Domini Bryer

Sustained response to long-term biologics and switching in psoriatic arthritis: results from real life experience

Objective: To investigate the response to biologic drugs in psoriatic arthritis and to quantify non-response and outcome from switching agents. Methods: 60 patients (33 men and 27 women, mean age 46 years, median disease duration 16 years) prescribed biologic drugs for psoriatic arthritis between 2001 and 2006 were studied. Response was evaluated using joint counts, C-reactive protein levels and disease activity scores (using 28 joints; DAS28). Results: The mean percentage improvements seen were 56% in tender joint count, 70% in swollen joint count, 64% in C-reactive protein level and 36% in the overall disease activity score. Improvements were sustained beyond 24 months with no loss of effect. Side-effects leading to cessation or switching of first-line therapy were only seen in 5% of patients and non-response occurred in 20% long term. Overall, 90% of patients achieved a significant response, using switching in 20% of cases. Outcomes were similar regardless of drug used, duration of disease and subtype of arthritis. Conclusions: Treatment of active psoriatic arthritis with anti-tumour necrosis factor agents leads to a sustained response over 3 years with most patients tolerating these drugs well. The rate of non-response is low with the majority of patients responding to second- and third-line therapies.

Differential effects of infliximab on absolute circulating blood leucocyte counts of innate immune cells in early and late rheumatoid arthritis patients

Anti‐tumour necrosis factor (TNF) biologics have revolutionized therapy of rheumatoid arthritis (RA). We compared the effects of infliximab on numbers of circulating leucocyte subsets in early RA (disease/symptom duration of ≤1 year) and late RA patients (>1 year). A control group consisted of early RA patients treated with a combination of methotrexate (MTX) and methylprednisolone. Blood samples were obtained at baseline (pre‐therapy) from all RA patients, divided into three groups: (i) late RA receiving infliximab/MTX, (ii) early RA–infliximab/MTX, (iii) early RA–steroid/MTX, and also from follow‐up patients at 2 and 14 weeks. Significant differences in absolute counts of monocytes and granulocytes were observed between healthy controls and RA patients. At baseline CD14bright monocytes and CD16+ granulocytes were increased in both early RA and late RA patients. CD4+ T cells, CD8+ T cells and B cells were all increased at baseline in early RA, but not in late RA. At 2 weeks following infliximab treatment decreased granulocytes were observed in both early and late RA and decreased natural killer (NK) cells in late RA. CD16+ granulocytes and NK cells were also decreased at 14 weeks post‐infliximab in early RA. Biotinylated infliximab was used to detect membrane‐associated TNF (mTNF)‐expressing leucocytes in RA patients. CD16+ granulocytes, NK cells and CD14dim monocytes all expressed higher levels of mTNF in RA patients. In summary infliximab is associated with decreased CD16+ granulocyte and NK cell counts, possibly through binding of mTNF. Differential effects of infliximab between early and late RA suggest that pathogenic mechanisms change as disease progresses.

Abatacept or tocilizumab after rituximab in rheumatoid arthritis? An exploratory study suggests non-response to rituximab is associated with persistently high IL-6 and better clinical response to IL-6 blocking therapy

Objectives To evaluate the efficacy and safety of two different targeted approaches—abatacept or tocilizumab—after rituximab therapy in rheumatoid arthritis, and to explain observed difference in efficacy using blood and synovial studies of interleukin 6 (IL-6) and B cells in patients receiving rituximab therapy. Methods Consecutive series of patients who had discontinued rituximab therapy owing to inefficacy or toxicity were treated with abatacept (n=16) or tocilizumab (n=35). Clinical response and reasons for discontinuation were evaluated. Serial blood and synovial samples were obtained from a group of 57 and 25 rituximab-treated patients, respectively, and were analysed for B cells and IL-6 using flow cytometry, immunohistochemistry and quantitative real-time PCR. Results In the abatacept group, mean (SEM) Disease Activity Score in 28 joints calculated using the erythrocyte sedimentation rate (DAS28-ESR) reduced from 5.69 (0.42) at baseline to 4.94 (0.44) at 6 months (p=0.12). In the tocilizumab group: mean (SEM) DAS28- ESR reduced from 5.75 (0.21) at baseline to 3.28 (0.26) at 6 months (p<0.001). This was paralleled by a significant swollen joint count reduction in the tocilizumab (5.47 (0.70) to 2.70 (0.61), p=0.033), but not abatacept (6.23 (1.3) to 4.15 (1.2), p=0.26), group. In the synovium, despite complete depletion of B cells in 19/22 patients, IL-6 mRNA expression was not significantly reduced after rituximab. Blood B cell numbers remained low 12 months after rituximab. Serum IL-6 was raised at baseline and significantly higher in rituximab clinical non-responders (p=0.035) than responders. A significant reduction in serum IL-6 was seen in rituximab clinical responders (p=0.005) but not in non-responders (p=0.237). Conclusion In patients with rheumatoid arthritis for whom rituximab therapy failed despite adequate B cell depletion, IL-6-directed therapy might be a more logical and effective treatment choice than T cell costimulation blockade. Further controlled studies investigating other possible mechanisms are needed to validate these initial findings.