Histological evidence that infliximab treatment leads to downregulation of inflammation and tissue remodelling of the synovial membrane in spondyloarthropathy

Objective: To confirm and extend the immunopathological evidence of effects of infliximab on the synovium in active spondyloarthropathy. Methods: Synovial biopsies obtained in patients with spondyloarthropathy at baseline and week 12 were stained and scored by two independent observers. Two study populations were evaluated: I, a cohort of 10 patients treated with 5 mg/kg infliximab at week 0, 2, and 6, plus three placebo treated patients; and II, a pooled cohort of 20 patients fulfilling identical inclusion and exclusion criteria and treated with the same loading dose regimen. Results: In study population I, treatment with infliximab induced reduction in synovial lining layer thickness (p = 0.015), endothelial activation (E-selectin, p = 0.034), and inflammatory cell infiltration with neutrophils (p = 0.041), macrophages (p = 0.034), and T cells (p = 0.026), but not with B cells and plasma cells; no such trends were observed in the placebo treated patients. Besides confirming the highly significant downregulation of inflammation, analysis of cohort II showed structural changes such as normalisation of lining layer thickness (p = 0.030), reduction in the number of blood vessels (p = 0.039), and downregulation of follicular organisation (p = 0.050). No differences in histopathological response were observed between spondyloarthropathy subtypes. Conclusions: Profound immunomodulatory changes in the synovium parallel the clinical benefit in patients with spondyloarthropathy treated with infliximab, independently of the subtype. The study provides histological evidence that TNFα blockade not only downregulates inflammation but also leads to tissue remodelling

Effects of a loading dose regimen of three infusions of chimeric monoclonal antibody to tumour necrosis factor α (infliximab) in spondyloarthropathy: an open pilot study

OBJECTIVE—To evaluate the efficacy and safety of a loading dose regimen of three intravenous infusions with infliximab in patients with active spondyloarthropathy.
METHODS—A monocentre, open-label pilot study of 21 patients with different subtypes of spondyloarthropathy was conducted. Treatment resistant patients with active disease (fulfilling inclusion criteria) received three infusions of 5 mg/kg infliximab (at weeks 0, 2,( )and 6). Standard clinical assessments were performed at baseline, and on days 3, 7, and 14, and from then on every two weeks. In patients who fulfilled criteria for ankylosing spondylitis, axial assessment was performed at baseline and on days 14, 42, and 84.
RESULTS—In all global assessments (visual analogue scale of patient global assessment, patient pain assessment, doctor global assessment), erythrocyte sedimentation rate, and C reactive protein, a highly significant decrease could be seen already at day 3 (compared with baseline), which was maintained up to day 84. In patients with peripheral disease (n=18), tender and swollen joint count significantly decreased. In patients with axial disease (n=11), functional and disease activity indices significantly improved. Moreover in eight patients with psoriatic arthritis a significant decrease of the psoriasis area and severity index was observed. The treatment was well tolerated in all patients; no significant adverse events were seen.
CONCLUSION—In this open-label pilot study of a loading dose regimen of three infusions of chimeric monoclonal antibody to tumour necrosis factor α in patients with active spondyloarthropathy, there was a fast and significant improvement of axial and peripheral articular manifestations, without major adverse experiences.


Systematic safety follow up in a cohort of 107 patients with spondyloarthropathy treated with infliximab: a new perspective on the role of host defence in the pathogenesis of the disease?

Background: Recent studies with infliximab indicate the therapeutic potential of tumour necrosis factor α blockade in spondyloarthropathy (SpA). Because defective host defence is implicated in the pathogenesis of SpA, the potential side effects of this treatment due to impact on the antimicrobial defence are a major concern. Objective: To report systematically the adverse events seen in a large cohort of patients with SpA treated with infliximab, with special attention to bacterial infections. Patients and methods: 107 patients with SpA were treated with infliximab for a total of 191.5 patient years. All serious and/or treatment related adverse events were reported. Results: Eight severe infections occurred, including two reactivations of tuberculosis and three retropharyngeal abscesses, and six minor infections with clear bacterial focus. One patient developed a spinocellular carcinoma of the skin. No cases of demyelinating disease or lupus-like syndrome were seen. Two patients had an infusion reaction, which, however, did not relapse during the next infusion. Finally, three patients with ankylosing spondylitis developed palmoplantar pustulosis. All patients recovered completely with adequate treatment, and infliximab treatment had to be stopped in only five patients with severe infections. Conclusions: Although the global safety of infliximab in SpA is good compared with previous reports in rheumatoid arthritis and Crohn's disease, the occurrence of infections such as tuberculosis and retropharyngeal abscesses highlights the importance of careful screening and follow up. Focal nasopharyngeal infections and infection related symptoms, possibly induced by streptococci, occurred frequently, suggesting an impairment of specific host defence mechanisms in SpA

