Lucky to meet RS3PE

Abstract

We present a florid case of remitting seronegative symmetrical synovitis with pitting edema that was actually a paraneoplastic syndrome of an asymptomatic undiagnosed adenosquamous lung cell carcinoma. The arthritis led to a screening for lung cancer and an early enough diagnosis for a curative intervention.

Background

We present a typical and florid case of remitting seronegative symmetrical synovitis with pitting edema (RS3PE) that probably saved the patient's life and brought together the surgical, oncology and internal medicine specialties.

This remarkable case illustrates how we should be alert to this association and how lucky this patient was to have his ‘aches and pains’.

Case presentation

A 60-year-old Caucasian male patient presented at his first clinic visit with small and large symmetrical polyarthritis in the previous 12 months. He reported that he had abruptly started bilateral ankle aching and swelling with progressive pitting oedema (figure 1) and then with hands and wrist involvement (figure 2) and later in the knees and hips, with up to an hour of morning stiffness. In the months that preceded his first clinic visit, he also noticed night sweats and low-grade fever, change in the shape of the nails and digital tips and no other symptoms. His history included a previous smoking habit of 70 packs per year until 7 years previously. He had previously been diagnosed with lung panacinar emphysema, obstructive sleep apnoea (resolved with surgery) and periodic limb movement disorder for which he was taking benzodiazepines. On examination, he had low-grade fever, synovitis on proximal interphalangeal (PIP) and metacarpophalangeal (MCP) joints, wrists, knees and ankles, with large right knee effusion, wrist and ankle pitting oedema and digital clubbing in both hands and feet.

Figure 1.

Ankle oedema.

Figure 2.

Polyarthritis and wrist pitting oedema.

Investigations

The patient's erythrocyte sedimentation rate was over 100 mm per first hour and he was slightly anaemic. An arthritis immunological panel was negative for the following: rheumatoid factor (RF), anticitrullinated peptide, antinuclear antibodies, extractable nuclear antibodies, antineutrophil cytoplasmatic antibodies and antisaccharomyces cerevisiae antibodies. He was also negative for HIV, hepatitis C and B viruses and tuberculosis. No joint erosions or bone cortical alterations were found on X-ray (figure 3).

Figure 3.

Hand and wrist X-ray showing no erosions or relevant periostosis.

Thoracic X-ray and CT scan (figure 4) were performed and a 4.5 cm diameter mass was found on the upper right lung. The fine-needle aspiration biopsy diagnosed non-small cell lung cancer. Vascular endothelial growth factor (VEGF) and metalloproteinase 3 (MMP 3) serum level measurements were not available in our institution. Positron emission tomography scan (figure 5) showed no metastatic disease—stage II B.

Figure 4.

Chest CT showing upper right lobe mass.

Figure 5.

Positron emission tomography scan showing upper right lobe mass with no metastatic disease.

Differential diagnosis

At this point, we had a 60-year-old man with one major problem (non-small cell lung carcinoma) that was being managed and three additional conditions that could not be related:

• Acute onset chronic additive symmetrical small and large joints polyarthritis;

• Digital clubbing;

• Pitting oedema in wrists and ankles.

For the differential diagnosis, the entire clinical picture was sought to be explained by one sole disease, based on the parsimony principle (Occam's razor). This principle is less applicable to older patients due to additional comorbidities with age.¹

Pitting oedema is a very common finding in older patients, much more in the ankles than the wrists and related to conditions related to volume expansion or venous insufficiency. This patient had no evidence of cardiac, renal or hepatic diseases; hence, we interpreted it in the overall picture.

In a case of chronic additive symmetrical small and large joints polyarthritis, rheumatoid arthritis (RA) had to be considered. Late onset rheumatoid arthritis (LORA) presents after 60 years of age and has some clinical differences from younger onset RA. It is less times seropositive for RF; although more frequent in women, the female to male ratio is lower (2.85 vs 1.48) and patients tend to develop less bone erosions, deformities and subcutaneous nodules.² This diagnosis had to be kept in mind but LORA did not explain clubbing or pitting oedema.

Spondyloarthropathies may present as pitting oedema and peripheral arthritis, but usually the swelling is unilateral and involves the lower limbs. Although spondyloarthropathies can initially present only with peripheral involvement, they very rarely present at this age and there were no signs of other common manifestations like sacroiliitis or spondylitis, or of any symptoms of extra-articular involvement (anterior uveitis, conjunctivitis, etc). This diagnosis was therefore considered not probable.

Sudeck’s atrophy or reflex sympathetic dystrophy syndrome can lead to unilateral localised swelling and changes in the skin, but it is usually precipitated by injury, surgery, myocardial infarction or stroke and is characterised by severe pain (burning and shooting pains). This autonomic dysregulation of the autonomic nervous system leads to functional loss and disability.³ The symptoms usually manifest near the site of an injury, which was not so in the case of our patient who had bilateral polyarthritis and no history of trauma, surgery or evidence of nerve damage.

Since our patient was over 60 years of age, polymyalgia rheumatica (PMR) should also be considered. It almost universally involves the girdles (neck, shoulder and hip) instead of the predominantly small joints like RS3PE, but some pitting oedema over the dorsal side of the hands and feet has been reported in PMR. However, we could hypothesise that those reports were actually RS3PE with PMR before the description of RS3PE by McCarty et al.⁵ The patient had large joint involvement outside of the shoulder or pelvic girdle; therefore, a different condition better explained his symptoms, and PMR was ruled out.

