Remitting Seronegative Symmetrical Synovitis with Pitting Edema (RS3PE), first described in 1985 by McCarty et al, is a rare syndrome that is a subset of the seronegative symmetrical polyarthritis of older people.1

RS3PE is a type of benign seronegative polyarthritis that affects older people and is characterised by sudden onset of oedema and swelling of the dorsum of the hands with symmetrical polysynovitis involving wrists, metacarpophalangeal, interphalangeal, tarsal and metatarsophalangeal joints, tenosynovitis of the flexors and extensors of the hands, morning stiffness with negative rheumatoid and anti-nuclear antibody tests and rapid response to low dose corticosteroids.1-3

Characteristics

The main characteristics of RS3PE syndrome are:

•     Acute onset 

•     Raised acute phase reactants

•     Bilateral diffuse, symmetrical swelling 

•     Rheumatoid factor negative

•     Hand and wrist involvement  

•     Human Leukocyte Antigen (HLA) B7 Positive

•     Dorsal pitting oedema of hands             

•     Positive response to low dose corticosteroids

•     Symmetrical synovitis               

•     X-rays show soft tissue swelling in the absence of erosions.

Olive et al2 also proposed the following diagnostic criteria for this syndrome:

1.    Bilateral pitting oedema of both hands

2.    Sudden onset of polyarthritis

3.    Age more than 50 years

4.    Seronegative for rheumatoid factor.

With a male predominance (2:1) affecting the elderly demographic more frequently, it is shown to have a remarkable response to low dose corticosteroids and has long term remission after withdrawal.1

The exact prevalence of RS3PE is not known. McCarty described the first case of RS3PE characterised by symmetrical distal synovitis and tenosynovitis of the mucous sheaths of the flexor and extensor tendons of the hands associated with pitting oedema of the hands and/or feet.3

Disease process

The exact pathophysiology of RS3PE remains unknown. The syndrome was reported to be associated with HLA B7 3 and HLA A2 haplotypes.4 One study has suggested that vascular endothelial growth factor (VEGF) contributes to the pathological changes responsible for both hypervascularity and vascular permeability, which in turn lead to synovitis and subcutaneous oedema.5

The aetiology of the pitting oedema is also unknown, however MRI studies suggest that distinct extensor tenosynovitis is the principle lesion responsible for oedema of subcutaneous and peritendinous soft tissue.6

Causes

RS3PE is a spectrum of symptoms that can be caused by other conditions. There is no diagnostic test for this syndrome and subsequently diagnosis is made through exclusion. Research suggests that it may not be a specific entity, but rather a syndrome representing the inaugural form of various rheumatic and neoplastic conditions of older people.7

Differential diagnosis

The main differential diagnosis of RS3PE is polymyalgia rheumatica (PMR). Despite the diagnostic symptoms of PMR (pain, stiffness and weakness affecting the proximal joints mainly shoulder and pelvic girdle), a prospective study showed that RS3PE could well be associated with PMR or in fact part of the same disease process. However RS3PE has never been described in association with giant cell arteritis unlike PMR.

In a 23 patient prospective study in 1999, it found that a subgroup (12%) of PMR patients had distal extremity swelling with pitting oedema of the hands which was consistent with RS3PE.8 This study from Italy shows similarities between RS3PE and PMR. There are similarities in age, sex, presence of raised acute phase reactants at diagnosis, frequency of peripheral synovitis and presence of HLA B7 antigen positivity in both groups. In neither group has the diagnosis been made below the age of 50 years. The disease frequency increases with age and is maximal at age 70-79 years. Both the conditions respond to steroids. Despite this similarity, protracted and higher dosages of corticosteroids are required to obtain remission in PMR compared to RS3PE.

There is a frequent association with knee synovitis and carpal tunnel syndrome. Some studies indicate that the disease can occasionally be unilateral.8,9,10

Other rheumatological conditions that elicit features similar to RS3PE include seronegative rheumatoid arthritis, acute sarcoidosis, ankylosing spondylitis, psoriatic arthropathy, mixed connective tissue disease, reflex sympathetic dystrophy, chondrocalcinosis, and amyloid arthropathy.

Associations

Of interest are paraneoplastic forms of RS3PE as primary or secondary manifestations of a neoplastic process without response to corticosteroids. The paraneoplastic RS3PE is associated with solid tumours with histological type predominantly adenocarcinomas, such as gastric,11 pancreatic cancers12 and haematological malignancies such as myelodysplasia and non-Hodgkin's lymphoma.13

The paraneoplastic RS3PE is usually characterised by systemic symptoms of fever, anorexia and weight loss and has a poor response to treatment with corticosteroids. It only seems to resolve with successful treatment of underlying malignancy.1

Diagnosis

The diagnosis is mainly based on clinical characteristics as mentioned above and by exclusion of other associated conditions.

