Efficacy and safety of switching from rituximab to biosimilar CT-P10 in rheumatoid arthritis: 72-week data from a randomized Phase 3 trial.

OBJECTIVE: To evaluate the efficacy and safety of CT-P10, a rituximab biosimilar after a single switch, during a multinational, randomized, double-blind Phase 3 trial involving patients with RA. METHODS: Patients received 48 weeks' treatment with CT-P10 or United States- or European Union-sourced reference rituximab (US-RTX and EU-RTX, respectively). Patients entering the extension period (weeks 48-72) remained on CT-P10 (CT-P10/CT-P10; n = 122) or US-RTX (US-RTX/US-RTX; n = 64), or switched to CT-P10 from US-RTX (US-RTX/CT-P10; n = 62) or EU-RTX (EU-RTX/CT-P10; n = 47) for an additional course. Efficacy endpoints included Disease Activity Score using 28 joints (DAS28), American College of Rheumatology (ACR) response rates, and quality of life-related parameters. Pharmacodynamics, immunogenicity and safety were also assessed. RESULTS: At week 72, similar improvements were observed by disease activity parameters including DAS28 and ACR response rate in the four extension period treatment groups. Quality of life improvements at week 72 vs baseline were similarly shown during the extension period in all groups. Newly developed anti-drug antibodies were detected in two patients following study drug infusion in the extension period. Similar pharmacodynamic and safety profiles were observed across groups. CONCLUSION: Long-term use of CT-P10 up to 72 weeks was effective and well tolerated. Furthermore, switching from reference rituximab to CT-P10 in RA was well tolerated and did not result in any clinically meaningful differences in terms of efficacy, pharmacodynamics, immunogenicity and safety. TRAIL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, NCT02149121.

Long-Term Efficacy and Safety of Biosimilar CT-P10 Versus Innovator Rituximab in Rheumatoid Arthritis: 48-Week Results from a Randomized Phase III Trial.

OBJECTIVE: The aim of this study was to investigate long-term clinical outcomes of extended treatment with CT-P10, a rituximab biosimilar, compared with rituximab reference products sourced from the USA and the EU (US-RTX and EU-RTX) in rheumatoid arthritis (RA) for up to 48 weeks. METHODS: In this multinational, randomized, double-blind trial, adults with active RA received up to two courses of CT-P10, US-RTX, or EU-RTX alongside methotrexate. Efficacy endpoints included Disease Activity Score 28-joint count (DAS28) and American College of Rheumatology (ACR) response rates. Pharmacokinetics, pharmacodynamics, immunogenicity, and safety were also assessed. RESULTS: Of 372 patients randomized to the study drug, 330 (88.7%) completed the second treatment course. Mean change from baseline to week 48 in DAS28-C-reactive protein was comparable in the CT-P10 and combined rituximab (US-RTX and EU-RTX) groups (- 2.7 and - 2.6, respectively). ACR20, ACR50, and ACR70 response rates at week 48 indicated no differences between groups (80.6%, 55.4%, and 31.7% vs. 79.8%, 53.9%, and 33.7% in the CT-P10 and combined rituximab groups, respectively). Similar improvements in the Health Assessment Questionnaire Disability Index and all medical outcomes in the Short Form 36-Item Health Survey, including physical and mental health, were seen in all groups. At week 48, antidrug antibodies were detected in 4.9%, 9.4%, and 8.6% of patients in the CT-P10, US-RTX, and EU-RTX groups, respectively. CT-P10 and rituximab displayed similar pharmacokinetic, pharmacodynamic, and safety profiles. CONCLUSION: CT-P10 was similar to EU-RTX and US-RTX in terms of efficacy, pharmacokinetics, pharmacodynamics, immunogenicity, and safety up to week 48. CLINICALTRIALS. GOV IDENTIFIER: NCT02149121.

Comparison of biosimilar CT-P10 and innovator rituximab in patients with rheumatoid arthritis: a randomized controlled Phase 3 trial.

