Long-term safety of sarilumab in rheumatoid arthritis: an integrated analysis with up to 7 years' follow-up.

OBJECTIVE: Sarilumab is a human monoclonal antibody that blocks IL-6 from binding to membrane-bound and soluble IL-6 receptor-α. We assessed the long-term safety of sarilumab in patients from eight clinical trials and their open-label extensions. METHODS: Data were pooled from patients with rheumatoid arthritis who received at least one dose of sarilumab in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs; combination group) or as monotherapy (monotherapy group). Treatment-emergent adverse events (AEs) and AEs and laboratory values of special interest were assessed. RESULTS: 2887 patients received sarilumab in combination with csDMARDs and 471 patients received sarilumab monotherapy, with mean exposure of 2.8 years and 1.7 years, maximum exposure 7.3 and 3.5 years, and cumulative AE observation period of 8188 and 812 patient-years, respectively. Incidence rates per 100 patient-years in the combination and monotherapy groups, respectively, were 9.4 and 6.7 for serious AEs, 3.7 and 1.0 for serious infections, 0.6 and 0.5 for herpes zoster (no cases were disseminated), 0.1 and 0 for gastrointestinal perforations, 0.5 and 0.2 for major adverse cardiovascular events, and 0.7 and 0.6 for malignancy. Absolute neutrophil counts <1000 cells/mm3 were recorded in 13% and 15% of patients, respectively. Neutropenia was not associated with increased risk of infection or serious infection. Analysis by 6-month interval showed no signal for increased rate of any AE over time. CONCLUSION: The long-term safety profile of sarilumab, either in combination with csDMARDs or as monotherapy, remained stable and consistent with the anticipated profile of a molecule that inhibits IL6 signalling.

Long-term safety and efficacy of sarilumab plus methotrexate on disease activity, physical function and radiographic progression: 5 years of sarilumab plus methotrexate treatment.

Objective: In MOBILITY (NCT01061736), sarilumab significantly reduced disease activity, improved physical function and inhibited radiographic progression at week 52 versus placebo in patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate. We report 5-year safety, efficacy and radiographic outcomes of sarilumab from NCT01061736 and the open-label extension (EXTEND; NCT01146652), in which patients received sarilumab 200 mg every 2 weeks (q2w) + methotrexate. Methods: Patients (n=1197) with moderately to severely active RA were initially randomised to placebo, sarilumab 150 mg or sarilumab 200 mg subcutaneously q2w plus weekly methotrexate for 52 weeks. Completers were eligible to enrol in the open-label extension and receive sarilumab 200 mg q2w + methotrexate. Results: Overall, 901 patients entered the open-label extension. The safety profile remained stable over 5-year follow-up and consistent with interleukin-6 receptor blockade. Absolute neutrophil count <1000 cells/mm3 was observed but not associated with increased infection rate. Initial treatment with sarilumab 200 mg + methotrexate was associated with reduced radiographic progression over 5 years versus sarilumab 150 mg + methotrexate or placebo + methotrexate (mean±SE change from baseline in van der Heijde-modified Total Sharp Score: 1.46±0.27, 2.35±0.28 and 3.68±0.27, respectively (p<0.001 for each sarilumab dose versus placebo)). Clinical efficacy was sustained through 5 years according to Disease Activity Score (28-joint count) using C reactive protein, Clinical Disease Activity Index (CDAI) and Health Assessment Questionnaire-Disability Index. The number of patients achieving CDAI ≤2.8 at 5 years was similar among initial randomisation groups (placebo, 76/398 (19%); sarilumab 150 mg, 68/400 (17%); sarilumab 200 mg, 84/399 (21%)). Conclusion: Clinical efficacy, including inhibition of radiographic progression, reduction in disease activity and improvement in physical function, was sustained with sarilumab + methotrexate over 5 years. Safety appeared stable over the 5-year period.

Clinical and immunogenetic characterization in psoriatic arthritis patients.

