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Abstract
Objective: To demonstrate the efficacy of intra-articular infliximab in a patient with a persistent monarthritis who had previously had two arthroscopic synovectomies with limited success, and to determine the effect of intra-articular infliximab on synovial membrane pathology
Method: Arthroscopic synovial biopsy specimens were collected before and after treatment with intra-articular infliximab. The synovial tissue was stained for a range of inflammatory cell subsets, cell adhesion molecules and cytokines using immunohistochemical techniques and quantified using digital image analysis and a semiquantitative scoring method.
Results: Clinical improvement in the knee synovitis was seen after the first two intra-articular infliximab treatments, with a sustained clinical remission lasting for more than 12 months after the third treatment. Significant changes in cellular infiltration and expression of cytokines and cell adhesion molecules occurred as a result of treatment with intra-articular infliximab, with a reduction in some but not all cells in the inflammatory infiltrate, as well as a reduction in the expression of cell adhesion molecules (intercellular adhesion molecule-1 and vascular adhesion molecule-1) and production of cytokines (interleukin 1β and tumour necrosis factor α).
Conclusion: Intra-articular infliximab administration is a viable treatment for a persistent monarthritis resistant to other treatment options and can successfully modulate the inflammatory milieu within the synovial membrane.
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Anti-tumour necrosis factor (TNF) treatments have been shown to be effective in the management of several inflammatory arthritides, including psoriatic arthritis and ankylosing spondylitis.1–3 While the parenteral use of these agents for polyarthritis or axial disease is well established, the role of these treatments for patients with a monarthritis is less clear. Several groups have reported the intra-articular (IA) use and variable success of these agents for a monarthritis in patients with rheumatoid arthritis or a seronegative spondyloarthropathy.4–8 No studies have examined the effects of IA infliximab on synovial tissue inflammation, although there are studies which demonstrate the effects of parenteral anti-TNF treatment on synovial tissue pathology.9–11 This paper demonstrates the clinical effects of IA infliximab and its effect on synovial tissue disease.
MATERIALS AND METHODS
A 43-year-old female patient presented with a history of recurrent iritis and a monarthritis affecting the right knee with no history of inflammatory back pain, inflammatory bowel disease or psoriasis. There was no family history of any spondyloarthropathy, inflammatory bowel disease or psoriasis. She was known to be HLA-B27 positive, rheumatoid factor negative with intermittent raised inflammatory markers (erythrocyte sedimentation rate (19–80 mm/1st h) and C-reactive protein (7–15 mg/l)). She had intermittent knee effusion aspirations (six over a 4-year period producing inflammatory synovial fluid with a high white cell count of predominantly neutrophils) and IA corticosteroid injections with limited benefits and was treated over a period of 3 years with sulfasalazine up to a dose of 3 g daily (for 11 months) and then combination therapy with sulfasalazine and methotrexate (up to a dose of 20 mg once a week) without any success. She underwent two arthroscopic synovectomies of the same knee joint (both showing a florid hypertrophic synovitis macroscopically) separated by 2 years, again with limited benefit. Three months after the second arthroscopic synovectomy, when she had further pain and swelling affecting the target knee joint, she underwent an arthroscopic washout of the knee joint and instillation of 100 mg infliximab in 10 ml normal saline. This procedure was repeated on two occasions, at 3 and 6 months later, because of residual knee synovitis. Her knee monarthritis has now been in remission for 12 months since the last IA infliximab treatment without any additional treatment.