This multinational, randomized, double-blind trial, (ClinicalTrials.gov identifier NCT02149121) was designed to demonstrate equivalence in pharmacokinetics and efficacy between CT-P10 and innovator rituximab (RTX) in patients with rheumatoid arthritis (RA). Adults with active RA were treated with CT-P10, United States-sourced RTX (US-RTX; Rituxan®), or European Union-sourced RTX (EU-RTX; MabThera®) at weeks 0 and 2. The co-primary pharmacokinetic endpoints were area under the serum concentration-time curve (AUC) from time zero to last measurable concentration (AUC0-last), AUC from time zero to infinity (AUC0-∞), and maximum concentration (Cmax) after two infusions. The primary efficacy endpoint was change from baseline to week 24 in Disease Activity Score using 28 joints-C-reactive protein (DAS28-CRP). Pharmacodynamics, immunogenicity, and safety were also assessed. 372 patients were randomly assigned to CT-P10 (n = 161) or RTX (n = 211 [US-RTX, n = 151; EU-RTX, n = 60]). For the co-primary pharmacokinetic endpoints, 90% confidence intervals (CI) for ratios of geometric means (CT-P10/US-RTX, CT-P10/EU-RTX or EU-RTX/US-RTX) all fell within the equivalence margin of 80-125%. Adjusted least squares (LS) mean (standard error) change from baseline in DAS28-CRP at week 24 was -2.13 (0.175) for CT-P10 and -2.09 (0.176) for RTX. The 95% CI (-0.29, 0.21) of the estimated treatment difference between CT-P10 and RTX (-0.04) was entirely within the efficacy equivalence margin of ±0.5. Pharmacodynamics, immunogenicity, and safety profiles were similar for CT-P10 and RTX. The pharmacokinetics of CT-P10, US-RTX, and EU-RTX were equivalent. CT-P10 and RTX were also equivalent in terms of efficacy and displayed similar pharmacodynamic, immunogenicity, and safety profiles up to week 24.

Efficacy, Safety and Pharmacokinetics of Up to Two Courses of the Rituximab Biosimilar CT-P10 Versus Innovator Rituximab in Patients with Rheumatoid Arthritis: Results up to Week 72 of a Phase I Randomized Controlled Trial.

BACKGROUND: CT-P10 is a biosimilar of innovator rituximab (RTX), a biological therapy used to treat patients with rheumatoid arthritis (RA) who have responded inadequately to anti-tumor necrosis factor agents. OBJECTIVE: Our objective was to compare the clinical profile of CT-P10 versus RTX in patients with RA who received up to two courses of treatment and were followed for up to 72 weeks. METHODS: In this multicenter double-blind phase I study, patients were randomized 2:1 to receive CT-P10 1000 mg or RTX 1000 mg at weeks 0 and 2. Based on disease activity, patients could receive a second course of treatment between weeks 24 and 48. Efficacy endpoints, including mean change from baseline in Disease Activity Score using 28 joints (DAS28), safety, immunogenicity, pharmacokinetics, and pharmacodynamics were evaluated. RESULTS: In total, 154 patients were randomized to CT-P10 or RTX (n = 103 and 51, respectively); 137 (n = 92 and 45) completed the first course of treatment, of whom 83 (n = 60 and 23) were re-treated. Improvements from baseline in all efficacy endpoints were highly similar between the CT-P10 and RTX groups over both treatment courses. At week 24 after the second course, mean change from week 0 of the first course in DAS28 erythrocyte sedimentation rate was -2.47 and -2.04 for CT-P10 and RTX, respectively, (p = 0.1866) and in DAS28 C-reactive protein was -2.32 and -2.00, respectively (p = 0.3268). The proportion of patients positive for antidrug antibodies at week 24 after the second treatment course was 20.0% and 21.7% in the CT-P10 and RTX groups, respectively. The safety profile of CT-P10 was comparable to that of RTX, and pharmacokinetic and pharmacodynamic properties were similar. CONCLUSIONS: In patients with RA, efficacy, safety, and other clinical data were comparable between CT-P10 and RTX after up to two courses of treatment over 72 weeks. (ClinicalTrials.gov identifier NCT01534884).

Efficacy and Safety of Switching from Innovator Rituximab to Biosimilar CT-P10 Compared with Continued Treatment with CT-P10: Results of a 56-Week Open-Label Study in Patients with Rheumatoid Arthritis.

