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 ::  Abstract
 :: Introduction
 :: Case Series
 :: Discussion
 :: Conclusion
 ::  References
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  Table of Contents     
Year : 2015  |  Volume : 61  |  Issue : 1  |  Page : 38-41

Syndrome of remitting seronegative symmetrical synovitis with pitting edema: A case series

Department of General Medicine, Division of Rheumatology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India

Date of Submission13-May-2014
Date of Decision20-May-2014
Date of Acceptance08-Jun-2014
Date of Web Publication15-Dec-2014

Correspondence Address:
Dr. A N Varshney
Department of General Medicine, Division of Rheumatology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0022-3859.147038

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 :: Abstract 

Remitting Seronegative Symmetrical Synovitis with Pitting Edema (RS3PE) is a rare clinical entity that is easily missed due to lack of knowledge. It was formerly considered as a subset of rheumatoid arthritis (RA), but is now regarded as a distinct disease/syndrome. The diagnosis of RS3PE is not easy, as it is always hindered by the lack of definite diagnostic criteria and presence of other much common rheumatological disorders that mimic it. We report a series of seven cases that attended our clinic in the last year, which highlight the salient features of the disease. The disease was found to have a heterogeneous presentation. Immunogenetic, clinical, laboratory, radiological, and possible etiological factors and associations with the neoplasm are described, as also other peculiar presentations. Finally, a comparison with other common rheumatological disorders is made to alert the clinician about this rare, but easily treatable disease.

Keywords: Rheumatoid arthritis, rheumatoid factor, RS3PE, synovitis

How to cite this article:
Varshney A N, Singh N K. Syndrome of remitting seronegative symmetrical synovitis with pitting edema: A case series. J Postgrad Med 2015;61:38-41

How to cite this URL:
Varshney A N, Singh N K. Syndrome of remitting seronegative symmetrical synovitis with pitting edema: A case series. J Postgrad Med [serial online] 2015 [cited 2023 Mar 30];61:38-41. Available from:

 :: Introduction Top

In 1985, Mc Carty and coworkers [1] described a distinct form of elderly onset of rheumatoid arthritis (RA) in 10 patients, characterized by symmetrical polyarthritis, with a dramatic onset of pitting edema over the hands, old age, male predominance, elevated acute phase reactants, negative rheumatoid factor, and an excellent prognosis to treatment. Ever since, it has always been a matter of debate between rheumatologists as to whether to consider it a disease or a syndrome. [2] Various rheumatic diseases, such as rheumatoid arthritis, polymyalgia rheumatic and spondyloarthropathies, which are much more common than RS3PE, may also present with distal extremity pain and swelling. [3] Also, the above criteria have been challenged by various studies and case reports and have added newer aspects to this entity. We present in this paper, 7 cases, a synthesis and analysis of existing literature, and comparison of the clinical, laboratory, and radiological features.

 :: Case Series Top

Case 1

A 68-year-old female, housewife by occupation, presented with chief complaints of pain in the metacarpophalangeal joints (MCP) and wrist on the left side and swelling of the hand for last five weeks. It was acute in onset, and pain was moderate-to-severe in intensity, to an extent that she was unable to make a fist. There was no radiation of pain. It was associated with morning stiffness lasting for about half an hour. She denied any history of previous joint pain, fever, trauma, rash, burning micturition, urethral discharge, or diarrhea. She consulted a private practitioner outside and was referred to the Surgery Outpatient Department (OPD), where she was diagnosed with cellulitis and given oral linezolid and clindamycin. She did not improve and her joint pain worsened for which a medical opinion was sought. On examination, there was marked pitting edema of the left hand extending up to the wrist joint. It was not warm but extremely tender. There was limitation of movements of the wrist and MCP joints, but there was no neurological deficit. Her vitals were within normal limits and in the rest of her systemic examination (including locomotor), no abnormality was detected. Laboratory investigations revealed hemoglobin = 9.4, total count = 6500, erythrocyte sedimentation rate (ESR) = 44 mm, and C-reactive protein (CRP) = 23.8. Both RA and anti-cyclic citrullinated peptides (CCP) were negative. X-ray of the hands was normal, without any evidence of erosions or fracture. The Color Doppler sonography of the left hand revealed extensor tenosynovitis of the hands. A diagnosis of unilateral RS3PE was made. The patient was given oral prednisolone (15 mg/day) along with NSAIDs. The patient responded, as pain started subsiding within a week, and all the symptoms were relieved within five weeks. Later during the follow up, she was screened for any hidden occult malignancy with a regular physical examination, peripheral blood smear examination, chest radiography, abdominal ultrasonography, and Papanicolaou test (PAP smear). She is in regular follow up since the last 18 months and is without any residual disability or deformity.

