Psoriatic arthritis (PsA) is a common inflammatory arthritis that can cause a deforming and disabling arthropathy with a devastating effect on the quality of life.¹ PsA is associated with diverse skeletal pathology such as enthesitis, synovitis, syndesmophyte formation and osteolysis, which can lead to mutilating arthritis. Active joint disease in PsA and other spondyloarthropathies (SpA) is shown as areas of bone oedema² which are thought to represent an osteitis in the subcortical bone on MRI,³ and may occur at entheseal sites.⁴ Recently, tumour necrosis factor (TNF) α blockade has been a major advancement in the treatment of PsA and skin psoriasis,^5,6 and MRI has shown that good clinical responses in SpA are associated with regression of enthesitis and osteitis in the axial skeleton.^7,8 Likewise, MRI studies have shown a beneficial effect of anti-TNF treatment on synovitis in PsA.⁹ Although there is radiographic evidence that anti-TNF agents inhibit periarticular small joint erosion in PsA,^10,11 there are no data on the effect of TNF blockade on the peripheral entheseal-related bone manifestations of PsA. This report documents responses to a 14-week infusion regimen of infliximab in patients with established PsA resistant to conventional disease-modifying agents (disease-modifying antirheumatic drugs (DMARDs)), and uses MRI to ascertain response on the bone oedema that may occur at entheseal areas in affected peripheral sites.

PATIENTS AND METHODS

This open-label study was approved by the local research ethics committee, and subjects (n = 18) gave written informed consent before entry. Inclusion criteria required subjects to have at least one affected peripheral joint, history of skin psoriasis, seronegativity for rheumatoid factor and to have failed therapeutic dosages of conventional DMARDs including methotrexate. Patients had at least one clinical subtype as described by Moll and Wright,¹² and were allowed to continue taking non-steroidal anti-inflammatory drugs and/or oral corticosteroids, provided the dose was unaltered during the study. Methotrexate was continued, but other DMARDs were stopped. Infliximab infusions (3 mg/kg in 259 ml 0.9% NaCl) were prepared by the hospital pharmacy under required aseptic conditions. The infusion regimen was planned for weeks 0, 2, 6 and 14.

RESULTS

A total of 18 patients (9:9 men:women) were recruited: median (range) age 41.5 (31–56) years, duration of PsA 14.8 (2–35) years and duration of skin psoriasis 20.3 (0–46) years. The pattern of disease was 50% polyarticular (9/18) and 39% oligoarticular (7/18); 27.7% (5/18) had a predominant distal interphalangeal joint involvement and 11% (2/18) had arthritis mutilans. In addition, past or present history of enthesitis and dactylitis was present in 89% (16/18) and 77.7% (14/18) of patients, respectively. Skin psoriasis was evident at baseline in 17 patients (median Psoriasis Area and Severity Index: 1.8). Table 1⇓ shows a summary of the participants’ baseline characteristics.

Imaging results

A total of 12 hand scans (n = 48 MCP joints) and 6 knee scans (n = 6 knee joints) were performed. All magnetic resonance images were suitable for assessment of bone oedema, which was seen in 50% of the patients (7 hands (n = 13 MCP joints) and 2 knees (n = 2 knee joints)) in 30% of scanned joints (n = 15/54). Of these, oedema was seen on an entheseal location, in five hand scans (corresponding to 38.4% (5/13) of MCP joints and in one knee scan (corresponding to one knee joint); however, periarticular erosions were seen at the same site in all cases. Because of the close anatomical proximity of the capsular entheses and the synovium and articular cartilage in small joints, and the diffuse nature of the MRI lesions seen in these joints, it was not always possible to state whether abnormalities were at the enthesis, and in such cases lesions were described as periarticular. Of the seven patients who had oedema at baseline in the hands, six showed complete resolution and one improved (p = 0.018; fig 1⇓). In the knee scans, bone oedema was seen in two patients at the posterior femoral condyle: one case subchondral (associated to an erosion and unchanged on follow-up) and the other entheseal, corresponding to the attachment of the posterior capsule (fully resolved at week 20).

