To date, anti-tumor necrosis factor alfa (anti-TNF-α) therapy is the only alternative to nonsteroidal anti-inflammatory drugs for the treatment of ankylosing spondylitis. Etanercept is a soluble TNF receptor, with a mode of action and pharmacokinetics different to those of antibodies and distinctive efficacy and safety. Etanercept has demonstrated efficacy in the treatment of ankylosing spondylitis, with or without radiographic sacroiliitis, and other manifestations of the disease, including peripheral arthritis, enthesitis, and psoriasis. Etanercept is not efficacious in inflammatory bowel disease, and its efficacy in the treatment of uveitis appears to be lower than that of other anti-TNF drugs. Studies of etanercept confirmed regression of bone edema on magnetic resonance imaging of the spine and sacroiliac joint, but failed to reduce radiographic progression, as do the other anti-TNF drugs. It seems that a proportion of patients remain in disease remission when the etanercept dose is reduced or administration intervals are extended. Etanercept is generally well tolerated with an acceptable safety profile in the treatment of ankylosing spondylitis. The most common adverse effect of etanercept treatment is injection site reactions, which are generally self-limiting. Reactivation of tuberculosis, reactivation of hepatitis B virus infection, congestive heart failure, demyelinating neurologic disorders, hematologic disorders like aplastic anemia and pancytopenia, vasculitis, immunogenicity, and exacerbation or induction of psoriasis are class effects of all the anti-TNF drugs, and have been seen in patients with ankylosing spondylitis. However, etanercept is less likely to induce reactivation of tuberculosis than the other anti-TNF drugs and it has been suggested that etanercept might be less immunogenic, especially in ankylosing spondylitis. Acute uveitis, Crohn’s disease, and sarcoidosis are other adverse events that have been rarely associated with etanercept therapy in patients with ankylosing spondylitis.
Patients treated with adalimumab (ADL) can induce anti-ADL antibodies (AAA) formation that is associated with low drug levels and clinical non-response. But, in the majority of the assays, the measurement of AAA is hampered by the presence of the drug itself. In support of immunogenicity assessment in clinical samples with subtherapeutic ADL levels, we proved acid pre-treatment for AAA detection with the Promonitor-enzyme-linked immunosorbent assay (ELISA). Were measured AAA after acidification in 32 serum samples with a subtherapeutic ADL trough level. ADL and AAA concentrations were measured by ELISA (Promonitor). The impact of drug concentration on AAA recovery (with or without acidification) was also evaluated by mixing known amounts of ADL (0.25, 0.5 and 1 mg/L) and AAA (100, 200, 300 and 400 AU/mL) from clinical samples in pooled serum. The drug significantly inhibited the detection of AAA in untreated samples. And progressively higher levels of ADL cause increasing inhibition of signal. Acid pre-treatment carried a significant increase in assay response, particularly at lower free ADL concentrations. AAA were detected in the 53 % of the samples after acid dissociation. In seven patients, the positive AAA after dissociation was detected in the first monitoring of ADL and five patients were positive 3 months later for AAA with the standard assay. Monitoring AAA using acid dissociation in patients with subtherapeutic circulating level of ADL could detect precocious problems of bioavailability, assess the immunogenicity of ADL and may be used to optimise dose regimens, thereby preventing prolonged use of inadequate therapy and guide change of treatment.