In psoriatic arthritis (PsA), genetic factors play a substantial role in disease susceptibility as well as in its expression. This study aims to determine the distribution of class I and class II HLA antigens in PsA patients and secondly to analyze the influence of genetic factors in the clinical expression of the disease. Consecutive PsA patients (CASPAR criteria) with less than 1 year of disease duration were included. Sociodemographic and clinical data were recorded. Blood samples were obtained, DNA was extracted by polymerase chain reaction (PCR), and class I (A, B, and C) and class II (DR) HLA antigens were determined by oligotyping. A control group of 100 nonrelated healthy controls from the general population served as control. p values were corrected (pc) according to the number of alleles tested. A total of 73 patients were included, 37 were females (50.7 %) with a median disease duration of 72 months (interquartile range (IQR) 24-149). Thirty-three patients (45.2 %) had a family history of psoriasis. When analyzing all the class I and class II HLA antigens, a significantly higher frequency of B38 (odds ratio (OR) 2.95, p = 0.03) and Cw6 (OR 2.78, p = 0.009) was found in PsA patients compared to the control group. On the contrary, the HLA-A11 (OR 0.14, p = 0.04) and B7 (OR 0.31, p = 0.03) were significantly more frequent among healthy controls. Furthermore, B18 was significantly more frequent in patients with early arthritis onset (less than 40 years): seven patients (22.6 %) with early onset compared to two patients (4.8 %) with late onset (p = 0.03). No association between HLA-B27 and spondylitis or HLA-DR4 with polyarticular involvement was observed. The HLA-B38 and Cw6 alleles are associated with a greater PsA susceptibility in Argentine population.

Fatigue assessment and its impact in the quality of life of patients with ankylosing spondylitis.

The most frequently reported symptoms by patients with ankylosing spondylitis (AS) are pain, stiffness, and fatigue. Previous studies have estimated a 63% prevalence of fatigue in AS, with a low correlation of fatigue with pain and functional capacity. The objective of this study is to assess fatigue prevalence in AS patients and establish the main associated factors. A case-control study including AS patients according to New York modified criteria was carried out. The control group included individuals of the general population without rheumatic conditions, matched by gender, age, and socioeconomic level. Disease-related variables were recorded. Functional capacity, disease activity, and quality of life were assessed using Bath Ankylosing Spondylitis Funcional Index (BASFI), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and ankylosing spondylitis quality of life (ASQoL). CES-D questionnaire was used to evaluate depression and fatigue severity scale (FSS) to evaluate fatigue. Sixty-four consecutive AS patients and 95 controls were included. Patients' median age was 44 years (interquartile range (IQR), 33.25-53), 89.1% were male, and had a median disease duration of 17 years (IQR, 10.3-25). Fatigue prevalence in AS was 73.4% compared to 30.5% in the control group (p < 0.001; OR, 2.08 (95% CI, 1.53-2.83)). Furthermore, fatigue in AS correlated with ASQoL (r = 0.65), BASFI (r = 0.52), BASDAI (r = 0.52), and depression (r = 0.51), whereas no correlation with age or disease duration was found. In the linear regression analysis using fatigue as the dependent variable, depression was the only associated variable (p = 0.01). No association with age, gender, disease duration, BASDAI, BASFI, or presence of comorbidities was found. Finally, BASDAI fatigue question correlated with the FSS (r = 0.55). Fatigue was significantly more prevalent in AS than in healthy controls. The main determinant factor of fatigue was the presence of depression, explaining 30% of its variability. Recognizing these factors could have important therapeutic implications.

Prevalence of psoriatic arthritis in psoriasis patients according to newer classification criteria.

The aim of this study is to determine the prevalence of psoriatic arthritis (PsA) according to CASPAR criteria, ASAS peripheral and axial SpA criteria, and New York criteria for AS. The first 100 patients consecutively attending a psoriasis dermatology clinic were assessed. Demographic and clinical data were collected; all patients were questioned and examined for joint manifestations. Rheumatoid factor and radiographies of hands, feet, cervical spine, and pelvis for sacroiliac joints were obtained. X-rays were read independently by two experienced observers in blind fashion. Patients with objective joint manifestations, both axial and peripheral, were evaluated for fulfillment of CASPAR, ASAS peripheral and axial, and New York criteria. Median age 48 years; 93 % of patients had psoriasis vulgaris and 56 % nail involvement. Seventeen patients had peripheral arthritis as follows: nine mono/oligoarticular and eight polyarthritis. Median arthritis duration was 8 years. Seventeen percent of patients fulfilled CASPAR and ASAS peripheral criteria, 6 % New York, and 5 % ASAS axial criteria. Patients who met CASPAR criteria showed a significantly higher psoriasis duration compared to those without arthritis (M 16 vs. 10 years, p = 0.02), and a higher frequency of nail involvement (88.2 vs. 49.4 %, p = 0.003). Five patients (29.4 %) fulfilled ASAS axial criteria; all of them had peripheral involvement as follows: mono/oligoarticular in three patients and polyarticular in two. Patients with peripheral and axial involvement presented a significantly higher frequency of erythrodermic psoriasis compared to the other patients (35.3 vs. 1.2 %, p = 0.0006 and 80 vs. 16.7 %, p = 0.02). Prevalence of PsA, for CASPAR and ASAS peripheral criteria, was of 17 %. Five percent of patients met ASAS axial criteria, while 6 % met New York criteria. Worth noting, few patients without signs or symptoms of arthritis had radiological changes, both axial and peripheral, precluding a proper classification.

