Rituximab (RTX) may be responsible for infectious event in RA patients. Immunological markers may be associated with the occurrence of infections.
Objectives
To evaluate lymphocyte counts and immunoglobulin concentrations over multiple cycles of RTX in RA patients, and to analyse the relationship between these markers and the occurrence of infections.
Methods
Retrospective monocentric study on 94 RA patients treated with RTX. At baseline and during follow up, lymphocyte phenotyping (CD4+, CD3+, CD19 +cells), gammaglobulin, IgG, IgM and IgA concentration were assessed. Patients were dichotomized according to the absence or presence of infectious events. A student's test was used to compare the continuous variables and a Chi2 test or the Fisher test was used for the dichotomous variables.
Results
A total of 119 infectious events occurred during follow-up, of which only 11 were serious, with respective incidences of 65 per 100 patient-years and 6 per 100 patient-years. Low IgM concentration at RTX initiation and low IgG concentration (<5 g/L) throughout follow-up were associated with an increased risk of infection. Both gammaglobulin and IgG concentrations decreased along with successive cycles of RTX in patients with infection, while they remained stable in patients without infection. Twelve patients had a CD4 +cell count<200/mm3 during follow up, of which one with a CD4 +cell count 233/mm3 at baseline, who subsequently presented an opportunistic infection.
Conclusions
Gammaglobulin, IgM and IgG concentrations and CD4 +cell count are valuable before RTX initiation in RA patients. IgG or gammaglobulin concentration should also be monitored before each cycle. CD4 +lymphocytes monitoring should be considered in patients with low value at initiation.
Disclosure of Interest
F. Martins: None declared, A. Bensalem: None declared, T. Bejan-Angoulvant: None declared, A. Lhommas: None declared, J. Mélet: None declared, S. Mammou: None declared, G. Thibault: None declared, L. Bernard: None declared, P. Goupille Consultant for: Abbvie, Biogaran, BMS, Hospira, Janssen-Cilag, MSD, Pfizer, Sanofi-Genzyme and UCB, D. Mulleman Grant/research support from: Abbvie and Nordic Pharma, Consultant for: MSD, Novartis, UCB and Pfizer
HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not.The documents may come from teaching and research institutions in France or abroad, or from public or private research centers.L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés. Trough infliximab concentration may predict long-term maintenance of infliximab in ankylosing spondylitis
IL-1 plays a key role in disc degeneration and could be a valid target for inhibiting this process. IL-1 receptor antagonist (IL-1ra) might be a good candidate to inhibit IL-1 activity. However, many questions need to be addressed before contemplating therapy in humans. IL-1 blockade is also a great challenge in osteoarthritis and results from animal models suggest that IL-1ra may have beneficial effects. The clinical benefit of a local injection of IL-1ra in knee osteoarthritis may be limited by the antagonist's short half-life. Further studies with longer-lasting antagonists are needed to explore this new therapeutic approach.
Anti-drug antibodies (ADA) are responsible for decreased adalimumab efficacy in axial spondyloarthritis (SpA). We aimed to evaluate the ability of methotrexate (MTX) to decrease adalimumab immunisation.A total of 110 patients eligible to receive adalimumab 40 mg subcutaneously (s.c.) every other week were randomised (1:1 ratio) to receive, 2 weeks before adalimumab (W-2) and weekly, MTX 10 mg s.c. (MTX+) or not (MTX-). ADA detection and adalimumab serum concentration were assessed at weeks 4 (W4), 8 (W8), 12 (W12) and 26 (W26) after starting adalimumab (W0). The primary outcome was the proportion of patients with ADA at W26. Four years after the study completion, we retrospectively analysed adalimumab maintenance in relation with MTX co-treatment duration.We analysed data for 107 patients (MTX+; n=52; MTX-; n=55). ADA were detected at W26 in 39/107 (36.4%) patients: 13/52 (25%) in the MTX+ group and 26/55 (47.3%) in the MTX- group (p=0.03). Adalimumab concentration was significantly higher in the MTX+ than MTX- group at W4, W8, W12 and W26. The two groups did not differ in adverse events or efficacy. In the follow-up study, MTX co-treatment >W26 versus no MTX or ≤W26 was significantly associated with adalimumab long-term maintenance (p=0.04).MTX reduces the immunogenicity and ameliorate the pharmacokinetics of adalimumab in axial SpA. A prolonged co-treatment of MTX>W26 seems to increase adalimumab long-term maintenance.
Table 1 Arguments for therapeutic drug monitoring of a tumour necrosis factor inhibitor in rheumatic diseases and requirements Rationale Requirement Pharmacokinetic interindividual variability Valid assay for drug concentration measurement and anti-drug antibody detection Dose-concentration relationship Algorithm based on clinical and biological assessment Risk of adverse events, outside the target concentration range* Personalised dosing-schedule modelling tool, to achieve the target concentration and response *Immunogenicity with low concentrations and infection with high concentrations.
Background: Adalimumab is a therapeutic antibody used for treating inflammatory diseases. To understand interindividual PK variability, there is a need to develop and validate an assay to measure serum adalimumab concentrations. Methods: An ELISA was developed on microtiter plates coated with TNF-α. Seven nonzero adalimumab standards ranging from 0.05 to 50 mg/l and three quality controls (0.2, 2.5 and 7 mg/l) were tested for their intra and interday precision on six occasions. Results: The LOD, LLOQ and ULOQ of the assay were 0.022, 0.073 and 9 mg/l, respectively. Conclusion: This method is accurate, reproducible and may be useful for PK studies and for therapeutic drug monitoring of adalimumab.
Fibromyalgia, rheumatoid arthritis, spondyloarthritis, and Sjögren's syndrome are chronic rheumatic diseases with very different clinical characteristics, but which share symptoms such as pain and fatigue. The aim of the study was to examine the impact of the disease on psychological adaptation in fibromyalgia compared with other rheumatic diseases (rheumatoid arthritis, spondyloarthritis, and Sjögren's syndrome).In a multicenter study, 165 women with rheumatic diseases (48 with fibromyalgia, 47 with rheumatoid arthritis, 47 with spondyloarthritis, 23 with Sjögren's syndrome) completed the General Health Questionnaire-28 (emotional distress), Fatigue Severity Scale (fatigue), Fibromyalgia Impact Questionnaire (impact of the disease), Coping Strategies Questionnaire (coping), and Mini International Neuropsychiatric Interview (comorbidity with DSM IV axis-I disorders). We used the Kruskal-Wallis test, Mann-Whitney U test, and chi2 test to compare comorbid anxiety and depressive disorders and to compare the impact of the disease on patients' mental well-being and daily life and adjustment (coping strategies).Anxiety and depressive disorders were more common in fibromyalgia patients; they had higher scores on impact of the disease, physical symptoms, pain, and fatigue than rheumatoid arthritis patients and reported more fatigue than patients with spondyloarthritis. Overall, they used more maladaptive coping strategies (less use of distancing from pain than patients with rheumatoid arthritis and spondyloarthritis, less use of ignoring pain sensations, and more use of catastrophizing than those with rheumatoid arthritis). No differences were found between fibromyalgia and Sjögren's syndrome on impact and adjustment.Compared with other rheumatic diseases, fibromyalgia has a greater impact on daily life; patients have more difficulty adjusting to the disease and generally use poorer strategies to cope with pain.
