Curr Rheumatol Rep (2015) 17:49
DOI 10.1007/s11926-015-0525-0
ORPHAN DISEASES (B MANGER, SECTION EDITOR)
RS3PE: Clinical and Research Development
Hongbin Li 1 & Roy D. Altman 2 & Qingping Yao 3,4
# Springer Science+Business Media New York 2015
Abstract Remitting seronegative symmetrical synovitis
with pitting edema or RS3PE is a rare elderly-onset rheu-
matic syndrome. Although there are overlapping clinical
manifestations between RS3PE, elderly-onset rheumatoid
arthritis, and polymyalgia rheumatica, RS3PE has distinct
characteristics. RS3PE can be associated with neoplasia
and various rheumatic conditions, suggesting that it may
be heterogeneous, and is considered as a paraneoplastic
rheumatic disease. The pathogenesis of RS3PE may in-
volve vascular endothelial growth factor and infection in
RS3PE based upon limited data. Patients with RS3PE
without concomitant malignancy respond well to small
doses of glucocorticoids and carry good prognosis.
Keywords RS3PE . Neoplasm . Vascular endothelial growth
factor . Rheumatoid arthritis . Polymyalgia rheumatica .
Infection
This article is part of the Topical Collection on Orphan Diseases
* Qingping Yao
yaoq@ccf.org; Qingpingyao@yahoo.com
1
The Division of Rheumatology, Inner Mongolia Medical University,
Hohhot, China
2
The Division of Rheumatology, David Geffen Medical School at
UCLA, Los Angeles, CA, USA
3
The Department of Rheumatic and Immunologic Disease,
Cleveland Clinic, Cleveland, OH, USA
4
The Division of Rheumatology, Allergy and Immunology, Stony
Brook University, Stony Brook, NY, USA
Introduction
Remitting seronegative symmetrical synovitis with pitting
edema or RS3PE is an elderly-onset rheumatic disease. Since
its initial description by Dr. Daniel McCarty et al. in 1985 [1],
it has been regarded as a distinct clinical entity, characterized
by symmetrical synovitis of the hands and ankles with pitting
edema, elevated acute phase reactants, and negative rheuma-
toid factor (RF), with an excellent prognosis [2]. While there
have been case reports of the disease, there are still issues that
need to be addressed in terms of relation to neoplasm and the
pathogenic mechanisms. We review the clinical manifesta-
tions of the RS3PE and focus on the associated diseases and
the pathogenesis, notably with concurrent malignancies.
RS3PE Is Distinct Entity and Differs
From Elderly-Onset Rheumatoid Arthritis
and Polymyalgia Rheumatica
RS3PE was initially thought to be a variant of rheumatoid
arthritis (RA) [1, 3]. Currently, the majority of the literature
supports RS3PE as a distinct and separate syndrome [4].
RS3PE is clinically characterized by pitting edema of both
hands and feet, lack of subcutaneous nodules, negative RF,
absence of radiographic erosions, no association with HLA-
DRB1 alleles, excellent response to glucocorticoids, and an
excellent prognosis [5, 6]. Although the pitting edema often
occurs in the hands (Fig. 1), it also occurs in the feet [8–11].
Also it is usually symmetrical, but it may be only unilateral.
RS3PE usually has its onset in the elderly and occurs in
more men than women [12••, 13]. According to a study of
3347 patients of aged 50 and greater in a single medical center
in Japan, three patients were diagnosed with RS3PE, with a
resultant disease incidence rate of 0.09 % [14]. Other elderly-
49 Page 2 of 6
Fig. 1 Pitting edema of the
hands, synovitis, and failure to
grip. (From [7], with permission)
onset rheumatic conditions, such as polymyalgia rheumatica
(PMR) and elderly-onset RA, can have overlapping clinical
pictures with RS3PE; however, they are dissimilar in certain
clinical aspects. The clinical manifestations of these three dis-
eases are summarized in Table 1. The significant pitting ede-
ma of the dorsal hands in RS3PE patients is usually caused by
extensor tenosynovitis [17]. An ultrasonographic study of 10
patients with RS3PE demonstrated tenosynovitis of both flex-
or and extensor tendons at the wrist and extensor tendons of
the feet as a defining feature of RS3PE [18].