Case 2

A 60-year-old male presented with pain in multiple joints (b/l MCP, proximal interphalangeal joints (PIP), wrist, elbow, ankle) along with swelling of the hand up to wrist, since the last two months [Figure 1]a. History of morning stiffness was present, lasting for one hour. Examination revealed asymmetrical pitting edema (left > right) on the back of the hands and pedal edema. His hemoglobin = 10, ESR = 37 (>10) in the first hour, CRP = 6.1(>5), RA factor was negative, and x-rays of the hands were normal, without any evidence of erosions. Ultrasonography of the upper limbs revealed extensor tenosynovitis. With the diagnosis of RS3PE, the patient was given prednisolone (15 mg) and the symptoms resolved within three weeks [Figure 1]b. Remission has been maintained since the last 14 months, without any relapse.
Figure 1: (a) Clinical photograph of the patient showing diffuse edema over the dorsum of the hands (boxing glove appearence) (b) Clinical photograph of the patient after three weeks of treatment, with complete resolution of the symptoms and signs

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Case 3

A 90-year-old female presented with an abrupt onset of polyarthralgia (b/l wrist, MCP, PIP) along with diffuse swelling of the hands since the last 45 days. History of morning stiffness was present for about an hour. Examination revealed pitting edema restricted to the dorsum of the hands and extreme tenderness. The rest of the systemic examination was within normal limits. Her hemoglobin = 12.8, ESR = 22 mm (>20), and CRP = 6.3 (>5). Both the rheumatoid factor and antinuclear antibodies (ANA) were negative. The x-ray of hands did not have any evidence of erosions and the color Doppler revealed tenosynovitis of both extensor and flexor tendons of the hands. The patient was referred to us and we diagnose it as RS3PE. The patient was given prednisolone (15 mg) for six weeks and improved completely, without any residual disability. She was in follow up for eight weeks and was lost to follow up after that.

Case 4

A 77-year-old male attended the Medicine Clinic with chief complaints of pain in multiple joints (b/l MCP, PIP, wrist, elbows) along with swelling on the back of his hand since the last one month. Morning stiffness was denied. Examination revealed diffuse edema at the back of the hands. ESR = 18 mm, CRP = 11 (> 5), and the RA factor was negative. On the x-ray of the hand no abnormality was detected and a diagnosis of RS3PE was arrived at. The patient was given prednisolone (15 mg) and he improved within four weeks, without any residual disease. At 24 months follow up, his remission is maintained.

Case 5

A 56-year-old female attended the Medicine OPD with complaints of pain in b/l MCP, PIP, wrist, knee, and ankle, along with diffuse swelling, for the last three weeks. History of morning stiffness was present, lasting for one hour. On examination, there was pitting edema present on both hands and feet. Her hemoglobin = 9-2, ESR = 54, CRP = 46, RA factor and anti-CCP were negative. X-ray of the hands were normal and USG revealed both extensor and flexor tenosynovitis of the hands. With a diagnosis of RS3PE, she was given prednisolone 20 mg and she improved within four weeks without any residual deformity or relapses and was subsequently lost to follow up.

Case 6

A 48-year-old female presented with an acute onset of polyarthralgia (b/l PIP, MCP, wrist, elbows) for the last one along, with swelling over both hands. There was associated history of morning stiffness. On examination, pitting edema was present over the dorsum of both hands. Her hemoglobin = 8.8, ESR = 114, CRP = 208, and RA factor was negative. Ultrasonography (USG) of the hands showed extensor tenosynovitis. Thus, it was diagnosed as RS3PE. She was given prednisolone = 20 mg/day. All symptoms were resolved in six weeks. The patient has maintained remission since the last 12 months.