Blood tests may show raised inflammatory markers (ESR and CRP), normocytic normochromic anaemia, a negative rheumatoid factor and a negative or a low titre for ANA.

X-rays of the hands and wrists may show soft tissue swelling in the absence of any erosions.

Ultrasound, a reliable and cost effective modality for investigation of patients where RS3PE is suspected can characteristically show tenosynovitis of flexor and extensor tendons.14 Tenosynovitis of both flexor and extensor tendons at the wrist and the extensor tendons of the feet is a hallmark of RS3PE. MRI can be used for assessing disease activity as it provides information about soft tissue, cartilage and bony erosions.15 Whole body Ga-67 scan show increased uptake in hands and feet and is rarely used for assessing disease activity.16

Treatment

Classic RS3PE responds well with low dose corticosteroids (10-15mg) with sustained and maintained remission within 6-18 months. NSAIDs and in some cases hydroxychloroquine have also proven to be effective.

Calcium and vitamin D supplementation along with bisphosphonates are  recommended for most older patients due to risk of osteoporosis with long-term steroid use. Proton pump inhibitors/H2 receptor antagonists may be needed for gastroprotection.

Conflict of interest: none declared

 

References

 

1.   Sayarlioglu M. Remitting Seronegative Symmetrical Synovitis With Pitting Edema (RS3PE) Syndrome and Malignancy. European Journal of General Medicine 2004; 1(2):3-5

2.   Olive A, del Blanco J, Pons M, et al. The clinical spectrum of remitting seronegative symmetrical synovitis with pitting edema. The Catalan Group for the Study of RS3PE. J Rheumatology 1997; 24: 333-36

3.   Mc Carty DJ, O' Duffy JD, Pearson L, Hunter JB. RS3PE syndrome. JAMA 1985; 254: 2763-67

4.   Schaeverbeke T, Vernhes JP, Bannwarth B, Dehais J. Is remitting seronegative symmetrical synovitis with pitting oedema (RS3PE syndrome) associated with HLA-A2? Br J Rheumatol. 1995; 34: 889-90

5.   Arima K, Origuchi T, Tamai M, et al. RS3PE syndrome presenting as vascular endothelial growth factor associated disorder. Ann Rheum Dis 2005; 64: 1653-55

6.   Oliveri I, Salvarani C, Cantini F. Remitting distal extremity swelling with pitting oedema: a distinct syndrome or a clinical feature of different inflammatory rheumatic diseases? J Rheumatol. 1997; 24: 249-52

7.   Schaeverbeke t, Fatout E, Marce S, et al. Remitting seronegative symmetrical synovitis with pitting oedema: disease or syndrome? Ann Rheum Dis 1995; 54: 681-84

8.   Cantini F, Salvarani C, Olivieri I, et al. Remitting seronegative symmetrical synovitis with pitting oedema (RS3PE) syndrome: a prospective follow up and magnetic resonance imaging study. Ann. Rheum. Dis 1999; 58 (4): 230-6.

9.   Parisier KM, Canoso JJ. Remitting seronegative symmetrical synovitis with pitting oedema-Two cases of RS3PE syndrome. J Rheumatol 1991; 18: 1260-62

10. Olivieri I, Padula A, Favaro L et al. RS3PE syndrome with unilateral involvement.(Letter). J Rheumatol 1994; 21: 372

11. Tada Y, Sato H, Yoshizawa S, et al. Remitting seronegative symmetrical synovitis with pitting oedema associated with gastric carcinoma. J Rheumatol. 1997; 24: 974-75.

12. Cantini F, Olivieri I, Salvarani C. More on remitting seronegative symmetrical synovitis with pitting oedema as paraneoplastic syndrome. J Rheumatol. 1998; 25: 188-89

13. Gisserot O, Cremades S, Landais C, Leyral G, Bernard P, de Jauréguiberry JP. RS3PE revealing recurrent non-Hodgkin's lymphoma. Joint Bone Spine. 2004; 71: 424-26

14. Agarwal V, Dabra AK, Kaur R, Sachdev A, Singh R. RS3PE: Ultrasonograph as a diagnostic tool. Clin Rheumatology 2005; 24: 476-79

15. Unlu Z, Orguc S, Ovali GY, et al. MRI findings in a case of remitting seronegative symmetrical synovitis with pitting edema. Clin Rheumatology 2005; 24: 648-51.

16.          Takeguchi T, Sugawara Y, Kikuchi K, et al. RS3PE: Scintigraphic and Magnetic resonance imaging findings. Clinical Nuclear Medicine. 2003; 28: 766-69