMR or may occur in its course. It is estimated that no more than 10% of patients with PMR may have an RS3PE syndrome, and some authors think that RS3PE can be considered an integral part of the spectrum of the PMR manifestations.(15) We have evaluated 200 elderly patients (> 65 years old) with PMR, consecutively observed at our rheumatologic outpatient clinic from 2002 to 2014, with regard to presence/absence of RS3PE and presence/absence of a paraneoplastic syndrome. The diagnosis of PMR was made, until 2013, using the criteria proposed by Healey(16) and, after 2013, using the criteria proposed by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR).(6) The minimum observation time for the appearance of an eventual cancer has been of 24 months from initial diagnosis of PMR. The lack of response to corticosteroid therapy and/or the appearance of signs or symptoms not consistent with typical PMR have shown to be warns for finding eventual cancer. In the same cohort of patients, the presence of RS3PE syndrome was highlighted in a binary way (yes / no): the fact that the RS3PE is a manifestation of onset or appears during the course of PMR in addition to other clinical manifestations did not constitute an element of assessment. The occurrence of cancer was compared between patients with PMR without RS3PE and those with PMR + RS3PE. The presence of RS3PE was observed in only seven patients with PMR (3.5%). In three of the seven patients with RS3PE associated with PMR (5 M, 2 F) it was possible to recognize a tumor: prostatic cancer, vescical cancer, multiple myeloma (Table 1). In all these patients, RS3PE presented before the discovery of the malignancies. Its reappearance after a short while represented in all three cases an element of strong suspicion. Subsequent diagnostic decisions were indicated by specific signs: significant rise of prostate specific antigen or appearance of hematuria or a monoclonal peak at Polymyalgia Rheumatica in Association with Remitting Seronegative Sinovitis with Pitting Edema: a Neoplastic Warning