BACKGROUND: CT-P10 is a biosimilar candidate of innovator rituximab (RTX) that demonstrated a comparable clinical profile to RTX in a phase I randomized controlled trial (RCT) in rheumatoid arthritis (RA) (ClinicalTrials.gov identifier: NCT01534884). OBJECTIVE: This open-label extension (OLE) study (NCT01873443) compared the efficacy and safety of CT-P10 in patients with RA who received CT-P10 from the outset (i.e., from the start of the RCT and also in the OLE; 'maintenance group') with those who received RTX during the RCT and switched to CT-P10 during the OLE ('switch group'). METHODS: Patients who completed the RCT were recruited. Based on the Disease Activity Score using 28 joints (DAS28) and predefined safety criteria, patients could receive up to two courses of CT-P10 during the OLE. Efficacy [DAS28 and European League Against Rheumatism (EULAR) response], safety and immunogenicity were assessed. RESULTS: Eighty-seven patients were enrolled; 58 and 29 had previously received CT-P10 or RTX, respectively, in the RCT. Of these, 38 (65.5%) and 20 (69.0%) were treated with CT-P10 in the OLE and therefore comprised the maintenance and switch groups, respectively. The mean change in DAS28-erythrocyte sedimentation rate (ESR) from baseline (week 0 of RCT) at week 24 of the first OLE treatment course in the maintenance and switch groups was -2.7 and -2.4, respectively. The proportion of patients with good/moderate EULAR responses was also comparable between groups. Antidrug antibodies were detected in 13.2 and 15.0% of patients in the maintenance and switch groups, respectively, at week 24 of the first OLE course. CT-P10 treatment was well-tolerated when administered for up to 2 years or after switching from RTX. CONCLUSION: In this study population, comparable efficacy and safety profiles were observed in patients who switched from RTX to CT-P10 and those maintained on CT-P10 throughout treatment.

A multicentre randomised controlled trial to compare the pharmacokinetics, efficacy and safety of CT-P10 and innovator rituximab in patients with rheumatoid arthritis.

OBJECTIVE: To demonstrate pharmacokinetic equivalence of CT-P10 and innovator rituximab (RTX) in patients with rheumatoid arthritis (RA) with inadequate responses or intolerances to antitumour necrosis factor agents. METHODS: In this randomised phase I trial, patients with active RA were randomly assigned (2:1) to receive 1000 mg CT-P10 or RTX at weeks 0 and 2 (alongside continued methotrexate therapy). Primary endpoints were area under the serum concentration-time curve from time zero to last quantifiable concentration (AUC0-last) and maximum serum concentration after second infusion (Cmax). Additional pharmacokinetic parameters, efficacy, pharmacodynamics, immunogenicity and safety were also assessed. Data are reported up to week 24. RESULTS: 103 patients were assigned to CT-P10 and 51 to RTX. The 90% CIs for the ratio of geometric means (CT-P10/RTX) for both primary endpoints were within the bioequivalence range of 80%-125% (AUC0-last: 97.7% (90% CI 89.2% to 107.0%); Cmax: 97.6% (90% CI 92.0% to 103.5%)). Pharmacodynamics and efficacy were comparable between groups. Antidrug antibodies were detected in 17.6% of patients in each group at week 24. CT-P10 and RTX displayed similar safety profiles. CONCLUSIONS: CT-P10 and RTX demonstrated equivalent pharmacokinetics and comparable efficacy, pharmacodynamics, immunogenicity and safety. TRIAL REGISTRATION NUMBER: NCT01534884.