Secondary hypertrophic osteoarthropathy has to be considered in every patient with digital clubbing, even more so in one with a diagnosed non-small cell lung carcinoma, which accounts for 80% of generalised hypertrophic osteoarthropathy in adults. Paraneoplastic hypertrophic osteoarthropathy is more common in subjects aged 50–70 years and clinical features include clubbing, skin hypertrophy, thickening of tubular bones, periostosis and effusions of large joints.⁴ The rheumatic symptoms have a mechanical diurnal pattern, which is not the case with our patient, as neither was there any bone alteration in the hand X-ray nor is any description of acute onset arthritis associated with hypertrophic osteoarthropathy.

McCarty et al⁵ described a benign symmetrical seronegative polysynovitis of acute onset associated with flexor digitorum tendons inflammation and pitting oedema in both wrists and ankles, which was more frequent in elderly^{6 7} and termed remitting symmetrical seronegative synovitis with pitting edema (RS3PE).

Although the digital clubbing could be explained by secondary hypertrophic osteoarthropathy, taking into account that every other feature fitted perfectly with McCarty's description, we therefore thought that our patient had an unequivocal paraneoplastic RS3PE indicated by the presence of systemic signs and symptoms and confirmed by the aspiration of lung mass: non-small cell lung cancer.

Treatment

Like in the first description by McCarty et al,⁵ this patient first responded to low-dose steroids (deflazacort 6 mg/day), but needed progressively higher doses up to 30 mg deflazacort/day to be able to handle daily activities. Despite maintaining steroid therapy for more than 4 months before surgery, the synovitis remained active and pitting oedema was still present.

The patient was submitted to surgery that completely removed the mass. The surgical specimen biopsy examination confirmed adenosquamous type lung adenocarcinoma (figure 6) with pleural involvement and immunoreactivity to the VEGF receptor in the cytoplasm and membrane (figure 7).

Figure 6.

Lung biopsy examination showing adenosquamous type lung adenocarcinoma (H&E staining).

Figure 7.

Lung biopsy examination showing immunoreactivity to vascular endothelial growth factor receptor in cytoplasm and membrane of the adenosquamous type lung adenocarcinoma cells.

Outcome and follow-up

Four days after surgery the patient had no synovitis or wrist oedema and complete resolution of the knee oedema, night sweats and fever. The maleolar oedema also resolved progressively, and he required no more steroids. The digital clubbing remained present but was less evident.

He was submitted to adjuvant chemotherapy with no serious adverse effects. Two years later, he was still free of arthritis or any evidence of tumour. Curiously, he also stopped having involuntary sleep movements despite ceasing to take benzodiazepines.

Discussion

In 1985, McCarty et al⁵ described a benign symmetrical seronegative polysynovitis of acute onset associated with flexor digitorum tendons inflammation and pitting oedema in both wrists and ankles. This was reported to be more frequent in the elderly.^{6 7}

In the years since the first description by McCarthy et al, there have been several descriptions of RS3PE associations including neoplasm,^{8 9} solid and haematological tumours^{9 10} and also inflammatory disorders,^{9 11 12} infections^{9 13 14} and even stroke.¹⁵

When paraneoplastic RS3PE cases were initially described, haematological tumours were those with which they were most frequently associated, including leukaemia, lymphoma, myelodysplastic syndrome and multiple myeloma. But in the most recent study,⁹ solid tumours seem to be the most common, particularly prostate, lung, gastric carcinoma, endometrial adenocarcinoma and renal cancer.

The pathological mechanism of RS3PE is still unclear. It seems that VEGF plays a major role⁹ due to its vasoactive and angiogenic proprieties that lead to the high permeability of vessels and consequently to oedema. Serum levels of VEGF in acute RS3PE are high when compared with other connective tissue diseases.⁹ The MMP 3 serum level has also been studied and it seems to be higher in paraneoplastic RS3PE than in non-paraneoplastic RS3PE.¹⁶

Although almost any anti-inflammatory drug and hydroxychloroquine can be used to treat this synovitis, patients typically became free of symptoms with low-dose steroids; however, some cases are not as benign as initially described.⁹

Digital clubbing and hypertrophic osteoarthropathy have been postulated for many authors as a single pathological entity.⁴ It has been increasingly reported that the role of VEGF in inducing stromal and vascular changes present in this entity.¹⁷ The lung cancer cells VEGF secretion could be in the basis of several of these paraneoplasic syndromes. Different clinical manifestations could be explained by an interaction with other factors not completely understood.

As previously reported in the literature, the symptoms and signs of RS3PE in our patient improved after tumour removal; however, such a rapid improvement as was observed in our patient was unexpected.

Furthermore, the restless leg syndrome of our patient resolved in the following months. It has not been reported as an association with RS3PE or lung cancer; its resolution so soon after treatment suggested that this might have been a second paraneoplastic syndrome.

Even if the adenocarcinoma relapses with time, the symptoms of RS3PE led our patient to an early diagnosis and successful treatment and to freedom from the disease for more than 2 years.

Learning points.

• Consider remitting seronegative symmetrical synovitis with pitting edema (RS3PE) when synovitis accompanies pitting oedema.

• RS3PE may precede the symptoms of solid and haematological neoplasms.

• Neoplasm associated with RS3PE may be curable if detected early enough.