RS3PE Is a Syndrome and Associated With
Numerous Disorders
Neoplasia
Both cancer and benign tumors have been reported in as-
sociation with RS3PE since 1985 [17, 19–22]. The types of
malignancies reported in the disease have included both
hematological malignancies and solid tumors. The hematologi-
cal malignancies associated with RS3PE encompassed non-
Hodgkin’s lymphoma [5, 13, 19, 21, 23], leukemia [5, 24–26],
myelodysplastic syndrome [21, 27], and angioimmunoblastic
T cell leukemia [28]. The solid tumors involved the prostate
[13, 20, 29], gastrointestinal [21, 29–31], lung [32], breast
[5], ovary [22], bladder [13], endometrium [33], and 1
fibrohistiocytoma [21]. There are additional three reported
cases of malignancies of unknown sites [17].
In addition to the single case reports, there were several
case series reports to address the incidence of malignancy in
RS3PE patients. For example, in a French study of six men
with RS3PE, solid malignancy was discovered on follow-up
of all these patients [29]. In a study of 12 patients of RS3PE in
Argentina in 2002, Pairas et al. found four malignancies over
4.4 years of follow-up [21]. One patient presented with symp-
toms of RS3PE prior to the diagnosis of rectal adenocarcino-
ma, and three cases were diagnosed with fibrohistiocytoma,
myelodysplastic syndrome, and non-Hodgkin’s lymphoma
preceding the diagnosis of RS3PE. In an American study of
Curr Rheumatol Rep (2015) 17:49
10 patients with RS3PE in 2005, Russell reported four cases
of cancer (one lymphoma, one leukemia, one breast cancer,
and one lung cancer) following the diagnosis of RS3PE [5]. In
a separate study of 14 cases of RS3PE in Mayo Clinic in 2007,
Bucaloiu [13] reported three cases of malignancies, including
one woman with non-Hodgkin’s lymphoma and two men with
non-Hodgkin’s lymphoma and bladder transitional cell carci-
noma over an average follow-up of 31 months. Hence, al-
though most often RS3PE presents before the discovery of a
malignancy, it can occasionally present after the diagnosis of a
malignancy.
Based upon the pooled data of the above separate studies,
the malignancy rate in association with European/American
RS3PE patients was estimated to be 31 % (11/36). In a Japa-
nese study of 28 patients with RS3PE [12••], 7 % (2/28) of
patients had malignancies including bladder and colon cancer.
In the same study, 2.4 % (3/123) of persons with pure PMR
had uterine cancer, hepatocellular carcinoma, and gastric can-
cer. The rate of associated malignancy was not statistically
different between the two diseases. These data may raise a
question whether there might be differences in the malignancy
rate between American/European (31 %) and oriental patients
(7 %) with RS3PE.
Nevertheless, the average malignancy rate was estimated to
be 20 % (13/64) considering the pooled data of European,
American, and oriental patients with RS3PE. These data sug-
gest that the incidence of malignancy may be significantly
higher in RS3PE than the general elderly population. Howev-
er, no large case series reports of RS3PE or population study
are available, and the true prevalence of the neoplasm in the
disease is not known.
It is known that the rates of malignancy occurrence in RA
and PMR are higher than the general population [34]. In a
recent study of 19,260 patients with RA in the USA, the over-
all malignancy incidence per 100 patient-years was 0.56 [35•].