Adherence to treatment in patients with ankylosing spondylitis.

This study aims to determine the level of adherence to treatment in ankylosing spondylitis (AS) patients and to identify possible factors associated to lack of adherence. We included consecutive AS patients (NY modified criteria). Sociodemographic and clinical data were collected. Patients answered auto-reported questionnaires: Bath Ankylosing Spondylitis Disease Activity Index, Bath Ankylosing Spondylitis Functional Index, Ankylosing Spondylitis Quality of Life, and Center for Epidemiological Studies Depression scale. Patients with rheumatoid arthritis (RA) (ACR'87 criteria) were assessed as the control group. The adherence of the studied groups to medical treatment and exercises was measured by means of two questionnaires: Compliance Questionnaire on Rheumatology (CQR) and Exercise Attitude Questionnaire-18 (EAQ-18). The study included 59 patients with AS and 53 patients with RA. Of the AS patients, 43 (72.9%) were male, median age 47 years (interquartile range (IQR) 33-57) and median disease duration of 120 months (IQR 33-57). Of the RA patients, 37 (69.8%) were female, had a median age of 56 years (IQR 43.5-60) and a median disease duration of 156 months (IQR 96-288). There were no significant differences in the results of the adherence questionnaires between both groups, with a total median of 68.42 for the CQR in both groups and of 40.7 in AS vs. 42.6 in RA for the EAQ. When dichotomizing patients as adherent and non-adherent, taking as good adherence a cut value in the CQR and EAQ higher than 60, adherence to pharmacological treatment was significantly higher in RA vs. AS (92.5 vs. 74.6%, p = 0.01) and there were no differences in the EAQ. On the uni- and multivariate analysis, lack of adherence to treatment was not associated to sex, age, disease duration, education, health insurance, depressive status, and disease activity parameters in neither group of patients. AS have an acceptable adherence to pharmacological treatment, although it is lower than RA patients; nonetheless, both groups show a lack of adherence to exercise.

Prevalence of periprosthetic osteolysis after total hip replacement in patients with rheumatic diseases.

Periprosthetic osteolysis (PO) is a frequent complication in patients with joint implants. There are no data regarding the prevalence of PO in patients with rheumatoid arthritis (RA), juvenile chronic arthritis (JCA), ankylosing spondylitis (AS), and osteoarthritis (OA). OBJECTIVES: To evaluate the prevalence of PO in patients with RA, JCA, AS, and OA, who have undergone total hip replacement (THR), and to identify factors associated with its development. METHODS: The study included patients diagnosed with RA (ACR 1987), AS (modified New York criteria), JCA (European 1977 criteria), and osteoarthritis (OA) (ACR 1990 criteria) with unilateral or bilateral THR. Demographic, clinical, and therapeutic data were collected. Panoramic pelvic plain radiographs were performed, to determine the presence of PO at acetabular and femoral levels. Images were read by two independent observers. RESULTS: One hundred twenty-two hip prostheses were analyzed (74 cemented, 30 cementless, and 18 hybrids). The average time from prosthesis implantation to pelvic radiograph was comparable among groups. PO was observed in 72 hips (59%). In 55% of cases, PO was detected on the femoral component, with a lower prevalence in RA (53%) vs AS (64.7%) and JCA (76.5%). Acetabular PO was more frequent in JCA patients (58.8%), compared with RA (11.6%) and OA (28.5%) patients (P = 0.0001 and P = 0.06, respectively). There was no significant association between the presence of PO and clinical, functional, or therapeutic features. CONCLUSION: The prevalence of PO was 59%, being more frequent at the femoral level. Larger studies must be carried out to determine the clinical significance of radiologic PO.

Impacto socioeconómico en pacientes con espondilitis anquilosante en Argentina / Costs of taking care of ankylosing spondylitis patients in Argentina