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Figure 1

 Coronal T1-weighted post-gadolinium-diethylenetriamine penta-acetic acid fat-suppressed images of the second (A,B) and fourth–fifth (C,D) metacarpophalangeal (MCP) joints from two of the study patients pre–and-post treatment with infliximab. (A) The white arrow shows entheseal bone oedema distal to the joint space and there is high signal around the second MCP joint representing active synovitis-both of which is resolved in the post-treatment scan (B). (C) Pretreatment scan of the second patient. There is high signal representing extensive bone oedema in the proximal phalanx of the fourth finger. There is also bone oedema distal to the joint space on the fourth MCP compatible with an entheseal location, and on the proximal fifth MCP joint there is an erosion with bone oedema (white arrows). These lesions have resolved in the post-treatment scan (D).

Scans from 15 patients (11 hands and 4 knees) were suitable for analysis of synovitis, with the rest (1 hand and 2 knees) being discarded because of technical problems (failure of FS (n = 1), enhancement (n = 1) or insufficient slice acquisition (n = 1). A reduction in the volume of synovitis was seen in 14 patients (10 hands and 4 knees). The range of synovitis reduction in the MCP joints was 9.8–60.0% and that in the ROI in the knee 37.8–91.90%.

DISCUSSION

This study focuses on the impact of infliximab on the bone oedema associated with active PsA. The patients were selected on the assumption that their disease was true PsA, based on its clinical features, rather than being seronegative RA and associated features.²⁰ Although it cannot be determined whether or not the individual bone abnormalities corresponded to entheseal lesions, our results show resolution of bone oedema at most sites regardless of location, and adds to the growing body of evidence confirming the efficacy and safety of infliximab in the treatment of PsA and skin psoriasis.

Peri-entheseal and subchondral bone oedema is a common finding at sites of disease in SpA both in the axial and in the peripheral skeleton,^4,21 although its pathogenesis is not well understood. MRI can identify areas of diffuse bone oedema or osteitis, which are clearly visible at large entheseal sites such as the knee, spine and heel.^4,21,22 However, owing to the smaller structure of the hand, it is difficult to say unequivocally whether diffuse peri-entheseal bone oedema represents an enthesitis, a periarticular erosion or both.²³ Indeed, in early RA, small joint erosions typically occur adjacent to collateral ligaments.¹⁴ Hence we thought it was not possible to differentiate between synovial- or entheseal-based disease in the hand, and termed all bone lesions as periarticular. Furthermore, we used the current Outcome Measures in Rheumatology Clinical Trials definitions, developed for RA, which apply to lesions within 1 cm from the joint margin in the MCP joints. Although most of the lesions seen in our patients were clearly away from this margin, they were always associated with erosions, making it impossible to the human eye to establish its origin, although they were always associated with diffuse and extensive oedema, a finding noted in other sites of disease in SpA but not in RA. Higher resolution imaging techniques applied to early disease should help elucidate the pathogenic meaning of these lesions.

Bone is pivotal for the expression of PsA, and bone-related changes including syndesmophytes and mutilating arthritis contribute significantly to the morbidity and loss of function associated with PsA. Ritchlin et al²⁴ have suggested the role of activated osteoclasts in PsA, raising the possibility that this is a disorder of bone remodelling. Recent short-term radiographic studies of the hand show that anti-TNF suppresses periarticular erosion formation in patients with MCP-related disease.^10,11 However, this is the first study to focus on bone oedema in PsA and to show that oedema seen on MRI improves significantly after anti-TNF treatment. This is an important observation, given the recent demonstration that anti-TNF suppression of MRI-determined spinal enthesitis and osteitis is associated with subsequent inhibition of entheseal-related disease progression shown on radiography.²⁵ Nevertheless, these results should be viewed in the light of the limitations of this study—namely, the small numbers studied and the fact that the trial was conducted in an open-label fashion. Further studies involving larger number of patients are needed to determine whether in fact anti-TNF prevents radiographic bone-related changes in PsA.

In conclusion, our results are in accordance with previous reports of the efficacy of infliximab in the treatment of clinical and pathogenic manifestations of disease in PsA. Whether regression of MRI-determined bone oedema in acute PsA could translate into disease modification will be confirmed in larger cohorts using more sensitive imaging methods.