Case 7

A 60-year-old male presented with pain in multiple peripheral joints (b/l PIP, MCP, wrist, elbow) along with swelling on the back of his hands, for the last one month. There was a history of associated morning stiffness. On examination, there was diffuse pitting edema on the dorsum of the hands. Investigations revealed hemoglobin = 11.8, ESR = 86mm, and CRP = 48. Both RA and anti-CCP were negative. The x-ray was normal and color Doppler ultrasonography revealed flexor tenosynovitis of the upper limbs. RS3PE was the diagnosis and he was given prednisolone = 15 mg. The patient improved within six weeks and remission has been maintained since the last three months.

Clinical and laboratory characteristics of all cases are summarized in [Table 1].
Table 1: Summary of the clinical and laboratory parameters of all patients

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 :: Discussion Top

Since Mc Carty's original description in 1985, over 150 cases of RS3PE have been described. Most of the cases are idiopathic and fulfill the original criteria. However, many cases do not fit the criteria adding new dimensions to this entity. Subcutaneous pitting edema has been undoubtedly the most characteristic feature. Both hand and feet edema has been reported. Bilaterally, symmetrical presentation had been classically described, but now unilateral RS3PE is well-recognized. [3],[4] Although the disease is more prevalent in the geriatric age group, a young case has also been reported. [4] Female cases are in abundance to challenge the male predominance that was originally described. [5] Even in our series there is a female predominance along with the young (case 6) and unilateral (case 1) cases.

The laboratory parameters include an elevated acute phase reactant (ESR, CRP) signifying an underlying inflammatory process. Rheumatoid factor and anti-CCP are typically negative. Anti-nuclear antibodies are positive, rarely. Varying degrees of anemia (particularly anemia of chronic disease) may be present. Our case also supports these parameters. [3]

Radiologically, erosions are classically absent on X-rays. [6] Ultrasonography/Magnetic Resonance imaging (USG/MRI) of the extremities have shown tenosynovitis [Figure 2] as a major cause of subcutaneous edema. A study reveals that extensor tenosynovitis is more common than flexor tenosynovitis. [7] In our study also, extensor tenosynovitis dominates flexor tenosynovitis. USG with a color Doppler is now considered to be a reliable, easily accessible and cost-effective modality of radiological evaluation.
Figure 2: Ultrasonography of patients with pedal edema showing tenosynovitis around the ankle joint

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The immunopathogenesis of the disease is still in dark. Various studies have established the role of the vascular endothelium derived growth factor (VEGF) as a major contributor to polysynovitis and subcutaneous edema of the extremities, by increasing vascular permeability. [8] IL-6 has been found to be elevated in the synovial fluid of patients with RS3PE and has also been implicated in its pathogenesis. Human leukocyte antigen (HLA) associations of RS3PE have been established with HLA-B7 and HLA-A2. HLA-CW7 and HLA-DQW2 are also found to be associated. However, their role in the inheritance is still dubious, as no case of familial association has been reported. In spite of these studies, a definite triggering factor is unknown. Infectious agents such as Parvovirus, Streptobacillus moniliformis, and Mycoplasma pneumoniae have been implicated. Studies have also described the role of Bacillus Calmette-Guerin (BCG) instillation as a trigger. [9]

Remitting seronegative symmetrical synovitis with pitting edema responds to relatively small doses of prednisolone (5-20 mg). Nonsteroidal anti-inflammatory drugs (NSAIDS) and hydroxychloroquine may provide an added advantage. There is very little role of the disease-modifying antirheumatic drugs (DMARDs). [10] This remission is usually well-sustained. On the other hand RS3PE, with an underlying malignancy, responds poorly, and treatment of the underlying malignancy is needed as a primary step.