La Espondilitis Anquilosante (EA) es una enfermedad inflamatoria crónica, con compromiso axial predominante que genera severa discapacidad. Las medidas destinadas a controlar la actividad de la enfermedad generan costos directos, y a su vez la incapacidad laboral y la alteración de la calidad de vida producen importantes costos indirectos. El objetivo de nuestro trabajo fue evaluar el impacto socioeconómico en pacientes con EA e identificar posibles factores sociodemográficos y/o clínicos asociados. Material y métodos: Se incluyeron pacientes con EA (criterios NY modificados) mayores de 16 años. Se recolectaron datos demográficos y clínicos, se determinó la actividad de la enfermedad, capacidad funcional y calidad de vida a través de los cuestionarios, BASDAI, BASFI y ASQol, respectivamente. Se evaluaron los costos anuales, tanto directos (medicación, terapias alternativas, atención profesional, estudios complementarios, internación, uso de ortesis, actividades recreativas, transporte, ayuda de terceros) como indirectos (costos generados por desocupación, ausentismo laboral, subsidio por discapacidad). Análisis estadístico: Análisis univariado (OR IC 95%) y regresión logística y lineal múltiple. Resultados: Se incluyeron 68 pacientes consecutivos, el 83,8% eran de sexo masculino. La edad de inicio y el tiempo de evolución tuvieron una mediana de 20 años. El compromiso articular periférico se observó en 41 pacientes (60,3%), de los cuales sólo un paciente requirió prótesis en el último año. El 64,7% de los pacientes presentaba enfermedades concomitantes y el 63,2% contaba con algún tipo de cobertura social. Las medianas de BASFI, BASDAI y ASQoL fueron 4,58 (RIC: 2,57-6,8), 4,55 (RIC: 2,35- 6,7) y 7,5 (RIC: 3,5-13,5), respectivamente.

Incapacidad laboral en pacientes con espondilitis anquilosante: puntos de corte y capacidad de discriminación de los principales cuestionarios de autoevaluación / Work disability in ankylosing spondylitis patients: cut-off points and discrimination capacity of the main auto-administrated questionnaires

Nuestro grupo demostró que la frecuencia de incapacidad laboral en Espondilitis Anquilosante (EA) es significativamente mayor que la de los controles sin esta enfermedad apareados por sexo, edad y clase social (J Clin Rheumatol 2008;14: 273–277). Los cuestionarios de autoevaluación en EA (BASDAI, BASFI, HAQ-S) son instrumentos útiles para evaluar actividad y capacidad funcional. El objetivo del presente estudio fue determinar la capacidad de discriminación y los puntos de corte de estos cuestionarios para evaluar incapacidad laboral en pacientes con EA. Material y métodos: Se incluyeron pacientes consecutivos con EA según criterios de NY modificados. Se consignaron características demográficas y clínicas de la enfermedad. Se evaluó la actividad de la enfermedad, capacidad funcional, calidad de vida, depresión y fatiga por cuestionarios validados: BASDAI, BASFI, HAQ-S, ASQoL, CES-D, FSS, respectivamente. Se determinó a través de una entrevista personal el status laboral y las características del trabajo, excluyéndose a aquellos pacientes jubilados por edad y las amas de casa. Incapacidad laboral fue definida como la imposibilidad para trabajar relacionada exclusivamente con la enfermedad. Análisis estadístico: Las variables categóricas fueron comparadas por Chi cuadrado y las continuas por prueba de Mann Whitney. La discriminación y los puntos de corte de los cuestionarios fueron evaluados por curvas COR. Resultados: Se incluyeron 53 pacientes, 49 varones con una edad mediana de 45 años (RIQ: 37-56) y una duración mediana de la enfermedad de 15 años (RIQ: 11-21). Once pacientes (20,8%) estaban desocupados por la enfermedad. No observamos diferencias entre los pacientes ocupados vs. desocupados en cuanto a edad, sexo, duración de la enfermedad, comorbilidades u otras variables categóricas.

Impacto socioeconómico en pacientes con espondilitis anquilosante en Argentina / Costs of taking care of ankylosing spondylitis patients in Argentina

La Espondilitis Anquilosante (EA) es una enfermedad inflamatoria crónica, con compromiso axial predominante que genera severa discapacidad. Las medidas destinadas a controlar la actividad de la enfermedad generan costos directos, y a su vez la incapacidad laboral y la alteración de la calidad de vida producen importantes costos indirectos. El objetivo de nuestro trabajo fue evaluar el impacto socioeconómico en pacientes con EA e identificar posibles factores sociodemográficos y/o clínicos asociados. Material y métodos: Se incluyeron pacientes con EA (criterios NY modificados) mayores de 16 años. Se recolectaron datos demográficos y clínicos, se determinó la actividad de la enfermedad, capacidad funcional y calidad de vida a través de los cuestionarios, BASDAI, BASFI y ASQol, respectivamente. Se evaluaron los costos anuales, tanto directos (medicación, terapias alternativas, atención profesional, estudios complementarios, internación, uso de ortesis, actividades recreativas, transporte, ayuda de terceros) como indirectos (costos generados por desocupación, ausentismo laboral, subsidio por discapacidad). Análisis estadístico: Análisis univariado (OR IC 95%) y regresión logística y lineal múltiple. Resultados: Se incluyeron 68 pacientes consecutivos, el 83,8% eran de sexo masculino. La edad de inicio y el tiempo de evolución tuvieron una mediana de 20 años. El compromiso articular periférico se observó en 41 pacientes (60,3%), de los cuales sólo un paciente requirió prótesis en el último año. El 64,7% de los pacientes presentaba enfermedades concomitantes y el 63,2% contaba con algún tipo de cobertura social. Las medianas de BASFI, BASDAI y ASQoL fueron 4,58 (RIC: 2,57-6,8), 4,55 (RIC: 2,35- 6,7) y 7,5 (RIC: 3,5-13,5), respectivamente.(AU)

