Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome is a specific category of "seronegative" rheumatoid arthritis (RA) and is characterized by seronegativity for rheumatoid factor (RF), the presence of distal pitting edema and an excellent joint prognosis without the development of bone erosions (1). Olivé et al proposed the criteria of the RS3PE syndrome as follows: bilateral pitting edema of the hands, sudden onset of polyarthritis, age >50 years and seronegativity for RF (2). Here, we describe a case of "seropositive" polyarthritis that featured several of the principal characteristics of the RS3PE syndrome such as distal inflammatory pitting edema. Apart from an elevated serum RF level, the results of magnetic resonance imaging (MRI) of the hand, bone scintigraphy and human leukocyte antigen (HLA) typing were used in an attempt to distinguish between RA and RS3PE syndrome (1, 3, 4). According to the findings of the present case, seropositive polyarthritis with distal pitting edema may be categorized as both RA and RS3PE syndrome.

A 64-year-old Japanese woman was admitted to our hospital in January 2003 with a 2-week history of polyarthralgia, edema affecting the hands and lower limbs and a persistent cough. There was no other significant past medical history except for transient liver dysfunction.

On admission, the patient had a low grade fever of 37.2ºC, a regular heart rate of 72 beats per minute and was normotensive (125/75 mmHg). Physical examination revealed bilateral tender pitting edema affecting the hands and lower limbs (Fig. 1). In addition, there was mild swelling of the 3rd proximal interphalangeal (PIP) joint of the right hand, the 3rd to 5th metacarpophalangeal (MCP) joints of the right hand, the 5th PIP joint of the left hand as well as both wrist, shoulder, hip, knee and ankle joints. The swollen joints were tender whilst the patient described marked morning stiffness which lasted more than fifteen hours. Her joint symptoms were sufficiently severe to markedly affect her walking. Examination of the temporal arteries, lymphoreticular system, chest, abdomen and skin was unremarkable.

Laboratory findings were as follows: erythrocyte sedimentation rate (ESR), 110 mm/h; white blood cell counts, 7.4×10³/μl; hemoglobin, 10.7 g/dl; platelet count, 540×10³/μl (normal range; 155–350×10³/μl); total protein, 7.5 g/dl; albumin, 2.6 g/dl; total bilirubin, 0.3 mg/dl; serum urea nitrogen, 15 mg/dl; creatinine, 0.7 mg/dl; uric acid, 3.5 mg/dl; sodium, 143 mmol/l; potassium, 3.5 mmol/l; chloride, 105 mmol/l; calcium, 4.2 mEq/l (normal range; 4.4–5.1 mEq/l); phosphorus, 3.3 mg/dl; aspartate aminotransferase (AST), 15 U/l; alanine aminotransferase (ALT), 9 U/l; lactic dehydrogenase (LDH), 110 U/l; alkaline phosphatase (ALP), 241 U/l; amylase, 71 U/l; creatine phosphokinase (CPK), 27 U/l; C-reactive protein (CRP), 24.2 mg/dl; ferritin, 153 μg/l (normal range; 50–80 μg/l); angiotensin converting enzyme (ACE), 9.1 U/l (normal range; 8.3–21.4 U/l); anti-streptolysin O (ASO) titre, 47 U/l (normal range; <160 U/l); KL-6, 218 U/ml (normal range; <500 U/ml); and matrix metalloproteinase-3 (MMP-3), 104 μg/l (normal range; 17.3–59.3 μg/l). Serological findings were as follows: IgG, 1,870 mg/dl; IgA, 288 mg/dl; IgM, 282 mg/dl; C3, 160 mg/dl; C4, 42 mg/dl; CH50, 61 U; rheumatoid factor (RF), 32 U/ml (normal range; <10 U/ml); IgG-RF, 1.3 (normal range; <2); immune complexes (C1q), 2.4 μg/ml (normal range; <3 μg/ml); anti-nuclear antibody (ANA), 1 in 80 (homogenous, speckled pattern); anti-double-stranded DNA antibody, 2.8 U/ml (normal range; <10 U/ml); anti-RNP, anti-Scl 70 and anti-centromere antibodies were negative; anti-Ro (SS-A) and anti-La (SS-B) antibodies were negative.

