Arthritis & rheumatology (Hoboken, N.J.), Jan 16, 2015
Determine the efficacy and safety of VX-509, an oral, selective Janus kinase 3 (JAK3) inhibitor i... more Determine the efficacy and safety of VX-509, an oral, selective Janus kinase 3 (JAK3) inhibitor in patients with rheumatoid arthritis (RA) who had an inadequate response to methotrexate therapy. In this 24-week, double-blind, phase 2b study, 358 patients with active RA were randomized and received at least 1 dose of VX-509 100 mg once daily (mg/d; n=71), 150 mg/d (n=72), 200 mg/d (n=72), 100 mg twice daily (n=72), or placebo (n=71). Primary efficacy assessments were the percentage of patients achieving 20% improvement in American College of Rheumatology criteria (ACR20) and change from baseline in Disease Activity Score for 28 joints using C-reactive protein (DAS28-CRP) at week 12. At week 12, the ACR20 response rates for VX-509 were 46.5% (100 mg/d), 66.7% (150 mg/d), 56.9% (200 mg/d), and 68.1% (100 mg twice daily) versus 18.3% for placebo (P < 0.001, all comparisons). Change from baseline in DAS28-CRP at week 12 was significantly greater in each VX-509 group versus placebo (P ...
International journal of clinical and experimental pathology
Confocal immunofluorescence is a valuable technique for the detection of relevant molecules in th... more Confocal immunofluorescence is a valuable technique for the detection of relevant molecules in the pathogenesis of arthritis in rat models; however, it requires efficient processing of tissues including bone decalcification. The decalcification process must ensure the complete removal of calcium and also a proper preservation of cellular structures and, specially, the antigenicity of the tissue to allow the immunodetection of the molecules of interest. In the present study, we evaluated the effect of four different decalcifying solutions: the Morse´s solution, 10% EDTA (pH 7.4), 7% HCl/2% EDTA and 5% Nitric acid, as well as four different treatments of the tissues (including microwave irradiation) in the processes of decalcification for large pieces of adult rat bones (hind paw, fore paw, knee and column). We assessed the time of decalcification, the easiness of slicing, the morphological preservation and finally, the antigenicity of two different bone proteins (Osteopontin (OPN) an...
Using humoral immune responses, Klebsiella pneumoniae has been implicated as a candidate microbia... more Using humoral immune responses, Klebsiella pneumoniae has been implicated as a candidate microbial trigger in ankylosing spondylitis (AS) by several investigators but refuted by others. The objective of this case-control study was to compare the cellular (T-cell proliferation) and humoral (IgG and IgA, by ELISA) immune responses of affected individuals in multiplex AS families with those of unaffected family members and normal healthy controls in order to find out whether affected individuals exhibit a predominant immune response to K. pneumoniae. Twenty-five families with two or more individuals affected with AS and 34 normal healthy controls matched with the affected family members for age, sex and ethnicity were enrolled in the study. All affected (n = 57) and unaffected (n = 37) family members had a detailed clinical evaluation. Peripheral blood was drawn to determine T-lymphocyte proliferation and the IgG and IgA (by ELISA analysis) immune responses to K. pneumoniae, Salmonella...
To evaluate the role of tumor necrosis factor-alpha (TNF-alpha) gene as susceptibility marker for... more To evaluate the role of tumor necrosis factor-alpha (TNF-alpha) gene as susceptibility marker for spondyloarthritis (SpA), two polymorphisms (-238 and -308 positions) were analyzed in 229 patients with SpA (113 with ankylosing spondylitis [AS], 92 with undifferentiated SpA [U-SpA], 24 with reactive arthritis), and 169 ethnically matched healthy control subjects. The HLA-B alleles were detected by PCR-SSP technique and the TNF-alpha polymorphism by PCR-RFLP. In comparison with healthy control subjects, the frequencies of TNF-238 in SpA were similar. In contrast, the analysis of -308 polymorphism showed increased frequencies of the T2(A) allele in the whole SpA group (p < 0.05, pC = NS, OR = 1.83) as well as the T2(A) allele (pC < 0.05, OR = 2.4) and T1T2(AG) genotype (p < 0.05, pC = NS, OR = 2.25) in U-SpA patients. Comparison of B27-negative patients and healthy control subjects yielded similar results. There was no significant correlation between TNF genotypes and clinical...