The data of elderly-onset RA-associated malignancy is still
lacking. In a study of 7566 patients (mean age=55.9 years)
with RA in Japan, 173 patients were identified to have malig-
nancies during an observation of 25,567 person-years, and the
age- and sex-standardized incidence rate of malignancy was
Curr Rheumatol Rep (2015) 17:49 Page 3 of 6 49

Table 1 Comparison between RS3PE, LORA, and PMR [12••, 15, 16]

Clinical features RS3PE EORA PMR

Onset age (years) >60 >60 >60

Gender M>F F≈M F>M
Abrupt onset Hours Often Rapid, days to weeks
Small joint synovitis Mild Prominent Mild
Pitting edema 100 %, prominent Unusual None
Pain/stiffness in pelvic girdle/thigh regions (%) 39.3 Rare 74.0
Fever (%) 35.7 Less 19.5
Radiographic erosion No Yes No
Synovitis and/or pannus by MRI or Ultrasonography Uncommon, mild, but marked tenosynovitis Marked Uncommon, mild
of both flexor and extensor tendons
Anti-CCP antibody (%) 0 Often Less
Rheumatoid factor Negative Positive (39–57 %) Positive (16.5 %)
Response to low-dose prednisone (10 to 15 mg/day) Dramatic Usually incomplete Dramatic
Malignancy rate (%) 20 0.44 0.56
Remission Yes Yes, with DMARDs Usually takes 2 to 3 years

RS3PE remitting seronegative symmetrical synovitis with pitting edema, EORA elderly-onset rheumatoid arthritis, PMR polymyalgia rheumatica, MRI
magnetic resonance imaging, DMARDs disease-modifying anti-rheumatic drugs

437.1 per 100,000 person-years [36]. In a recent study of
malignancy association with PMR in the UK, there was a
69 % increased risk of a cancer diagnosis within the first
6 months after a diagnosis of PMR. It could not be established
whether or not the risk in PMR was different from that of
controls, beyond this point [37]. However, there have been
no comparative studies of the neoplastic prevalence among
these rheumatic conditions, namely, elderly-onset RA, PMR,
and RS3PE, to date. Our prior review of the literature in
reference to the malignancy incidence associated with RS3PE
suggested that the neoplastic pattern occurring in RS3PE might
appear different from RA in general [15]. Overall, the current
consensus is that RS3PE represents a form of paraneoplastic
rheumatic syndromes [20].
Paraneoplastic syndromes comprise diseases or symptoms
that are not caused directly by the tumor or by its metastases,
but are mediated by soluble factors, such as hormones and
cytokines from a tumor, or are a consequence of humoral or
cellular immune mechanisms directed against tumor cells and,
therefore, often occur at regions distant from the underlying
malignancy. In the case of paraneoplastic syndromes in rheu-
matology, musculoskeletal symptoms arise in the joints, fasciae,
muscles, vessels, or bones generally no longer than 2 years
before the diagnosis of an associated neoplasm [38, 39•].
RS3PE Is Associated With Diseases and Medications
Other Than Malignancy
Various rheumatic diseases occurring in RS3PE have been
reported. These rheumatic conditions are systemic lupus
erythematosus [40], gout [41], Sjogren’s syndrome [42],
polyarteritis nodosa [43], ankylosing spondylitis [44], sarcoid-
osis [45], amyloidosis [46], relapsing polychondritis [27], and
bronchiolitis obliterans organizing pneumonia [47]. In addi-
tion, other medical conditions or drugs associated with RS3PE
include diabetes mellitus [48], dipeptidyl peptidase-4 inhibi-
tors [49], rifampin [50], and insulin therapy [51]. RS3PE may
be associated with infection, such as bacillus Calmette-Guerin
(BCG) [52], parvovirus [53], and Streptobacillus moniliformis
infection [54].
Advances of Pathogenic Study in RS3PE
The above data of multiple conditions in association with
RS3PE support that RS3PE is a syndrome with potentially
heterogeneous etiologies. A significant percentage of patients
with RS3PE have associated malignancies as aforementioned.
In the neoplastic microenvironment, angiogenesis is an
underlying promoter for tumor growth, invasion, and
metastasis. Vascular endothelial growth factor (VEGF)
plays an important role in the angiogenic process [55].
VEGF has potent vasodilatory effects and increases vascular
permeability [56]. Prior Japanese studies have suggested that
VEGF may be involved in the pathogenesis of the RS3PE
syndrome [57]. Arima et al. measured serum VEGF levels
of three RS3PE patients and compared it with those of patients
with several classic connective tissue diseases in 2005 and
found several-fold increase of VEGF levels in patients with
RS3PE over the controls [57]. In the same report, tumor ne-
crosis factor α and interleukin-1 levels were not different
49 Page 4 of 6
between RS3PE patients and controls. The elevated VEGF
levels in patients with RS3PE decreased after glucocorticoid
treatment, indicating a possible role of VEGF in the disease.
