Analysis of efficacy and safety of multiple intravenous infusion of anti-tumor necrosis factor-alpha monoclonal antibody (Remicade) combined with methotrexate compared with sodium aurothiomalate and intramuscular depot methylprednisolone in rheumatoid arthritis

The objective of the paper was compare the effects and tolerability of combined therapy of multiple intravenous infusions of anti-tumour necrosis factor-alfa (TNF-alfa) monoclonal antibody (Remicade) with methotrexate versus treatment with sodium aurothiomalate and intramuscular depot methylprednisolone in rheumatoid arthritis (RA). We investigate also the interval necessary to obtain the improvement in both treatment groups. 36 patients commencing intramuscular sodium aurothiomalate therapy with intramuscular depot methylprednisolone acetate at weeks 0, 4, 8 and 12 in addition to chrysotherapy were compared in retrospective analysis with 32 patients starting with multiple intravenous infusions of infliximab, anti-TNF-alfa monoclonal antibody (Remicade) and methotrexate at a stable dose. Patients were assessed by composite clinical score (DAS 28) and C-reactive protein during 22 weeks of therapy. At week 2 and 6 a significantly greater percentage of infliximab-treated than gold-treated RA patients achieved improvement in each clinical measurement of disease activity. At 22 week of treatment moderate and good response according to EULAR criteria was achieved in 91% of infliximab-treated patients and 58% gold treated patients (p < 0.001). Adverse events were more frequently observed in infliximab-treated patients, but only gold-treated patients discontinued treatment because adverse events (2 patients due to proteinuria, 2 patients due to mucocutaneous changes and one patient due to leucopenia). The higher percentage of adverse events in infliximab-treated patients was caused mainly by the occurrence of infusion reactions (23 reactions out of 160 infusions); most of them were mild (somnolentia and headache) and transient. Viral infections (including herpes simplex and zoster) were more common in patients treated with infliximab and methotrexate. Combination therapy of infliximab and methotrexate is more effective in reducing clinical and biochemical disease activity than gold with methylprednisolone treatment in RA patients during 22 weeks of treatment, especially in the first 6 weeks.     

Patients with the most advanced rheumatoid arthritis remain with Th1 systemic defects after TNF inhibitors treatment despite clinical improvement

Systemic immune defects might reflect severely dysregulated control of chronic inflammation related to disease progression. Th17/Treg cell imbalance has been demonstrated to be involved in rheumatoid arthritis (RA) pathogenesis. Despite controversial results, a growing anti-inflammatory role in this process has been recently attributed to Th1 responses. The aim of the study was to estimate the extent of Th1/Th17/Treg imbalance in peripheral blood (PB) of patients with short- and long-term RA in relation to cytokine milieu and its reversal after therapy with methotrexate and/or TNF inhibitors, respectively. Patients with different duration of RA (median 6 vs. 120 months) in the active phase of RA were enrolled in this study. We performed flow cytometric analysis of PB Th1, Th17, and Treg populations together with estimation of serum cytokine concentrations using cytometric bead array. Disease activity was calculated on the basis of clinical and biochemical indices of inflammation (DAS28, ESR, CRP). All parameters were measured and correlated with each other before and after 6 months therapy. Elevated levels of circulating Th17 cells and IL-6 were found in all active patients, of which Th17 cells were down-regulated by the treatment. Significantly reduced Th1 and functional CTLA-4+ Treg cell frequencies as well as Th1 cytokines observed only in progressive RA seemed to be irreversible. Although therapy induced clinical improvement in almost all patients, those with advanced RA remained with signs of inflammation. Our report demonstrates that both the extent of systemic immune abnormalities and their restoration are dependent on duration of the active RA.     

Tacrolimus exposure in the real world: an analysis from the Mycophenolic acid Observational REnal transplant study

