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 CD14(bright) 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 CD14(dim) 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.

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.

Real life experience confirms sustained response to long-term biologics and switching in ankylosing spondylitis.

OBJECTIVE: To investigate the long-term response to biological therapies in AS in a real life clinical setting and to quantify non-response and response to 'switching' therapies in these cases. METHODS: All patients prescribed TNF-blocking therapies for AS between 1999 and 2006 were studied. Response was evaluated using Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI) and CRP results. RESULTS: A total of 113 patients (84 males: 29 females, mean age 45 yrs, median disease duration 16 yrs, 87% HLA-B27 positive) were identified. At baseline they had a mean BASDAI of 6.57, BASFI 6.57 and CRP of 31 g/dl. At the end of follow-up, these values had reduced to mean BASDAI of 3.12, BASFI 4.16 and CRP of 7 g/dl. Improvements were sustained for 24 months and beyond with no loss of effect. Only nine patients (8%) suffered side-effects leading to cessation or switching of first-line therapy and non-response occurred in 15 patients (13%) in the long term. Fifteen patients (13%) switched to a second drug and 14 of these (93%) had a significant and sustained response. Outcomes were similar regardless of drug used, duration of disease and HLA-B27 status. CONCLUSION: Treatment of active AS with TNF blockers according to the British Society of Rheumatology guidelines leads to a sustained response for over 2 yrs with most patients tolerating the drugs well. The rate of non-response is significantly lower than that seen in RA and nearly all of these patients respond well to a second-line agent.

Comparative efficacies of erythromycin-sulfisoxazole and cefaclor in acute otitis media: a double blind randomized trial.

A prospective double blind trial compared the fixed combination of erythromycin-sulfisoxazole (E/S) with cefaclor in the treatment of acute otitis media. One hundred nineteen children in six centers across Canada were studied. Diagnostic tympanocentesis of 134 ears yielded 135 bacterial isolates: Streptococcus pneumoniae (42%); Haemophilus influenzae (21%); Branhamella catarrhalis (10%); Streptococcus pyogenes (5%); and other bacteria (22%). Seventy-seven percent of strains of B. catarrhalis and 14% of strains of H. influenzae were beta-lactamase producers. E/S exhibited greater in vitro activity against H. influenzae and B. catarrhalis. Twenty-three patients had bacteriologically sterile middle ear fluid. The overall clinical outcome at Days 10 and 31 was identical in both treatment groups. Otoscopic findings improved more rapidly in the E/S group than in the cefaclor group at 10 and 31 days (P less than or equal to 0.04). In cases where pre-treatment middle ear fluid was negative on routine bacterial culture, complete cure at 10 days was observed in 75% of patients treated with E/S but only in 14% of those treated with cefaclor (P = 0.02). Side effects were infrequent and comparable between the test drugs. E/S is at least as effective as cefaclor in the management of acute otitis media and may be superior, particularly for cases not yielding bacteria on routine culture.

Long-term infliximab treatment in rheumatoid arthritis: subsequent outcome of initial responders.

OBJECTIVE: Patients may cease therapy with anti-tumour necrosis factor (TNF) agents due to inefficacy at 12 weeks (termed primary non-response) or later. Until now, the extent of this later secondary non-response has not been clearly defined. We followed-up a substantial single-centre cohort to determine kinetics of this secondary loss of response. The licensed dose of 3 mg/kg was used throughout. METHODS: Prospective data collection since anti-TNF therapy introduction in 1999 formed the basis of the analysis. Patients with rheumatoid arthritis who received infliximab as their first biologic agent, with at least 2 yrs follow-up were included. All relevant clinical data to calculate DAS-28 score and EULAR response were collected at 3, 6, 9, 12, 18 and 24 months. Reasons for cessation in those patients achieving a EULAR response at 3 months (secondary failures) were determined. RESULTS: Of a total of 309 patients commenced on infliximab, 290 received this as their first biologic agent.; 195 commenced > or = 2 yrs ago. Efficacy data to identify EULAR responders at 3 months was available in 174 patients. Sixty-seven per cent achieved a 'moderate' or 'good' EULAR response; 25% failed to achieve a response, 8% developed toxicity within the first 12 weeks. Of the primary responders, over 55% subsequently ceased therapy in the first year, the predominant reason was a secondary loss of response; other reasons included high disease activity despite achieving a definable response, toxicity, and intercurrent illness. Subsequent loss of response in the second year was less pronounced. CONCLUSIONS: This study of patients treated in clinical practice with infliximab demonstrated that secondary non-response occurred in around half the patients in the first year. The data highlight the need to continue development of other therapies as well as investigation of the underlying causes of this loss of response.