Immunohistochemistry
Cryosections (4 μm thick) were prepared on APTS (3-aminopropyltriethoxysilane; Sigma, St Louis, Missouri, USA) treated glass slides and fixed in ice-cold acetone for 4 minutes. Sections were brought to room temperature, washed in phosphate-buffered saline and immunohistochemical labelling for a range of cell surface markers (anti-CD68 (EBM11; Dako Australia, Botany Bay, New South Wales, Australia) to detect macrophages, Mab 67 (Serotec, Kidlington, Oxford, UK), which recognises CD55, to detect fibroblast-like synoviocytes, anti-CD3 (BD Biosciences, San Jose, California, USA) and anti-CD45Ro to detect T cells and memory T cells, respectively, anti-CD22 (Central Laboratory of the Netherlands Red Cross Blood Transfusion Service, Amsterdam, The Netherlands) to detect B cells, anti-CD38 (BD Biosciences) to detect plasma cells); cell adhesion molecules (vascular adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1) and E-selectin and cytokines (interleukin (IL) 1β, IL6 and TNFα)) was performed on all tissues using a double enhancement method as previously published.12 To eliminate bias from run-to-run variability, all staining for a particular antibody was performed on all synovial tissue on the same day.
After immunohistochemical staining, sections were analysed by a single observer, unaware of the timing of the synovial biopsy and in a random order by computer-assisted image analysis, analysing six high-power fields for each section as previously published.12 In addition, these sections were also scored by a semiquantitative method on a five-point scale by two independent observers in a random order, as described previously.13
RESULTS
The patient described in this case report had recurrent synovitis of a single knee joint without evidence of a generalised inflammatory arthritis. Treatment with sulfasalazine and methotrexate, including combination treatment and a temporary response to IA corticosteroids and two arthroscopic synovectomies, failed to produce an adequate response. She has now received three IA injections of infliximab (100 mg in normal saline at each of three arthroscopies), the last being given more than 12 months ago. She has remained in clinical remission since the third IA infliximab treatment.
Arthroscopic synovial biopsies were performed on the same knee joint over a 5-year period before and after the start of IA infliximab and biopsy samples were stained for a range of cell surface markers, cytokines and cell adhesion molecules as described in the methods section. Figure 1 presents an example of synovial biopsy specimens stained for macrophages. The results of immunohistochemical staining were measured by digital image analysis and semiquantitative scoring and fig 2 presents the results for digital image analysis for those variables which changed with treatment. Similar results were seen when measurement was performed with a semiquantitative scoring system. There was a reduction in cellular infiltrate, especially macrophages but also T cells, as a result of IA infliximab. In addition, both TNFα and IL1β content in the synovial membrane was reduced after IA infliximab injection; expression of cell adhesion molecules (ICAM-1 and VCAM-1) was also reduced. There was no significant change in B-cell or plasma cell numbers in the synovial membrane, IL6 production or expression of E-selectin before or after IA infliximab.
DISCUSSION
Clinical outcomes from the use of IA anti-TNFα treatments have been variable. One group reported the outcomes from treatment of six patients with a single dose of 100 mg infliximab, with relapses of synovitis from 2 to 7 weeks after treatment.4 Other groups have reported better clinical outcomes from IA infliximab, with improvement lasting up to 8 months.5–8 The patient reported here had a background of HLA-B27-associated spondyloarthropathy with severe monarthritis affecting the knee joint, which failed to respond adequately to systemic treatment with sulfasalazine and MTX or to local treatment with corticosteroids or surgical synovectomy. Although she did respond to a single IA injection of 100 mg infliximab, as has been used in previously published case series, she still had residual synovitis in the knee joint both clinically, at arthroscopy and on synovial histology. Repeated local injections of infliximab over a short period have resulted in a sustained remission of the monarthritis over a period of 12 months with demonstration of macroscopic improvement at arthroscopy and also histologically from inspection of repeated synovial biopsy specimens.
This is the first study, to our knowledge, which has demonstrated the effect of IA infliximab on the inflammatory infiltrate in the synovial membrane. We conclude that local injection of infliximab in patients with a persistent monarthritis, resistant to other treatments, is a therapeutic option which is likely to reduce chronic inflammation in the synovial membrane but it may require more than one treatment to achieve a prolonged response. A clinical trial with larger patient numbers will be needed to confirm this observation.
REFERENCES
Footnotes
Funding: Supported by the Daw Park Research Foundation, National Health and Medical Research Council of Australia and the Arthritis Foundation of Australia.
Competing interests: None declared.
Ethics approval: Ethics committee approval obtained.
Patient consent: Obtained.