Anti-interleukin-6 receptor antibody for the treatment of remitting seronegative symmetrical synovitis with pitting oedema: a new outlook?

Abstract

We present the case of an elderly man with a small-joint polyarthritis, accompanied by pitting oedema, involving hands and feet, raising clinical suspicion of remitting seronegative symmetrical synovitis with pitting oedema (RS3PE). Treatment with corticosteroids was initiated with significant improvement, but unacceptable iatrogeny ensued, and tapering was not possible without disease flare-up. A trial of tocilizumab allowed disease activity control, slow weaning of corticosteroids and, ultimately, its suspension. RS3PE is a rare rheumatological entity, initially thought to be a variant of rheumatoid arthritis (RA), with shared traits with polymyalgia rheumatica (PMR), and other seronegative spondyloarthropathies, thereby implying a shared pathophysiological background. Elevated levels of interleukin 6 (IL-6) are found in patients with RA, have shown to mirror disease activity in PMR and have also been described in the serum and synovial fluid of patients with RS3PE. Tocilizumab, an anti-IL-6 receptor antibody, shows auspicious results in several other rare rheumatic diseases other than RA.

Background

Remitting seronegative symmetrical synovitis with pitting oedema (RS3PE) is a rare rheumatological entity, more common among the elderly and men, first described by McCarty et al in 1985¹ and later elucidated with specific diagnostic criteria by Olivé et al in 1997² (box 1). Clinical features include an acute onset of polyarthritis with pitting oedema of both hands and feet, usually symmetrical; elevation of inflammatory parameters; seronegativity for rheumatoid factor (RF); absence of radiographic bone erosions; and exquisite response to glucocorticoids. Most cases are idiopathic but cases of RS3PE accompanied by solid or blood malignancies have been reported, manifesting as paraneoplastic RS3PE.^{3 4} This goes in line with findings that patients with RS3PE may have an increased risk for malignancy (as high as 54%) compared with the general population.⁵ Generally, patients with RS3PE without concomitant malignancy carry a good prognosis,^{6 7} with little deterioration in general health status.^{4 6}

Box 1. Proposed diagnostic criteria for remitting seronegative symmetrical synovitis with pitting oedema (RS3PE) by Olivé et al².

Diagnostic criteria for RS3PE

• Age over 50 years of age

• Painful oedema of both hands

• Sudden onset of polyarthritis

• Rheumatoid factor negative

• Radiological evidence showing the absence of articular destruction or alteration

RS3PE was initially thought to be a variant of rheumatoid arthritis (RA)¹ but, as patients do not evolve to fulfil American College of Rheumatology/European Alliance of Associations for Rheumatology 2010 Classification Criteria of RA, RS3PE is set as a distinct and separate syndrome, and therefore considered different from that of late-onset rheumatoid arthritis, polymyalgia rheumatica (PMR) and other seronegative spondyloarthropathies.⁶ Other authors however postulate that PMR and RS3PE may form part of the clinical spectrum of the same disease, the former being the proximal-dominant form, and the latter the distal-dominant form.⁸ Regardless, we aim to highlight a possible shared pathophysiological background among these diseases, with potential significance for the management of RS3PE.

Case presentation

An elderly white man in his early 70s presented in the emergency department with a 3-day history of acute pain and noticeable swelling of both hands and feet, unresponsive to non-steroidal anti-inflammatory drugs. These problems had been recurrent in the last few months, lasting a few days, with spontaneous ameliorating. However, on this occasion, the patient could no longer walk nor hold any instruments with his hands, and had great trouble manipulating cutlery and eating, due to the generalised swelling and pain in his hands. He had not noticed any weight loss or fever, and he had not conveyed any other problems.

The patient’s medical history included diabetes mellitus type 2 (well controlled under oral hypoglycaemic agents), dyslipidaemia and arterial hypertension (both medicated and well managed), chronic kidney disease (stage G3aA1) and deep-vein thrombosis over 15 years prior.

Physical examination revealed an asymmetrical, additive, small joints polyarthritis, accompanied by swelling with pitting oedema over the dorsum of both hands, ankles and feet (figure 1A,B). Although the oedema affected all four extremities, it was more pronounced on the left hand. Fine finger movements were severely affected; he could not button himself, write or make a fist due to finger swelling/stiffness. No other joints were found tender or swollen nor was the range of motion limited elsewhere.

Figure 1.