Hand X-rays did not reveal erosions or narrowing of the joint spaces. Chest computed tomography (CT) demonstrated bronchiolitis obliterans organizing pneumonia (BOOP) affecting the right upper lobe and both lower lobes (Fig. 2A). Gallium scintigraphy with Ga-67 citrate revealed tracer accumulation only in the right middle lung thereby indicating an active interstitial pneumonia i.e. BOOP. No accumulation was evident in the juxta-articular regions. During these investigations, her serum RF level became elevated to 107 U/l on day 16 of the admission. The development of a positive RF in association with relatively symmetrical polyarthritis and morning stiffness was consistent with a diagnosis of early RA (5, 6). However, other findings such as pitting edema of the dorsal hands and the proximal polyarthritis are uncommon in RA but are characteristic features of the RS3PE syndrome. Indeed, our case fulfilled all the criteria of the RS3PE syndrome except the requirement for a negative serum RF (2). Further investigations were therefore performed in an attempt to determine whether the diagnosis was early RA or the RS3PE syndrome. The results of human leukocyte antigen (HLA) typing were A 24/24, B 52/7, C W7/W7 and DR 1/5 with HLA B7 being compatible with the RS3PE syndrome (1). Tc-99m-MDP bone scintigraphy revealed an accumulation of tracer only in the right ankle (Fig. 3). This was not typical of RA which is characterized by juxta-articular tracer accumulation in most of the affected joints (3). Magnetic resonance imaging (MRI) of the right hand revealed tenosynovitis of the flexor digitorum sheaths (Fig. 4A, B), which strongly suggested a diagnosis of the RS3PE syndrome since tenosynovitis of the flexor digitorum sheaths is a diagnostic hallmark of the syndrome (4). These findings supported a diagnosis of RS3PE syndrome rather than early RA. Therefore, a diagnosis of seropositive polyarthritis with features of the RS3PE syndrome was made. There was no evidence of malignant disease affecting lung, breasts, gastrointestinal tract, pancreas, ovaries or uterus (7). On day 29, treatment with prednisolone (PSL, 30 mg/day), rather than disease modifying anti-rheumatic drugs (DMARDs), was commenced for the BOOP and the polyarthritis. The polyarthralgia and morning stiffness began to improve one day after starting PSL such that she could peel an orange. On day 34, the polyarthralgia had further improved and she was able to walk independently. In addition, her productive cough resolved gradually. The CRP and MMP-3 levels fell and were normal on day 35. By day 40, both the polyarthralgia and morning stiffness had disappeared entirely and no joint swelling was evident. Although a moderate flexor contracture of the 3rd digital PIP joint of the right hand persisted, she remained clinically well with good locomotor function. On day 44, the serum RF level had fallen to 64 U/l. Furthermore, the pitting edema of the hands and lower limbs decreased during treatment with PSL and finally resolved completely. On day 54, a repeat chest CT scan revealed the remission of BOOP (Fig. 2B) whilst the platelet count also normalized to 243×10³/μl. After 4 weeks of treatment with 30 mg PSL daily, the dose was tapered to 25 mg per day. On day 68, the dose of PSL was tapered to 20 mg per day and the patient was discharged from the hospital. Eight weeks after discharge, the polyarthritis remained in remission and the serum RF level had further fallen to 16 U/l. Twelve weeks after discharge, the dose of PSL was tapered to 10 mg per day.