Duración del tratamiento con etanercept y razones de discontinuación en una cohorte de pacientes con patología reumática.JM Senabre-Gallego1, J Rosas-Gómez1, G Santos-Soler1, C Santos-Ramírez2, X BarberVallés3, M Sánchez-Barrioluengo4, E Salas-Heredia1, C Cano-Pérez5, R Riestra-Juán5, N Llahí-Vidal5.1. Reumatología, Hospital Marina Baixa, Villajoyosa (Alicante).2. Hospital Marina Salud, Denia (Alicante).3. CIO-UMH de Elche (Alicante). INTRODUCCIÓN:La terapia biológica, iniciada con los inhibidores del TNF-α (tumor necrosis factor α) infliximab (INF), adalimumab (ADA) y etanercept (ETN), ha cambiado radicalmente el tratamiento de ciertas enfermedades reumáticas como la artritis reumatoide (AR) o la espondilitis anquilosante (EA). La eficacia de estos fármacos anti-TNF ha sido demostrada en numerosos ensayos clínicos, pero ninguno de los tres es superior a los demás según los metaanálisis existentes y no existen ensayos clínicos comparativos 1 .
Objectives To analyse the clinical relevance of serum levels of infliximab (INF) and adalimumab (ADA) and the production of anti-INF (INF-Abs) or anti-ADA antibodies (ADA-Abs) from a local registry of patients with rheumatic diseases on treatment with INF or ADA. Methods We included 74 consecutive patients receiving treatment for more than 6 months with INF (31 tests in 25 patients) and ADA (56 test in 49 patients). Clinical characteristics, clinical activity index (DAS in 28 joints for rheumatoid arthritis -RA- and psoriatic arthritis -PsA-; BASFI, BASDAI for ankylosing spondylitis -AE-) were recorded. Serum levels of INF or ADA and INF-Abs or ADA-Abs (ELISA kit. Promonitor®-INF, ADA. Proteomika, Derio. Vizcaya. Spain) were evaluated. Cut-off level for serum Abs for INF was >37 U/mL, and for ADA >8 U/mL and cut-off level for serum level of INF and ADA were <0.04 mg/L and <0.002 mg/L respectively. Serum samples were collected at the time of infusion of INF or before injection of ADA, and stored frozen until analysis. Infusion reactions with INF were defined as any event appearing during infusion requiring either arrest of drug infusion or the administration of parenteral medication. Patients were considered responders if they had at the same time of extraction, DAS28-ESR≤3 in RA or PsA patients; BASDAI≤4 in AE patients. Results We enrolled 74 patients, 50 (68%) were women; the mean age was 54±15years (range: 16-78 years). The diagnosis of patients was: RA (47%), AE (30%), PsA (12%) and others (11%). The average time of treatment for the whole population was 31±22 months (mean; 27 months): for INF group: 43.7 months (median: 42, range: 6-127) and for ADA: 23.9 months (median: 21; range: 6-51). INF was the first anti-TNF received in 24 (96%) of the patients, and ADA was the first in 37 (76%) of the patients. Antibodies were detected in 9/74 patients (12%): 4/25 patients (16%) INF-Abs and 5/49 patients (10%) ADA-Abs. In the INF-Abs and ADA-Abs patients: all of them had low level of INF or ADA respectively, with a range level of Abs for INF between 67-121.849 U/mL and for ADA between 132-717.824 U/mL. Three patients had infusion reaction with INF, all of them with high level of Abs (61, 1.282, 121.849 U/mL). Table 1 showed the characteristics in responders and non-responders patients. Responders (n: 18)Non Responders (n: 8)P INF level, mean (range)20.22±18,06(3.60-73.21)0.16±0,34 (0.04-1.14)<0.001 INF-Abs0%62.5%<0.01 DAS28-ESR2.553.76<0.001 Responders (n: 28)Non Responders (n: 15) ADA-level mean (range)9,49±4.96 (1.56-19.84)2,70±3,41 (0.002-11.28)<0.001 ADA-Abs0%23%0.01 DAS28-ESR2.484.34<0.001 Conclusions 1. Serum antibodies were detected in 16% of patients receiving treatment with INF and 10% of patients with ADA. 2. Patients responders have absence of Abs and significantly higher serum concentrations of anti-TNF than non-responders. 3. Immunogenicity can induce inefficacy in patients on treatment with anti-TNF. Disclosure of Interest J. Rosas Grant/Research support from: Asociaciόn para la Investigaciόn en Re...
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