Precisiones sobre la historia de la quina / No disponible

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Terapia biológica e infecciones / Biologic therapy and infections

La terapia biológica es una adición importante en el arsenal terapeútico de las enfermedades reumáticas. Los fármacos anti-TNF afectan las defensas contra infecciones, ya que el TNF modula inflamación e inmunidad celular. Se han observado casos de tuberculosis en pacientes tratados con anti-TNF, principalmente por la presencia de infección tuberculosa latente o “dormida” (LTB1). Otros microorganismos asociados a infecciones con terapia biológica son patógenos intracelulares que pueden evadir el sistema inmune y condicionar estado de latencia, persistiendo por grandes períodos sin causar daño: Mycobacterium sp., Listeria monocytogenes, Legionella sp., Brucella sp., toxoplasmosis y micosis profundas. El diagnóstico puede requerir elevado índice de sospecha clínica y obtener muestras y/o tejidos para análisis microscópico y cultivos. Los pacientes que desarrollan infecciones al estar en terapia biológica deben ser moniterados estrechamente. La administración de anti-TNF debe descontinuarse si en presencia de infección severa o sepsis. La relación entre inhibición de TNF y riesgo de infección debe esclarecerse mejor, ya que muchas de las infecciones severas se han observado en pacientes con terapia inmunosuporesora concomitante, que adicionado a enfermedades reumatológicas agresivas puede predisponer a infecciones, y la mayoría de los reportes publicados tienen un bajo nivel de evidencia. Sin embargo, un diagnóstico temprano y tratamiento oportuno es necesario para prevenir mortalidad secundaria a infecciones(AU)

Biologic therapy is an important therapeutic arsenal in rheumatic diseases. Anti-TNF therapies affect host defenses against infections, since TNF mediates inflammation and modulates cellular immune responses. Cases of tuberculosis have been observed in patients treated with TNF antagonists, mainly due to the presence of latent or “dormant” tuberculosis infection (LTB1). Other microorganisms responsible for the infectious complications associated with biologic therapy are generally intracellular pathogens or pathogens that commonly exist in a chronic latent state: Mycobacterium sp., Listeria monocytogenes, Legionella sp., Brucella sp., toxoplasmosis and deep mycoses, that are normally held in control by cell-mediated immunity. Diagnosis may require a high index of suspicion and prompt acquisition of appropriate tissue samples for microscopic examination and microbiologic culture. Patients who develop a new infection while undergoing treatment with biologic therapy should be monitored closely. Administration of anti-TNF should be discontinued if a patient develops a serious infection or sepsis. The relationship between TNF-inhibition and infection risk remains unclear, many of the serious infections have occurred in patients on concomitant immunosuppressive therapy that, in addition to severe rheumatic diseases, could predispose them to infections, and most reports present low level of evidence. Nevertheless, prompt diagnosis and empiric therapy infections is necessary to prevent mortality(AU)

[Biologic therapy and infections]. / Terapia biológica e infecciones.

Biologic therapy is an important therapeutic arsenal in rheumatic diseases. Anti-TNF therapies affect host defenses against infections, since TNF mediates inflammation and modulates cellular immune responses. Cases of tuberculosis have been observed in patients treated with TNF antagonists, mainly due to the presence of latent or "dormant" tuberculosis infection (LTB1). Other microorganisms responsible for the infectious complications associated with biologic therapy are generally intracellular pathogens or pathogens that commonly exist in a chronic latent state: Mycobacterium sp., Listeria monocytogenes, Legionella sp., Brucella sp., toxoplasmosis and deep mycoses, that are normally held in control by cell-mediated immunity. Diagnosis may require a high index of suspicion and prompt acquisition of appropriate tissue samples for microscopic examination and microbiologic culture. Patients who develop a new infection while undergoing treatment with biologic therapy should be monitored closely. Administration of anti-TNF should be discontinued if a patient develops a serious infection or sepsis. The relationship between TNF-inhibition and infection risk remains unclear, many of the serious infections have occurred in patients on concomitant immunosuppressive therapy that, in addition to severe rheumatic diseases, could predispose them to infections, and most reports present low level of evidence. Nevertheless, prompt diagnosis and empiric therapy infections is necessary to prevent mortality.

Rheumatic manifestations of human immunodeficiency virus infection.

Rheumatic complaints are common in patients with human immunodeficiency virus (HIV) infection. With the advent of the modern combined antiretroviral treatment, life-long control of HIV infection and normalization of life expectancy in HIV-positive patients have become realistic perspectives, but new rheumatic complications, such as osteoporosis, osteonecrosis, gout, and mycobacterial and mycotic osteoarticular infections may be more prevalent. Rheumatologists, internists, and general physicians need to be familiar with the presentation and treatment of these conditions in HIV-positive patients.