Incapacidad laboral en pacientes con espondilitis anquilosante: puntos de corte y capacidad de discriminación de los principales cuestionarios de autoevaluación / Work disability in ankylosing spondylitis patients: cut-off points and discrimination capacity of the main auto-administrated questionnaires

Nuestro grupo demostró que la frecuencia de incapacidad laboral en Espondilitis Anquilosante (EA) es significativamente mayor que la de los controles sin esta enfermedad apareados por sexo, edad y clase social (J Clin Rheumatol 2008;14: 273¹277). Los cuestionarios de autoevaluación en EA (BASDAI, BASFI, HAQ-S) son instrumentos útiles para evaluar actividad y capacidad funcional. El objetivo del presente estudio fue determinar la capacidad de discriminación y los puntos de corte de estos cuestionarios para evaluar incapacidad laboral en pacientes con EA. Material y métodos: Se incluyeron pacientes consecutivos con EA según criterios de NY modificados. Se consignaron características demográficas y clínicas de la enfermedad. Se evaluó la actividad de la enfermedad, capacidad funcional, calidad de vida, depresión y fatiga por cuestionarios validados: BASDAI, BASFI, HAQ-S, ASQoL, CES-D, FSS, respectivamente. Se determinó a través de una entrevista personal el status laboral y las características del trabajo, excluyéndose a aquellos pacientes jubilados por edad y las amas de casa. Incapacidad laboral fue definida como la imposibilidad para trabajar relacionada exclusivamente con la enfermedad. Análisis estadístico: Las variables categóricas fueron comparadas por Chi cuadrado y las continuas por prueba de Mann Whitney. La discriminación y los puntos de corte de los cuestionarios fueron evaluados por curvas COR. Resultados: Se incluyeron 53 pacientes, 49 varones con una edad mediana de 45 años (RIQ: 37-56) y una duración mediana de la enfermedad de 15 años (RIQ: 11-21). Once pacientes (20,8%) estaban desocupados por la enfermedad. No observamos diferencias entre los pacientes ocupados vs. desocupados en cuanto a edad, sexo, duración de la enfermedad, comorbilidades u otras variables categóricas.(AU)

Prevalence and clinical significance of eosinophilia in patients with rheumatoid arthritis in Argentina.

BACKGROUND: The presence of eosinophilia in peripheral blood has been considered by some authors as an indicator of bad prognosis in patients with rheumatoid arthritis (RA); however, the methodology and the number of patients included in those studies were not appropriate. OBJECTIVE: To determine the prevalence and possible causes of eosinophilia in patients with RA, and its relationship with a more severe disease. MATERIAL AND METHODS: Patients with RA (American College of Rheumatology '87) were included, demographic, clinical, and laboratory data were collected. The presence of eosinophilia was defined as an eosinophil absolute count above 350/mm. Disease activity, health assessment questionnaire, and hand x-rays were performed in all patients. A coproparasitologic test and serology for Toxocara by enzyme-linked immunosorbent assay (ELISA) were determined in patients with eosinophilia. RESULTS: One hundred nine patients were included, 95 women (87.2%), mean age 50.6 +/- 13 years, mean disease duration 10.8 +/- 7.6 years. Eight patients (7.33%) showed eosinophilia. When demographic and clinical characteristics of patients with or without eosinophilia were compared, the former showed a higher erythrocyte sedimentation rate levels and significantly more frequency of dry mouth, anal pruritus, and paresthesia. The remaining clinical variables, as well as radiologic structural damage were comparable. Parasites in feces (Ascaris lumbricoides and Enterobius vermicularis) were found in 2 patients with eosinophilia. Seven patients with eosinophilia (87.5%) versus 4 (19%) without eosinophilia showed positive serology for Toxocara (P = 0.001). CONCLUSION: The frequency of eosinophilia in our population of patients with RA was 7.33%. It was not an indicator of severity of the disease and in all cases evidence for secondary causes (parasitosis) was found.