ABSTRACT Background The Abatacept (ABA) Comparison of Sub[QU]cutaneous (SC) versus Intravenous (I... more ABSTRACT Background The Abatacept (ABA) Comparison of Sub[QU]cutaneous (SC) versus Intravenous (IV) in Inadequate Responders to MethotrexatE (MTX) (ACQUIRE) study showed comparable efficacy and safety of SC vs IV ABA over 6 mths.1 Objectives To present 32-mth safety and efficacy data from the long-term extension (LTE) of ACQUIRE, during which all patients (pts) received SC ABA. Methods ACQUIRE was a Phase IIIb, 6-mth, double-blind (DB) study in which pts with active RA (³10 swollen and ³12 tender joint count [SJC and TJC], C-reactive protein (CRP) ≥0.8 mg/dL) refractory to MTX received IV or SC ABA, plus MTX, followed by an open-label LTE when pts received SC ABA 125 mg/wk. Not all pts had reached later time points at time of analysis, as a result of differential enrolment in the trial. Results Of 1372 pts entering the LTE, 1134 (82.7%) remained on therapy at time of reporting. Mean baseline RA duration was 8 yrs, TJC and SJC were 30 and 20, respectively, and HAQ-DI was 1.7. Median (range) ABA exposure was 33 (8–44) mths. The incidence rate (IR; events/100 pt-yrs) of serious adverse events for pts treated with SC ABA in the LTE (8.76 [95% CI: 7.71–9.95]) was comparable with that for SC ABA in the DB period (9.02 [6.31–12.90]) and did not increase with increasing exposure. The IR of overall and serious infections in the LTE (44.80 [41.81–48.01] and 1.72 [1.30–2.27], respectively) did not increase vs the DB period (84.62 [74.50–96.11] and 1.48 [0.62–3.56], respectively). Bacterial, viral and hospitalised infections occurred at IRs of 27.28 (25.16–29.57), 18.25 (16.61–20.06) and 1.55 (1.16–2.07) during the LTE. The IR of malignancy did not increase in the LTE (1.19 [0.86–1.66]) vs the DB period (0.59 [0.15–2.36]). Injection-site reactions occurred in 27 (2.0%) pts in the LTE (none serious) and 19 (2.6%) pts in the DB period. Overall, 139/1365 (10.2%) and 1/153 (0.7%) pts experienced immunogenicity during the LTE and DB periods, respectively. ACR responses were maintained and comparable with original SC and IV groups: at Day 169, ACR 20 response rates were 80.2% (95% CI: 77.2, 83.2) and 80.0% (77.0, 83.0) and at Day 981 were 84.8% (80.8, 88.8) and 84.7% (80.7, 88.8). DAS28 (CRP) &lt;2.6 rates (95% CI) were 24% (21–27; n=685) and 25% (22–28; n=667) at Day 169, and 39% (33–44; n=288) and 35% (29–40; n=275) at Day 981 for the original SC and IV groups, respectively. HAQ-DI responses (change from baseline ≥0.3) were 73% (95% CI: 69–76; n=691) and 68% (65–72; n=672) at Day 169, and 74% (69–79; n=313) and 70% (65–75; n=303) at Day 981 for the original SC and IV groups, respectively. Conclusions Over 32 mths, SC abatacept showed consistent safety with high patient retention. ACR, HAQ-DI response and DAS28 remission rates were maintained through the LTE. References Disclosure of Interest R. Alten Grant/research support from: BMS, Merck Pharma GmbH, Wyeth Pharmaceuticals, Pfizer, Consultant for: Abbott Laboratories, Horizon Pharma, Merck Pharma GmbH, Nitec Pharma GmbH, Novartis Pharmaceuticals Corporation, Roche, Speakers bureau: Abbott Laboratories, BMS, Horizon Pharma, Merck Pharma GmbH, Novartis Pharmaceuticals Corporation, Roche, C. Pacheco-Tena: None Declared, A. Covarrubias Shareholder of: UNIDAD REUMATOLOGICA LAS AMERICAS SCP, Grant/research support from: BMS, Pfizer, Lilly ICOS, G. Leon: None Declared, E. Mysler Grant/research support from: BMS, Consultant for: BMS, Speakers bureau: BMS, M. Keiserman Grant/research support from: Abbott Laboratories, Biogen Idec, Bristol-Myers Squibb, Eli Lilly and Company, Human Genome Sciences, Inc., MSD, Pfizer Inc, Roche, UCB, Inc, Novartis, Consultant for: Abbott Laboratories, Bristol-Myers Squibb, MSD, Speakers bureau: Bristol-Myers Squibb, MSD, R. Valente Grant/research support from: Pfizer, UCB, BMS, Roche, Takeda, Lilly, P. Nash Grant/research support from: BMS, Consultant for: BMS, Speakers bureau: BMS, J. Simon-Campos: None Declared, J. Box Shareholder of: Box Arthritis and Rheumatology of the Carolinas PLLC, Consultant for: BMS, Speakers bureau: BMS, C. Legerton III Consultant for: BMS, E. Nasonov Speakers bureau: Roche; Bristol-Myers Squibb Company; Abbott Laboratories; Merck Sharp &amp; Dohme Corp; UCB Pharma, Inc, P. Durez Speakers bureau: BMS, I. Delaet Shareholder of: BMS, Employee of: BMS, M. Genovese Consultant for: Bristol-Myers Squibb