Additional Japanese reports showed elevated VEGF levels in
one patient with sarcoidosis and RS3PE, with subsequent re-
duction after glucocorticoid treatment [45], one patient with
angioimmunoblastic T cell lymphoma [28], and another pa-
tient with RS3PE and myasthenia gravis [58]. In addition,
interleukin-6 and matrix metalloproteinase-3 have been re-
portedly elevated in RS3PE patients with neoplasia versus
those without as well [59, 60].
It is postulated that neoplasia, other medical conditions,
and drugs may trigger production of VEGF and other mole-
cules, which in turn result in polyarthritis/polysynovitis and
subcutaneous pitting edema of the extremities by inducing
vascular permeability in RS3PE syndrome [61]. It should be
mentioned that the studies of the pathogenesis of RS3PE were
limited to Japanese reports. The reported patient sample sizes
were small, and the patients did not have concomitant neopla-
sia. Given that RS3PE is a heterogeneous syndrome and as-
sociated with malignancies in a significant number of cases,
further study of other potential mechanisms in RS3PE pa-
tients, particularly those with neoplasia, is needed.
Therapy and Prognosis of RS3PE
To treat RS3PE patients without underlying disease, small
doses of prednisone are used with an average treatment dura-
tion of 18 months [21, 62]. Most patients respond well and
begin to notice significant symptomatic improvement within
24 to 72 h following starting glucocorticoids. In our rheuma-
tology practice, prednisone or other glucocorticoid equiva-
lents of 10–15 mg daily are used for 2 to 3 weeks and may
be tapered every week thereafter to maintain controlling the
disease with the lowest dosage possible for 12 to 18 months.
Disease-modifying anti-rheumatic drugs were rarely tried or
needed [13, 63]. No reports of biologic use to treat RS3PE
have been seen to our knowledge. Generally, patients with
RS3PE without concomitant neoplasm carry a good prognosis
[64, 65].
For RS3PE patients with neoplasia, treatment of the under-
lying malignancy in RS3PE may be important [21]. Patients
with coexisting RS3PE and malignancy tend to respond
poorly to glucocorticoid therapy and to have more dramatic
systemic symptoms [20]. Manifestations of RS3PE patients
may improve after surgical tumor removal. The prognosis
of these patients may depend on the underlying malignancies.
Currently, there are no data to support cost-effectiveness of
screening for a malignancy in the setting of RS3PE; however,
age-appropriate screening is favored, particularly for non-
steroid responders.
Curr Rheumatol Rep (2015) 17:49
Compliance with Ethics Guidelines
Conflict of Interest Hongbin Li, Roy D. Altman, and Qingping Yao
declare no conflicts of interest.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
References
Papers of particular interest, published recently, have been
highlighted as:
• Of importance
•• Of major importance
1. McCarty DJ, O’Duffy JD, Pearson L, Hunter JB. Remitting sero-
negative symmetrical synovitis with pitting edema. RS3PE syn-
drome. JAMA. 1985;254:2763–7.
2. Bhakta BB, Pease CT. Late-onset rheumatoid arthritis: is pitting
oedema of the hands at onset a good prognostic indicator? Br J
Rheumatol. 1997;36:214–9.
3. Mavragani CP, Moutsopoulos HM. Rheumatoid arthritis in the
elderly. Exp Gerontol. 1999;34:463–71.
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. Russell EB. Remitting seronegative symmetrical synovitis with
pitting edema syndrome: followup for neoplasia. J Rheumatol.
2005;32:1760–1.
6. Toussirot E, Berthier S, Wendling D, Tiberghien P. Lack of associ-
ation between HLA DRB1* alleles and RS3PE syndrome. Ann
Rheum Dis. 1998;57:442.
7. Serrano Ostoa B, Alvarez Hernández E. Remmiting symmetric se-
ronegative synovitis with pitting edema (RS3PE). Reumatol Clin.
2012;8(3):156–7. doi:10.1016/j.reuma.2011.05.008.
8. Varshney AN, Kumar N, Tiwari A, et al. Unilateral RS3PE in a
patient of seronegative rheumatoid arthritis. Case Rep Rheumatol.
2013;2013:923797.