(A) Swollen hands with pitting oedema. (B) Swollen feet and ankles.

Investigations

Laboratory results showed increased inflammatory parameters—C reactive protein (CRP) of 68 mg/L (reference range: <5 mg/L), without any further changes. Treatment with corticosteroids was initiated and the patient was referred to an internal medicine consultation. At his follow-up appointment, 3 weeks later, under a daily dose of prednisolone 20 mg, he reported substantial improvement of the oedema and pain in his fingers and hands, and resolution of the problems in feet, within the first week of treatment. By then, his laboratory abnormalities had also improved, with a CRP of 14 mg/L. Neither interleukin 6 (IL-6) nor matrix metalloproteinase-3 (MMP-3) and vascular endothelial growth factor (VEGF) serum concentration measurement were available in our centre.

An extensive panel of infections was ruled out, and the immunological study (including antinuclear and antineutrophil cytoplasmic antibodies; RF and anticitrullinated protein antibodies) was negative. Imaging studies of the hands revealed no bone erosion on radiographs—ultrasound or MRI examination had not been formally performed at this time. These symptoms, laboratory and instrumental findings led to the diagnosis of RS3PE.

Differential diagnosis

The patient had been for several years medicated with vildagliptine (an inhibitor of dipeptidyl peptidase 4), which, despite lack of temporal relation, was suspended given the possible correlation with RS3PE,⁹ but it did not lead, in the following weeks, to any clinical or laboratory improvement, as one would expect if secondary to the gliptine treatment. Furthermore, to exclude it from being a potential form of paraneoplastic polyarthritis, the patient underwent a thorough malignancy screening workup (peripheral blood lymphocyte immunophenotyping, thyroid ultrasound, endoscopic studies, prostate-specific antigen serum levels and prostate ultrasound, and thoracic-abdominal-pelvic CT scan), with unremarkable results. Thus, the diagnosis of idiopathic RS3PE was made.

Treatment

After clinical stabilisation, weaning of corticosteroids was initiated but the disease activity flared up when daily prednisolone dosage was reduced below 15 mg—with relapsing oedema and pain, and an increase of inflammatory parameters. Concurrently, the patient gradually developed impermissible iatrogenic effects, including a major worsening of glycaemic control (and need to start insulin therapy); subsequent worsening of his diabetic nephropathy and chronic kidney disease; and frequent corticosteroid-induced psychosis-like episodes of aggressiveness and anxiety.

He was initially started on methotrexate, as a steroid-sparing agent, with progressive increase of dosage up to 12.5 mg/week (maximum dose, adjusted for the worsened kidney impairment), with no clinical improvement or possibility of tapering corticosteroids.

A trial of tocilizumab (162 mg subcutaneously every other week) was then proposed, and the patient reported significant improvement of pain and objective reduction of the swelling of his hands and feet, which allowed for slow weaning of corticosteroids up until their suspension (figure 2).

Figure 2.

Prednisolone tapering over time according to inflammatory parameters and use of corticosteroid-sparing agents. CRP - C reactive protein; ESR - erythrocyte sedimentation rate.

Outcome and follow-up

The patient has been under tocilizumab for 18 months, nearly 12 of which as monotherapy, and has been doing well, with only 1 minor clinical flare-up (resolved with temporary reintroduction of prednisolone 2.5 mg). Apart from a mild herpes zoster reactivation, he has not reported any side effects.

Discussion

To treat patients with RS3PE without underlying disease, low-dose corticosteroids are recommended, and most patients respond well, beginning to notice significant clinical improvement within days.^{6 8 10} However, a recent multicentric study has shown that outcomes may be worse than expected, as over 80% of patients still needed corticosteroids at 1 year of follow-up and over 50% required a dosage of prednisolone ≥5 mg/day.¹⁰ Disease-modifying antirheumatic drugs (DMARDs) have rarely been required,^{7 10} and there is scarce literature on the use of biological drugs on RS3PE.¹¹

IL-6 is a pleiotropic proinflammatory, multifunctional cytokine, crucial for both innate and adaptive immunity. IL-6 is known not only to influence numerous cell types with several biological activities, but it is also a T-cell-derived factor inducing B cells to differentiate into antibody-producing cells.¹² IL-6 classic pathway removes infectious agents and heals damaged tissue, thus having a regenerative and protective function. On the other hand, the IL-6 trans-signalling pathway plays a role in its proinflammatory activity.¹³ Several cell types, including lymphocytes, monocytes and fibroblasts, produce IL-6, and, at sites of inflammation, IL-6 secretion is strongly enhanced,¹⁴ on which endothelial cells release chemokines which recruit more immune cells and hepatocytes synthesise and secrete acute-phase proteins.¹⁵