Patients with juvenile-onset spondyloarthritis (SpA) may develop ankylosis of the midfoot resembl... more Patients with juvenile-onset spondyloarthritis (SpA) may develop ankylosis of the midfoot resembling the spinal changes seen in patients with ankylosing spondylitis (AS). The study of the histopathology of the feet of patients with tarsitis could help us understand the pathogenesis of bone formation in affected structures in the SpA. The objective of our study was to describe the histopathologic characteristics of the midfoot in patients with tarsitis associated with SpA. We obtained synovial sheaths, entheses, and bone samples from 20 patients with SpA with midfoot pain/tenderness and swelling. Tissue samples underwent H&E staining; immunohistochemistry for CD3, CD4, CD8, CD68, and CD20 cell identification; and immunofluorescence for bone lineage proteins, including osteocalcin, osteopontin, parathyroid hormone-related protein, bone sialoprotein, and alkaline phosphatase. Slight edema and hyalinization were found in some tendon sheaths, and few inflammatory cells were detected in t...
RESUMEN Las recomendaciones para el tratamiento médico de la artritis reumatoide (AR) con fármaco... more RESUMEN Las recomendaciones para el tratamiento médico de la artritis reumatoide (AR) con fármacos antirreumáticos modificadores de la enfermedad (FARME), tanto convencionales como biológicos, deben basarse en la seguridad, efectos adversos, ...
Arthritis & rheumatology (Hoboken, N.J.), Jan 16, 2015
Determine the efficacy and safety of VX-509, an oral, selective Janus kinase 3 (JAK3) inhibitor i... more Determine the efficacy and safety of VX-509, an oral, selective Janus kinase 3 (JAK3) inhibitor in patients with rheumatoid arthritis (RA) who had an inadequate response to methotrexate therapy. In this 24-week, double-blind, phase 2b study, 358 patients with active RA were randomized and received at least 1 dose of VX-509 100 mg once daily (mg/d; n=71), 150 mg/d (n=72), 200 mg/d (n=72), 100 mg twice daily (n=72), or placebo (n=71). Primary efficacy assessments were the percentage of patients achieving 20% improvement in American College of Rheumatology criteria (ACR20) and change from baseline in Disease Activity Score for 28 joints using C-reactive protein (DAS28-CRP) at week 12. At week 12, the ACR20 response rates for VX-509 were 46.5% (100 mg/d), 66.7% (150 mg/d), 56.9% (200 mg/d), and 68.1% (100 mg twice daily) versus 18.3% for placebo (P < 0.001, all comparisons). Change from baseline in DAS28-CRP at week 12 was significantly greater in each VX-509 group versus placebo (P ...
International journal of clinical and experimental pathology
Confocal immunofluorescence is a valuable technique for the detection of relevant molecules in th... more Confocal immunofluorescence is a valuable technique for the detection of relevant molecules in the pathogenesis of arthritis in rat models; however, it requires efficient processing of tissues including bone decalcification. The decalcification process must ensure the complete removal of calcium and also a proper preservation of cellular structures and, specially, the antigenicity of the tissue to allow the immunodetection of the molecules of interest. In the present study, we evaluated the effect of four different decalcifying solutions: the Morse´s solution, 10% EDTA (pH 7.4), 7% HCl/2% EDTA and 5% Nitric acid, as well as four different treatments of the tissues (including microwave irradiation) in the processes of decalcification for large pieces of adult rat bones (hind paw, fore paw, knee and column). We assessed the time of decalcification, the easiness of slicing, the morphological preservation and finally, the antigenicity of two different bone proteins (Osteopontin (OPN) an...