9. Nygaard U, Vestergaard C, Koppelhus U. Remitting seronegative
symmetrical synovitis with pitting oedema (RS3PE) of hands and
feet in an 83-year-old man. Acta Derm Venereol. 2013;93:491–2.
10. Ozsahin M, Ataoglu S, Turan H. Unilateral RS3PE with young-
onset rheumatoid arthritis. Semin Arthritis Rheum. 2011;40:e1.
11. 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.
12.•• Kimura M, Tokuda Y, Oshiawa H, et al. Clinical characteristics
of patients with remitting seronegative symmetrical synovitis
with pitting edema compared to patients with pure polymyalgia
rheumatica. J Rheumatol. 2012;39:148–53. This is a compara-
tive study between RS3PE and PMR.
13. Bucaloiu ID, Olenginski TP, Harrington TM. Remitting seronega-
tive symmetrical synovitis with pitting edema syndrome in a rural
tertiary care practice: a retrospective analysis. Mayo Clin Proc.
2007;82:1510–5.
14. Okumura T, Tanno S, Ohhira M, Nozu T. The rate of polymyalgia
rheumatica (PMR) and remitting seronegative symmetrical synovi-
tis with pitting edema (RS3PE) syndrome in a clinic where primary
care physicians are working in Japan. Rheumatol Int. 2012;32:
1695–9.
Curr Rheumatol Rep (2015) 17:49
15. Yao Q, Su X, Altman RD. Is remitting seronegative symmetrical
synovitis with pitting edema (RS3PE) a subset of rheumatoid ar-
thritis? Semin Arthritis Rheum. 2010;40:89–94.
16. Sugihara T, Ishizaki T, Hosoya T et al. Structural and functional
outcomes of a therapeutic strategy targeting low disease activity
in patients with elderly-onset rheumatoid arthritis: a prospective
cohort study (CRANE). Rheumatology (Oxford) 2014 Oct 8. pii:
keu395. [Epub ahead of print].
17. 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;58:230–6.
18. Agarwal V, Dabra AK, Kaur R, et al. Remitting seronegative sym-
metrical synovitis with pitting edema (RS3PE) syndrome: ultraso-
nography as a diagnostic tool. Clin Rheumatol. 2005;24:476–9.
19. Gisserot O, Cremades S, Landais C, et al. RS3PE revealing recur-
rent non-Hodgkin’s lymphoma. Joint Bone Spine. 2004;71:424–6.
20. Tunc SE, Arslan C, Ayvacioglu NB, et al. Paraneoplastic remitting
seronegative symmetrical synovitis with pitting edema (RS3PE
syndrome): a report of two cases and review of the literature.
Rheumatol Int. 2004;24:234–7.
21. Paira S, Graf C, Roverano S, Rossini J. Remitting seronegative
symmetrical synovitis with pitting oedema: a study of 12 cases.
Clin Rheumatol. 2002;21:146–9.
22. Vinci M, Malaguarnera L, Pistone G. RS3PE and ovarian cancer.
Ann Rheum Dis. 2001;60:429–31.
23. Goldenberg K, Rozenbaum M, Rosner I, et al. Remitting symmetric
seronegative synovitis with pitting edema (RS3PE) secondary to
non-Hodgkin’s lymphoma. Clin Exp Rheumatol. 1998;16:767–8.
24. Cobeta-Garcia JC, Domingo-Morera JA, Martinez-Burgui J.
RS3PE syndrome and chronic lymphoid leukaemia. Clin Exp
Rheumatol. 1999;17:266–7.
25. Chiappetta N, Gruber B. Remitting seronegative symmetrical syno-
vitis with pitting edema associated with acute myeloid leukemia. J
Rheumatol. 2005;32:1613–4.
26. Ekenel M, Yavuz S, Karti S, et al. Remitting seronegative symmet-
rical synovitis with pitting oedema associated with chronic lympho-
cytic leukaemia. Clin Rheumatol. 2000;19:247–8.
27. Manganelli P, Delsante G, Bianchi G, et al. Remitting seronegative
symmetrical synovitis with pitting oedema in a patient with
myelodysplastic syndrome and relapsing polychondritis. Clin
Rheumatol. 2001;20:132–5.