Repeated infusions of infliximab, a chimeric anti-TNFα monoclonal antibody, in patients with active spondyloarthropathy: one year follow up

Background: In a pilot study, the anti-tumour necrosis factor α monoclonal antibody, infliximab, induced a rapid and significant improvement in global, peripheral, and axial disease manifestations of patients with active spondyloarthropathy. Objective: To determine whether repeated infusions of infliximab would effectively and safely maintain the observed effect. Methods: Safety and efficacy of a maintenance regimen (5 mg/kg infliximab every 14 weeks) was evaluated using the measurements reported in the pilot study. Of the 21 patients, 19 completed the one year follow up for efficacy; two patients changed to another dosing regimen after week 12 owing to partial lack of efficacy. However, they are still being followed up for safety analysis. Results: After each re-treatment a sustained significant decrease of all disease manifestations was observed. Before re-treatment, symptoms recurred in 3/19 (16%) at week 20, in 13/19 (68%) at week 34, and in 15/19 (79%) at week 48. No withdrawals due to adverse events occurred. Twelve minor infectious episodes were observed. Twelve patients (57%) developed antinuclear antibodies; in four of them (19%) anti-dsDNA antibodies were detected. However, no lupus-like symptoms occurred. Conclusion: In this open study of infliximab in patients with active spondyloarthropathy, the significant improvement of all disease manifestations was maintained over a one year follow up period without major adverse events. Although recurrence of symptoms was noted in a rising number of patients before each re-treatment, no loss of efficacy was observed after re-treatment

Impaired Th1 cytokine production in spondyloarthropathy is restored by anti-TNFα

OBJECTIVES—To evaluate the effect of anti-TNFα on the Th1 and Th2 cytokines in patients with spondyloarthropathy (SpA).
METHODS—Peripheral blood mononuclear cells (PBMC) were obtained from 20 patients with active SpA treated with infliximab (5 mg/kg). For comparison, PBMC were also obtained from 15 healthy controls and 19 patients with active rheumatoid arthritis (RA). After stimulation with PMA/ionomycin, the intracellular cytokines interleukin (IL)2, IL4, IL10, and interferon (IFN)γ were determined in CD3+ T cells and in CD3+/CD56+ natural killer (NK) T cells by flow cytometry.
RESULTS—At baseline the percentage of T cells positive for IFNγ (p=0.020) and IL2 (p=0.046) was decreased in patients with SpA compared with healthy controls, while IL10 (p=0.001) was increased. This cytokine profile, confirmed by the mean fluorescence intensities (MFI), was more pronounced in CD3+/CD8- cells and contrasted with higher IL2 production in RA. NK T cells, characterised by high IL4 and IL10 numbers, were also increased in patients with SpA (p=0.017). Treatment with infliximab induced a significant and persistent increase in IFNγ and IL2 in patients with SpA. Moreover, there was a transient decrease in IL10 and NK T cells in patients with high baseline values, resulting in values comparable with those of healthy controls. This switch in cytokine profile was seen in both the CD3+/CD8- and CD3+/CD8+ subsets.
CONCLUSIONS—Before treatment patients with SpA had an impaired Th1 cytokine profile compared with healthy controls and patients with RA. TNFα blockade induced restoration of the Th1 cytokines, resulting in a normal cytokine balance. These data confirm the effect of anti-TNFα on the immune changes in SpA, and provide insights into the mechanisms involved in TNFα blockade.


Successful use of infliximab in a patient with treatment resistant spondyloarthropathy related uveitis

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