In patients with RA, elevated levels of IL-6 in the serum and synovial fluid play an important role in the chronic inflammatory process,¹⁴ and correlate positively with disease activity. Not only elevated serum levels of IL-6 are also described in patients with giant cell arteritis (GCA) and PMR,¹⁶ but those have been shown to likewise mirror disease activity.^{17 18} Oide et al measured concentrations of IL-6 in the serum and synovial fluid in patients with RS3PE, and similarly found an increase of IL-6 activity in both serum and synovial fluid, which was consistently much higher in the synovial fluid than in the serum.⁸ Although the aetiology of RS3PE is still unclear, it is licit to presume that IL-6 is involved in the development of the disease. Since the synovium is considered to be a primary target of this disease, it was proposed that locally produced IL-6 in the synovium may then be released into circulation, leading up to the generalised symptoms of RS3PE.⁸

Blocking the IL-6 signalling opens up new therapeutic strategies, not only for RA but also for other autoimmune inflammatory diseases. Tocilizumab is a recombinant humanised antihuman IgG1 monoclonal antibody directed against the interleukin-6 receptor (IL-6R) that binds specifically to both soluble and membrane-bound IL-6R, thereby inhibiting IL-6-mediated signalling and blocking both classic and trans-signalling pathways.¹⁹

Tocilizumab was initially developed and approved for the treatment of RA, GCA, systemic juvenile idiopathic arthritis, polyarticular juvenile idiopathic arthritis and chimeric antigen receptor T cell-induced severe or life-threatening cytokine release syndrome. It may be used as monotherapy or concomitantly with methotrexate or other non-biological DMARDs, as an intravenous infusion, or as a subcutaneous injection.²⁰

Since the introduction of tocilizumab, a plethora of reports has paved way for its use in other indications, although rare, such as amyloidosis, adult-onset Still’s disease, ankylosing spondylitis, PMR, relapsing polychondritis, systemic lupus erythematosus, systemic sclerosis or Takayasu arteritis.²¹ Although safety studies on tocilizumab have not been performed specifically on RS3PE, on RA and GCA it has shown a very safe profile.

Similarly to our case, Tanaka et al have also presented a patient on which the effect of tocilizumab in alleviating the manifestations of RS3PE was clear, but treatment had to be discontinued due to the complication of cholecystitis, after five intravenous infusions.¹¹ Therefore, to our knowledge, we report the longest-standing successful treatment with IL-6 blockade on RS3PE refractory to low-dose corticosteroids. As such, tocilizumab may be an alternative treatment for patients with RS3PE who cannot reach adequate control disease activity with a low dose of corticosteroids or on which the iatrogenic complications associated to the corticosteroid treatment are more damaging than the disease itself.

Hinging on the shared pathological pathways of RA and non-RA systemic inflammatory rheumatic diseases, IL-6 inhibition sets a new outlook for an unanticipated sizeable set of patients with RS3PE, who are classically older and often multimorbid, and thereof in which corticosteroids are particularly deleterious.

Patient’s perspective.

In my opinion, tocilizumab has helped me fight the pain associated with my disease and it is also easy to take since it only requires taking one dose every 15 days.

Learning points.

• Remitting seronegative symmetrical synovitis with pitting oedema (RS3PE) is an inflammatory disease, which affects mainly elderly men, with usually excellent prognosis and remarkable response to corticosteroids, although it may also present as a paraneoplastic manifestation of solid or blood malignancies.

• This syndrome could be mistaken for other polyarthritis, which normally affects the elderly, such as late-onset rheumatoid arthritis (RA), polymyalgia rheumatica (PMR)/giant cell arteritis (GCA) or seronegative spondyloarthritis.

• Increased IL 6 (IL-6) activity has been described in patients with RA, GCA and PMR, correlating with disease activity, and elevated levels of IL-6 have been found in the serum and synovial fluid in patients with RS3PE.

• IL-6 inhibition with tocilizumab may be a promising option for patients suffering from various rare, non-RA rheumatic diseases, including refractory RS3PE.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s)