28. Tabeya T, Sugaya T, Suzuki C et al. A case of angioimmunoblastic
T-cell lymphoma with high serum VEGF preceded by RS3PE syn-
drome. Mod Rheumatol. 2013.
29. Sibilia J, Friess S, Schaeverbeke T, et al. Remitting seronegative
symmetrical synovitis with pitting edema (RS3PE): a form of
paraneoplastic polyarthritis? J Rheumatol. 1999;26:115–20.
30. Ethiopia A, Bell D. Gastric carcinoma in association with remitting
seronegative symmetrical synovitis with pitting edema. J
Rheumatol. 1999;26:1203–4.
31. Tada Y, Sato H, Yoshizawa S, et al. Remitting seronegative sym-
metrical synovitis with pitting edema associated with gastric carci-
noma. J Rheumatol. 1997;24:974–5.
32. Mattace-Raso FU, van der Cammen TJ. Remitting seronegative
symmetrical synovitis with pitting oedema associated with lung
malignancy. Age Ageing. 2007;36:470–1.
33. Olivo D, Mattace R. Concurrence of benign edematous
polysynovitis in the elderly (RS3PE syndrome) and endometrial
adenocarcinoma. Scand J Rheumatol. 1997;26:67–8.
34. Smitten AL, Simon TA, Hochberg MC, Suissa S. A meta-analysis
of the incidence of malignancy in adult patients with rheumatoid
arthritis. Arthritis Res Ther. 2008;10:R45.
35.• Gross RL, Schwartzman-Morris JS, Krathen M, et al. A comparison
of the malignancy incidence among patients with psoriatic arthritis
and patients with rheumatoid arthritis in a large US cohort. Arthritis
Page 5 of 6 49
Rheumatol. 2014;66:1472–81. This is a new study of malignancy
rate in rheumatoid arthritis.
36. Yamada T, Nakajima A, Inoue E, et al. Incidence of malignancy in
Japanese patients with rheumatoid arthritis. Rheumatol Int.
2011;31:1487–92.
37. Muller S, Hider SL, Belcher J, et al. Is cancer associated with
polymyalgia rheumatica? A cohort study in the general practice
research database. Ann Rheum Dis. 2014;73:1769–73.
38. Azar L, Khasnis A. Paraneoplastic rheumatologic syndromes. Curr
Opin Rheumatol. 2013;25:44–9.
39.• Manger B, Schett G. Paraneoplastic syndromes in rheumatology. Nat
Rev Rheumatol. 2014;10:662–70. This is a recent review of malig-
nancies in rheumatology where the concept of paraneoplastic
syndromes were defined, including RS3PE.
40. Hegazi MO, Saleh F, Al Rashidi A, Yaktien MM. Synovitis with
pitting edema as the presenting manifestation of systemic lupus
erythematosus. Lupus. 2014;23:1069–72.
41. Sugisaki K, Hirose T. Remitting seronegative symmetrical synovitis
with pitting edema (RS3PE) syndrome following spontaneous rup-
ture of a gouty tophus. Mod Rheumatol. 2008;18:630–3.
42. Fietta P, Manganelli P. Sjogren’s syndrome presenting as remit-
ting seronegative symmetric synovitis with pitting edema
(RS3PE): comment of the article by Choi et al. J Korean
Med Sci. 2003;18:921.
43. Billey T, Navaux F, Lassoued S. Remitting seronegative symmetri-
cal synovitis with pitting edema (RS3PE) as the first manifestation
of periarteritis nodosa. Report of a case. Rev Rhum Engl Ed.
1995;62:53–4.
44. Koeger AC, Karmochkine M, Chaibi P. RS3PE syndrome associ-
ated with advanced ankylosing spondylitis. J Rheumatol. 1995;22:
375–6.
45. Matsuda M, Sakurai K, Fushimi T, et al. Sarcoidosis with high
serum levels of vascular endothelial growth factor (VEGF), show-
ing RS3PE-like symptoms in extremities. Clin Rheumatol.
2004;23:246–8.
46. Magy N, Michel F, Auge B, et al. Amyloid arthropathy revealed by
RS3PE syndrome. Joint Bone Spine. 2000;67:475–7.