Association of RS3PE with neoplasms has always raised suspicion of it being a paraneoplastic syndrome. [9] It has been described in association with lung, prostrate, ovary, endometrium, breast, bladder, gastrointestinal, and hepatocellular carcinoma. Its association has been widely accepted with hematological malignancies (non-Hodgkin's lymphoma, leukemia, and myelodysplastic syndrome), fibrohistiocytoma, and Kaposi's sarcoma. A higher prevalence is suggested by both retrospective and perspective studies. One study suggests that the malignancy rate associated with RS3PE may be as high as 54%. [9] Thus, it is always advisable to look for malignancy in a patient with a diagnosis of RS3PE, although in our series we found none.

While Mc Carty initially described RS3PE as a distinct form of late-onset rheumatoid arthritis. Now, after 28 years, it has been found to coexist with various rheumatic diseases, such as, Sjogren's syndrome, polyarteritisnodosa, ankylosing spondylitis, sarcoidosis, amyloidosis, relapsing polychondritis, and bronchiolitis obliterans organizing pneumonia.

On the basis of these facts RS3PE is now considered as a distinct clinical entity. However, in a clinical setting, it is not as easy to diagnose, as the mimickers (rheumatoid arthritis, spondyloarthropathy, polymyalgiarheumatica) are much more common. Even non-rheumatological disorders such as reflex sympathetic dystrophy can present in a similar manner. The differential features are compared [Table 2].
Table 2: Predominant clinical features of common diseases

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 :: Conclusion Top

Remitting seronegative symmetrical synovitis with pitting edema is a disease/syndrome characterized by an acute onset of polyarthritis with pitting edema, negative rheumatoid factor, absence of joint erosions on radiographs, synovitis suggested by USG/MRI, and an exquisite response to low-dose steroids, with a sustained long-term response. An early prompt diagnosis is required, as proper treatment results in a dramatic relief to the patient, while misdiagnosis results in a more intensive and expensive therapy, over a long period of time.

 :: References Top

McCarty DJ, O'Duffy JD, Pearson L, Hunter JB. Remitting seronegative symmetrical synovitis with pitting edema.RS3PE syndrome. JAMA 1985;254:2763-7.  Back to cited text no. 1
Schaeverbeke T, Fatout E, Marcé S, Vernhes JP, Hallé O, Antoine JF, et al. Remitting seronegative symmetrical synovitis with pitting oedema: Disease or syndrome? Ann Rheum Dis 1995;54:681-4.  Back to cited text no. 2
Keenan RT, Hamalian GM, Pillinger MH. RS3PE presenting in a unilateral pattern: Case report and review of the literature.Semin Arthritis Rheum 2009;38:428-33.  Back to cited text no. 3
Ozşahin M, Ataoğlu S, Turan H. Unilateral RS3PE with young-onset rheumatoid arthritis. Semin Arthritis Rheum 2011;40:e1.  Back to cited text no. 4
Oide T, Ohara S, OguchiK, Maruyama M,Yazawa M, Inoue K, et al. Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome in Nagano, Japan: Clinical, radiological,and cytokine studies of 13 patients. ClinExp Rheumatol 2004;22:91-8.  Back to cited text no. 5
Sekhon L. Remitting seronegative symmetrical synovitis with pitting edema. JAAPA 2010;23:38, 40, 43.  Back to cited text no. 6
Agarwal V, Dabra A, Sachdev A, Singh R, Lehl S. Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome: A prospective follow up and ultrasound study. J IndRheumatolAssoc 2003;11(Suppl 1):2.  Back to cited text no. 7
Matsuda M, Sakurai K, Fushimi T, Yamamoto K, Rokuhara S, Hosaka N, et al. Sarcoidosis with high serum levels of vascular endothelial growth factor (VEGF), showing RS3PE-like symptoms in extremities. ClinRheumatol 2004;23:246-8.  Back to cited text no. 8
Yao Q, Su X, Altman RD. Is remitting seronegative symmetrical synovitis with pitting edema (RS3PE) a subset of rheumatoid arthritis? Semin Arthritis Rheum 2010;40:89-94.  Back to cited text no. 9
Hartley AJ, Manson J, Jawad AS. Remittingseronegative symmetrical synovitis with pitting edema.Grand Rounds 2010;10:71-3.  Back to cited text no. 10


  [Figure 1], [Figure 2]

  [Table 1], [Table 2]

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