Tacrolimus exposure and renal function data to 36 months post‐transplant were analyzed from the prospective, observational Mycophenolic acid Observational REnal transplant (MORE) registry in which de novo kidney transplant patients were managed according to local practice. Tacrolimus trough (C₀) concentration at month 12 was stratified as low (<6 ng/mL), moderate (6–8 ng/mL), or high (>8 ng/mL) in 724 patients. Estimated glomerular filtration rate (eGFR) was stratified as low (<60 mL/min/1.73 m²) or high (≥60 mL/min/1.73 m²). High tacrolimus C₀ (>8 ng/mL) was observed in 47.7%, 34.1%, 26.8%, and 26.7% of patients at baseline and months 12, 24, and 36, respectively. Biopsy‐proven acute rejection was similar to month 36 regardless of tacrolimus C₀ category at month 12. Tacrolimus C₀ >8 ng/mL vs. <6 ng/mL at month 12 was predictive of low eGFR at month 24 (p = 0.023) with a nonsignificant trend at month 36 (p = 0.085). Infections (p < 0.013) and BK virus infection (p < 0.001) were most frequent in the low tacrolimus C₀ cohort. Neutropenia was most frequent in the high tacrolimus C₀ category (p = 0.010). In conclusion, over a quarter of patients were exposed to high tacrolimus C₀ to 36 months post‐transplant. Tacrolimus exposure did not affect rejection risk, but tacrolimus C₀ >8 ng/mL at month 12 was predictive of subsequent low eGFR compared to C₀ <6 ng/mL.     

Long‐term outcomes in African American kidney transplant recipients under contemporary immunosuppression: a four‐yr analysis of the Mycophenolic acid Observational REnal transplant (MORE) study

Mycophenolic acid Observational REnal transplant (MORE) was a prospective, observational study of de novo kidney transplant patients receiving mycophenolic acid (MPA). Four‐yr data on 904 patients receiving tacrolimus and enteric‐coated mycophenolate sodium (EC‐MPS) or mycophenolate mofetil (MMF) were analyzed to evaluate immunosuppression and graft outcomes in African American (AA, n = 218) vs. non‐AA (n = 686) patients. Mean tacrolimus dose was higher in AA vs. non‐AA patients but mean tacrolimus trough concentration was similar. Use of the recommended MPA dose in AA patients decreased from 78.9% at baseline to 33.1% at year 3. More AA patients received the recommended MPA dose with EC‐MPS than MMF at month 6 (56.2% vs. 35.7%, p = 0.016) and month 36 (46.6% vs. 16.7%, p = 0.029), with no safety penalty. Significantly, more AA patients received corticosteroids than non‐AA patients. Biopsy‐proven acute rejection was higher in AA vs. non‐AA patients (18.9% vs. 10.7%, p = 0.003), as was graft loss (10.9% vs. 4.4%, p = 0.003); differences were confirmed by Cox regression analysis. Patient survival was similar. Estimated GFR was comparable in AA vs. non‐AA patients. Kidney allograft survival remains lower for AA vs. non‐AA recipients even under the current standard of care.     

Significance of association of HLA-C and HLA-E with psoriatic arthritis

Psoriatic arthritis (PsA) is a complex genetic disorder that results from an interplay between multiple genetic and environmental factors. The aim of the study was to assess the significance of the association between the HLA-C and HLA-E allelic groups and PsA. Our results confirm the association between HLA-C^∗06 and PsA (OR = 5.16, p < 0.0001). Furthermore, HLA-C^∗06-positive patients develop more severe disease (p < 0.01) and more frequently present with polyarticular pattern of PsA (p = 0.08). Additionally our study revealed that the HLA-C^∗02 allele was more frequently observed in PsA patients (OR = 5.40, p < 0.0005) and also that the HLA-E^∗01:01 allele was significantly over-represented among HLA-C^∗02-negative patients in comparison to healthy individuals (OR = 6.44, p = 0.045). Therefore these results suggest that the HLA-E and HLA-C^∗02 molecules may also play an important role in determination immune response contributing to the PsA development.     

Daclizumab induction in solid organ transplantation

Antibody induction therapy is used in solid organ transplantation to prevent rejection in the early postoperative period. It is especially useful in high-risk groups such as retransplants, patients with delayed graft function to delay the initiation of nephrotoxic calcineurin inhibitors (tacrolimus, cyclosporin), highly sensitised recipients and African-American recipients. Historically, antibody induction has been associated with a high incidence of adverse effects and a complicated administration regimen. Daclizumab is a monoclonal antibody that exerts its effect by binding to the alpha subunit (CD25) of the human interleukin (IL)-2 receptor on the surface of activated lymphocytes, thus preventing the binding of IL-2. It is used for induction therapy and is well-tolerated with easy administration. Although originally studied as a five-dose regimen, there is a growing accumulation of data that fewer doses (two or three) are efficacious and less costly for preventing rejection.