47. Kato T, Ubara Y, Sawa N, et al. An abrupt onset of seropositive
polyarthritis with prominent distal tenosynovitis concomitant with
bronochiolitis obliterans organizing pneumonia (BOOP): consider-
ation of the relationship with RS3PE syndrome. Intern Med.
2004;43:143–7.
48. Sakoda H, Ito S, Kanda H, et al. Association between type 1 dia-
betes mellitus and remitting seronegative symmetrical synovitis
with pitting edema: a case report. Diabetes Res Clin Pract.
2011;91:e43–4.
49. Yamauchi K, Sato Y, Yamashita K, et al. RS3PE in association with
dipeptidyl peptidase-4 inhibitor: report of two cases. Diabetes Care.
2012;35:e7.
50. Smyth D, Rehman R, Remund K, Egan J. Remitting seronegative
symmetrical synovitis with pitting oedema associated with rifampi-
cin. Ir J Med Sci. 2011;180:585–6.
51. Mainali NR, Schmidt TR, Alweis R, George DL. Novel develop-
ment of remitting seronegative symmetrical synovitis with pitting
edema (RS3PE) syndrome due to insulin therapy. Am J Case Rep.
2014;15:119–22.
52. El Mahou S, Popa L, Constantin A, et al. Remitting seronegative
symmetrical synovitis pitting oedema after BCG instillation. Clin
Rheumatol. 2006;25:566–7.
53. Perandones CE, Colmegna I, Arana RM. Parvovirus B19: another
agent associated with remitting seronegative symmetrical synovitis
with pitting edema. J Rheumatol. 2005;32:389–90.
54. Torres A, Cuende E, De Pablos M, et al. Remitting seronegative
symmetrical synovitis with pitting edema associated with subcuta-
neous Streptobacillus moniliformis abscess. J Rheumatol. 2001;28:
1696–8.
49 Page 6 of 6
55. Mittal K, Ebos J, Rini B. Angiogenesis and the tumor microenvi-
ronment: vascular endothelial growth factor and beyond. Semin
Oncol. 2014;41:235–51.
56. Ku DD, Zaleski JK, Liu S, Brock TA. Vascular endothelial growth
factor induces EDRF-dependent relaxation in coronary arteries. Am
J Physiol. 1993;265:H586–92.
57. Arima K, Origuchi T, Tamai M, et al. RS3PE syndrome presenting
as vascular endothelial growth factor associated disorder. Ann
Rheum Dis. 2005;64:1653–5.
58. Horai Y, Honda M, Nishino A, et al. Anti-citrullinated protein
antibody-positive rheumatoid arthritis associated with RS3PE
syndrome-like symptoms and an elevated serum vascular endothe-
lial growth factor level in a patient with myasthenia gravis. Intern
Med. 2014;53:895–8.
59. Oide T, Ohara S, Oguchi K, et al. Remitting seronegative symmet-
rical synovitis with pitting edema (RS3PE) syndrome in Nagano,
Japan: clinical, radiological, and cytokine studies of 13 patients.
Clin Exp Rheumatol. 2004;22:91–8.
Curr Rheumatol Rep (2015) 17:49
60. Origuchi T, Arima K, Kawashiri SY, et al. High serum matrix me-
talloproteinase 3 is characteristic of patients with paraneoplastic
remitting seronegative symmetrical synovitis with pitting edema
syndrome. Mod Rheumatol. 2012;22:584–8.
61. Baumgartner I, Rauh G, Pieczek A, et al. Lower-extremity edema
associated with gene transfer of naked DNA encoding vascular
endothelial growth factor. Ann Intern Med. 2000;132:880–4.
62. van Schaardenburg D, Breedveld FC. Elderly-onset rheumatoid
arthritis. Semin Arthritis Rheum. 1994;23:367–78.
63. Finnell JA, Cuesta IA. Remitting seronegative symmetrical
synovitis with pitting edema (RS3PE) syndrome: a review of
the literature and a report of three cases. J Foot Ankle Surg.
2000;39:189–93.
64. Queiro R. RS3PE syndrome: a clinical and immunogenetical study.
Rheumatol Int. 2004;24:103–5.
65. Guma M, Casado E, Tena X, Olive A. RS3PE: six years later. Ann
Rheum Dis. 1999;58:722–3.