Here, we described a case of seropositive polyarthritis with some features of the RS3PE syndrome in association with BOOP. MMPs are a family of proteolytic enzymes that can degrade all components of the extracellular matrix and are involved in both remodeling of normal connective tissue and pathological tissue destruction as occurs in inflammatory diseases such as RA (8). MMP-3 is produced by synovial tissue in rheumatic diseases such as RA, psoriatic arthritis and PMR and plays an active role in the destruction of joints (9). The serum MMP-3 level is associated with disease activity of RA and also predicts therapeutic outcome in RA (10). In addition, the production of MMP-3 in synovial tissues significantly decreases in RA during remission and the normalization of the MMP-3 level suggests the remission of RA (8). In the present case, the rapidly normalizing serum MMP-3 level during the steroid treatment suggests that the polyarthritis should achieve a prompt remission which may be compatible with the RS3PE syndrome. However, the administration of PSL for three months increases serum MMP-3 levels in the cases of lupus nephritis (9). In RA, low-dose PSL treatment over 2 years may also increase serum pro-MMP-3 (proenzyme form of MMP-3) levels although synovium-derived markers such as hyaluronate decrease suggesting the remission of the articular synovitis (11). According to these findings, the serum pro-MMP-3 level may be increased by changes of joint tissue metabolism due to PSL therapy despite the fact the therapy ameliorates the synovitis (11). In the present case, the serum MMP-3 level decreased six days after the start of PSL therapy following the clinical improvement. The short duration between the start of PSL administration and the measurement of serum MMP-3 level during the resolution phase may explain why the serum MMP-3 level decreased despite PSL administration in our case.

Although distal pitting edema has been suggested as a rare extra-articular manifestation in RA (12), no specific documentation about the symptom was performed until McCarty et al proposed the RS3PE syndrome in 1985 (1). In 1997, Bhakta and Pease reported a prospective study indicating that RA associated with distal pitting edema had a better joint prognosis than RA without distal pitting edema (12). In their study, patients were followed up for a 1-year period and more than 90% of patients with RA with distal pitting edema entered remission with joint erosions occurring in only 17% of patients (12). In contrast, 55% of patients with RA without distal pitting edema entered remission with joint erosions occurring in 48% of patients (12). More than half of the RA patients in both groups were treated with DMARDs (12). Of RA patients with distal pitting edema, 18% exhibited seropositive IgM-RF whilst 43% of RA patients without distal pitting edema exhibited seropositive IgM-RF (12). In conclusion, their report suggested that RA with distal pitting edema tended to be seronegative and had an excellent joint prognosis following treatment with DMARDs.

PMR is considered to be a similar pathological condition to the RS3PE syndrome. Around 10% of PMR patients also exhibit episodes of transient distal pitting edema as is found in the RS3PE syndrome (13). Although the rapid resolution of clinical symptoms following low-dose PSL therapy is characteristic of both conditions, the frequency of recurrence is rarer and a lesser cumulative dosage of PSL is necessary to achieve clinical remission in the RS3PE syndrome compared to PMR without distal pitting edema (13). Thus, the presence of distal pitting edema may also be indicative of a better clinical prognosis between RS3PE syndrome and PMR (13).

BOOP is one of the major pulmonary manifestations of RA (14) and rarely occurs in other collagen diseases such as PMR (15). The characteristic pathologic findings comprise the polypoid plugs of loose, fibrous tissue filling both bronchioles and alveoli (14). Although the pathogenesis is unclear, T cells are necessary for the development of the intra-luminal fibrosis associated with BOOP (16). In contrast, acute respiratory distress syndrome (ARDS) represents intra-alveolar and interstitial fibrosis which is unrelated to T cells (16). Furthermore, the co-stimulatory molecule B7-1 of antigen-presenting cells which plays an important role in T cell activation is aberrantly expressed by bronchiolar epithelial cells in BOOP (17). In our case, the same autoantigen in both the synovium and the lung may be recognized by helper T cells thereby facilitating the simultaneous development of polyarthritis and BOOP.

The RS3PE syndrome has been described in neoplastic condition such as adenocarcinoma of the gastrointestinal tract, prostate and endometrium as well as hematological malignancies (7). In the present case, investigations for underlying malignancy were negative.

Finally, although our case exhibited clinical and laboratory features of both RA and the RS3PE syndrome, further investigations including hand MRI, bone scintigraphy and HLA-typing indicated that features of the RS3PE syndrome were predominant. Thus, similar to the RS3PE syndrome, the joint prognosis of our case may be excellent during steroid treatment. Cases of pure RS3PE syndrome do not develop RA over a five-year period (13) and therefore prolonged observation will be necessary in the present case. According to our case, seropositive polyarthritis with several features of the RS3PE syndrome such as distal pitting edema may be categorized as both RA and RS3PE syndrome.