Using humoral immune responses, Klebsiella pneumoniae has been implicated as a candidate microbia... more Using humoral immune responses, Klebsiella pneumoniae has been implicated as a candidate microbial trigger in ankylosing spondylitis (AS) by several investigators but refuted by others. The objective of this case-control study was to compare the cellular (T-cell proliferation) and humoral (IgG and IgA, by ELISA) immune responses of affected individuals in multiplex AS families with those of unaffected family members and normal healthy controls in order to find out whether affected individuals exhibit a predominant immune response to K. pneumoniae. Twenty-five families with two or more individuals affected with AS and 34 normal healthy controls matched with the affected family members for age, sex and ethnicity were enrolled in the study. All affected (n = 57) and unaffected (n = 37) family members had a detailed clinical evaluation. Peripheral blood was drawn to determine T-lymphocyte proliferation and the IgG and IgA (by ELISA analysis) immune responses to K. pneumoniae, Salmonella...
To evaluate the role of tumor necrosis factor-alpha (TNF-alpha) gene as susceptibility marker for... more To evaluate the role of tumor necrosis factor-alpha (TNF-alpha) gene as susceptibility marker for spondyloarthritis (SpA), two polymorphisms (-238 and -308 positions) were analyzed in 229 patients with SpA (113 with ankylosing spondylitis [AS], 92 with undifferentiated SpA [U-SpA], 24 with reactive arthritis), and 169 ethnically matched healthy control subjects. The HLA-B alleles were detected by PCR-SSP technique and the TNF-alpha polymorphism by PCR-RFLP. In comparison with healthy control subjects, the frequencies of TNF-238 in SpA were similar. In contrast, the analysis of -308 polymorphism showed increased frequencies of the T2(A) allele in the whole SpA group (p < 0.05, pC = NS, OR = 1.83) as well as the T2(A) allele (pC < 0.05, OR = 2.4) and T1T2(AG) genotype (p < 0.05, pC = NS, OR = 2.25) in U-SpA patients. Comparison of B27-negative patients and healthy control subjects yielded similar results. There was no significant correlation between TNF genotypes and clinical...
ABSTRACT Background The Abatacept (ABA) Comparison of Sub[QU]cutaneous (SC) versus Intravenous (I... more ABSTRACT Background The Abatacept (ABA) Comparison of Sub[QU]cutaneous (SC) versus Intravenous (IV) in Inadequate Responders to MethotrexatE (MTX) (ACQUIRE) study showed comparable efficacy and safety of SC vs IV ABA over 6 mths.1 Objectives To present 32-mth safety and efficacy data from the long-term extension (LTE) of ACQUIRE, during which all patients (pts) received SC ABA. Methods ACQUIRE was a Phase IIIb, 6-mth, double-blind (DB) study in which pts with active RA (³10 swollen and ³12 tender joint count [SJC and TJC], C-reactive protein (CRP) ≥0.8 mg/dL) refractory to MTX received IV or SC ABA, plus MTX, followed by an open-label LTE when pts received SC ABA 125 mg/wk. Not all pts had reached later time points at time of analysis, as a result of differential enrolment in the trial. Results Of 1372 pts entering the LTE, 1134 (82.7%) remained on therapy at time of reporting. Mean baseline RA duration was 8 yrs, TJC and SJC were 30 and 20, respectively, and HAQ-DI was 1.7. Median (range) ABA exposure was 33 (8–44) mths. The incidence rate (IR; events/100 pt-yrs) of serious adverse events for pts treated with SC ABA in the LTE (8.76 [95% CI: 7.71–9.95]) was comparable with that for SC ABA in the DB period (9.02 [6.31–12.90]) and did not increase with increasing exposure. The IR of overall and serious infections in the LTE (44.80 [41.81–48.01] and 1.72 [1.30–2.27], respectively) did not increase vs the DB period (84.62 [74.50–96.11] and 1.48 [0.62–3.56], respectively). Bacterial, viral and hospitalised infections occurred at IRs of 27.28 (25.16–29.57), 18.25 (16.61–20.06) and 1.55 (1.16–2.07) during the LTE. The IR of malignancy did not increase in the LTE (1.19 [0.86–1.66]) vs the DB period (0.59 [0.15–2.36]). Injection-site reactions occurred in 27 (2.0%) pts in