Artritis séptica: reporte de 65 casos / Septic arthritis: report of 65 cases

Se estudiaron 65 casos de adultos vistos en el Hospital de Especialidades del Centro Médico La Raza. En el 93 por ciento los factores predisponentes fueron metabólicos, neoplásicos y reumatológicos. El cuadro clínico fue con fiebre, inflamación y dolor. El inicio fue monoarticular en 60 casos y la localización más frecuente fue la rodilla (39 casos); en 5 pacientes la presentación fue poliarticular. La aceleración de la velocidad de sedimentación globular y la leucocitosis fueron los datos de laboratorio más comunes. La tinción de Gram tiene gran utilidad para el diagnóstico presuncional y fue positiva en 43 (69 por ciento) de los casos. El líquido sinovial mostró leucocitosis con predominio de polimorfonucleares. Los gérmenes aislados fueron: Staphylococcus aureus (33 por ciento), Salmonella enteritidis (15 por ciento), Eschirichia coli (10 por ciento), Pseudomona aeruginosa (7 por ciento), Klebsiella pneumoniae (7 por ciento), Streptococcus pneumoniae (5 por ciento). La artritis por Gram negativos fue más frecuente que la artritis séptica por Gram positivos y se presentó en pacientes inmunocomprometidos. Conclusiones: El tratamiento de antibiotecoterapia con punciones evacuadoras cotidianas fue tan efectivo con el tratamiento quirúrgico. Nueve de los 10 casos de artritis por Salmonella sp. tenían LES con terapia inumodepresora y requirieron manejo quirúrgico. Las secuelas en 31 pacientes estuvieron relacionadas con el retraso en el diagnóstico y consecuentemente con el inicio del manejo

Impacto del virus de inmunodeficiencia humana sobre manifestaciones reumatológicas en poblaciones de alto riesgo

Las manifestaciones reumáticas de han reportado hasta en el 71 por ciento de los pacientes con infección por VIH, frecuentemente en estadios avanzados. Objetivo. Determinar el impacto en la frecuencia de manifestaciones reumáticas en pacientes con infección por VIH, comparados con controles de poblaciones similares VIH -. Pacientes y métodos. Se estudiaron en forma prospectiva, descriptiva y observacional 128 pacientes VIH+, 103 hombres y 25 mujeres, con edad promedio de 31.5 años (grupo I), comparándose con 130 pacientes con factores de riesgo semejantes, pero con serología negativa para VIH (Grupo II). Resultados. En el grupo I se identificaron alteraciones en 85/128 (66 por ciento); 52 tuvieron artralgias, 42 mialgias, entesitis y bursitis en 29, artritis asimétrica en 9 casos; y con hipersensibilidad, incapacitante y autolimitada en 7 pacientes. En este mismo grupo se encontró síndrome de Reiter en 10 casos (7 por ciento), fibromialgia en 10 (5 por ciento), complejo sicca, osteonecrosis, dermatopolimiositis, artritis séptica y podagra. En el grupo II, 6/130 pacientes (4 por ciento), tuvieron alteraciones menores (fibromialgia y artralgias) (p < 0.0001). Laboratorio. La eritrosedimentación acelerada (Grupo I) en 87/128 (67 por ciento), factor reumatoide 24/128 (18 por ciento), TTP prolongado 39/128 (30 por ciento), VDRL+ falso en 11/128 (8 por ciento), anticuerpos antinucleares en 16/128 (12 por ciento), anticuerpos anticardiolipina IgC 116/128 (86 por ciento), IgM 52/128 (40 por ciento). Se encontró hiperuricemia en 48/128 (37 por ciento) del grupo I y en 2 del grupo II (p < 0.0001), mientras que hipouricemia sólo en 6 pacientes VIH+. Once de dieciséis pacientes con sarcoma de Kaposi y enfermedades linfoproliferativas tuvieron alteraciones en los niveles de urato. Conclusiones. Las manifestaciones reumatológicas son frecuentes en pacientes VIH+, y su presencia puede indicar infección temprana en poblaciones de riesgo. En etapas tardías, la presencia de hiperuricemia puede ser utilizada como marcador y/o predictor de neoplasia