the LTE (none serious) and 19 (2.6%) pts in the DB period. Overall, 139/1365 (10.2%) and 1/153 (0.7%) pts experienced immunogenicity during the LTE and DB periods, respectively. ACR responses were maintained and comparable with original SC and IV groups: at Day 169, ACR 20 response rates were 80.2% (95% CI: 77.2, 83.2) and 80.0% (77.0, 83.0) and at Day 981 were 84.8% (80.8, 88.8) and 84.7% (80.7, 88.8). DAS28 (CRP) &lt;2.6 rates (95% CI) were 24% (21–27; n=685) and 25% (22–28; n=667) at Day 169, and 39% (33–44; n=288) and 35% (29–40; n=275) at Day 981 for the original SC and IV groups, respectively. HAQ-DI responses (change from baseline ≥0.3) were 73% (95% CI: 69–76; n=691) and 68% (65–72; n=672) at Day 169, and 74% (69–79; n=313) and 70% (65–75; n=303) at Day 981 for the original SC and IV groups, respectively. Conclusions Over 32 mths, SC abatacept showed consistent safety with high patient retention. ACR, HAQ-DI response and DAS28 remission rates were maintained through the LTE. References Disclosure of Interest R. Alten Grant/research support from: BMS, Merck Pharma GmbH, Wyeth Pharmaceuticals, Pfizer, Consultant for: Abbott Laboratories, Horizon Pharma, Merck Pharma GmbH, Nitec Pharma GmbH, Novartis Pharmaceuticals Corporation, Roche, Speakers bureau: Abbott Laboratories, BMS, Horizon Pharma, Merck Pharma GmbH, Novartis Pharmaceuticals Corporation, Roche, C. Pacheco-Tena: None Declared, A. Covarrubias Shareholder of: UNIDAD REUMATOLOGICA LAS AMERICAS SCP, Grant/research support from: BMS, Pfizer, Lilly ICOS, G. Leon: None Declared, E. Mysler Grant/research support from: BMS, Consultant for: BMS, Speakers bureau: BMS, M. Keiserman Grant/research support from: Abbott Laboratories, Biogen Idec, Bristol-Myers Squibb, Eli Lilly and Company, Human Genome Sciences, Inc., MSD, Pfizer Inc, Roche, UCB, Inc, Novartis, Consultant for: Abbott Laboratories, Bristol-Myers Squibb, MSD, Speakers bureau: Bristol-Myers Squibb, MSD, R. Valente Grant/research support from: Pfizer, UCB, BMS, Roche, Takeda, Lilly, P. Nash Grant/research support from: BMS, Consultant for: BMS, Speakers bureau: BMS, J. Simon-Campos: None Declared, J. Box Shareholder of: Box Arthritis and Rheumatology of the Carolinas PLLC, Consultant for: BMS, Speakers bureau: BMS, C. Legerton III Consultant for: BMS, E. Nasonov Speakers bureau: Roche; Bristol-Myers Squibb Company; Abbott Laboratories; Merck Sharp &amp; Dohme Corp; UCB Pharma, Inc, P. Durez Speakers bureau: BMS, I. Delaet Shareholder of: BMS, Employee of: BMS, M. Genovese Consultant for: Bristol-Myers Squibb
Patients with juvenile-onset spondyloarthritis (SpA) may develop ankylosis of the midfoot resembl... more Patients with juvenile-onset spondyloarthritis (SpA) may develop ankylosis of the midfoot resembling the spinal changes seen in patients with ankylosing spondylitis (AS). The study of the histopathology of the feet of patients with tarsitis could help us understand the pathogenesis of bone formation in affected structures in the SpA. The objective of our study was to describe the histopathologic characteristics of the midfoot in patients with tarsitis associated with SpA. We obtained synovial sheaths, entheses, and bone samples from 20 patients with SpA with midfoot pain/tenderness and swelling. Tissue samples underwent H&E staining; immunohistochemistry for CD3, CD4, CD8, CD68, and CD20 cell identification; and immunofluorescence for bone lineage proteins, including osteocalcin, osteopontin, parathyroid hormone-related protein, bone sialoprotein, and alkaline phosphatase. Slight edema and hyalinization were found in some tendon sheaths, and few inflammatory cells were detected in t...
RESUMEN Las recomendaciones para el tratamiento médico de la artritis reumatoide (AR) con fármaco... more RESUMEN Las recomendaciones para el tratamiento médico de la artritis reumatoide (AR) con fármacos antirreumáticos modificadores de la enfermedad (FARME), tanto convencionales como biológicos, deben basarse en la seguridad, efectos adversos, ...
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Papers by Cesar Pacheco-tena