RESUMEN
OBJECTIVE: To investigate the relationship between markers of collagen II synthesis and degradation with disease activity measures, autoantibodies, and radiographic outcomes in a 4-year protocol on patients with early rheumatoid arthritis (RA) who are naïve to disease-modifying antirheumatic drugs. METHODS: One hundred sixty patients with newly diagnosed, untreated RA entered the Cyclosporine, Methotrexate, Steroid in RA (CIMESTRA) trial. Disease activity and radiograph status were measured at baseline and 4 years. The N-terminal propeptide of collagen IIA (PIIANP) and the cross-linked C-telopeptide of collagen II (CTX-II) were quantified at baseline by ELISA. PIIANP was also assayed at 2 and 4 years. Anticyclic citrullinated peptide (anti-CCP) was recorded at baseline. An uncoupling index for cartilage collagen metabolism was calculated from PIIANP and CTX-II measurements. RESULTS: PIIANP was low at diagnosis and 4 years on (p < 0.001), irrespective of treatment and disease activity. PIIANP was lowest in anti-CCP positive patients (p = 0.006), and there was a negative correlation between PIIANP and anti-CCP titers (rho = -0.25, p 0.002). CTX-II was increased (p < 0.001) and correlated positively with disease activity and radiographic progression, but not with anti-CCP (p = 0.93). The uncoupling index was not superior to CTX-II in predicting radiographic changes. CONCLUSION: These results suggest that cartilage collagen formation and degradation are unbalanced when RA is diagnosed. The different associations of collagen II anabolism (PIIANP) and collagen II degradation (CTX-II) with anti-CCP, synovitis, and radiographic progression indicate that at this early stage of RA, cartilage collagen degradation is mainly driven by synovitis, while anti-CCP antibodies may interfere with cartilage regeneration by inhibiting collagen IIA formation. Trial registration j.nr NCT00209859.
Asunto(s)
Artritis Reumatoide/metabolismo , Colágeno Tipo II/biosíntesis , Fragmentos de Péptidos/biosíntesis , Péptidos Cíclicos/inmunología , Procolágeno/biosíntesis , Adolescente , Adulto , Anciano , Artritis Reumatoide/inmunología , Artritis Reumatoide/fisiopatología , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Biomarcadores/metabolismo , Cartílago Articular/metabolismo , Colágeno Tipo II/sangre , Colágeno Tipo II/inmunología , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fragmentos de Péptidos/sangre , Fragmentos de Péptidos/inmunología , Péptidos Cíclicos/sangre , Procolágeno/sangre , Procolágeno/inmunología , Índice de Severidad de la Enfermedad , Sinovitis/metabolismo , Adulto JovenRESUMEN
INTRODUCTION: Surfactant protein D (SP-D) is a collectin with immuno-regulatory functions, which may depend on oligomerization. Anti-microbial and anti-inflammatory properties have been attributed to multimeric SP-D variants, while trimeric subunits per se have been suggested to enhance inflammation. Previously, we reported low circulating SP-D in early rheumatoid arthritis (RA), and the present investigation aims to extend these data by serial SP-D serum measurements, studies on synovial fluid, SP-D size distribution and genotyping in patients with early RA. METHODS: One-hundred-and-sixty disease-modifying antirheumatic drug (DMARD) naïve RA patients with disease duration less than six months were studied prospectively for four years (CIMESTRA (Ciclosporine, Methotrexate, Steroid in RA) trial) including disease activity measures (C-reactive protein, joint counts and Health Assessment Questionnaire (HAQ) score), autoantibodies, x-ray findings and SP-D. SP-D was quantified by enzyme-linked immunosorbent assay (ELISA) and molecular size distribution was assessed by gel filtration chromatography. Further, SP-D Met11Thr single nucleotide polymorphism (SNP) analysis was performed. RESULTS: Serum SP-D was significantly lower in RA patients at baseline compared with healthy controls (P < 0.001). SP-D increased slightly during follow-up (P < 0.001), but was still subnormal at four years after adjustment for confounders (P < 0.001). SP-D in synovial fluid was up to 2.5-fold lower than in serum. While multimeric variants were detected in serum, SP-D in synovial fluid comprised trimeric subunits only. There were no significant associations between genotype distribution and SP-D. Baseline SP-D was inversely associated to CRP and HAQ score. A similar relationship was observed regarding temporal changes in SP-D and CRP (zero to four years). SP-D was not associated to x-ray findings. CONCLUSIONS: This study confirms that circulating SP-D is persistently subnormal in early and untreated RA despite a favourable therapeutic response obtained during four years of follow-up. SP-D correlated negatively to disease activity measures, but was not correlated with x-ray progression or SP-D genotype. These observations suggest that SP-D is implicated in RA pathogenesis at the protein level. The exclusive presence of trimeric SP-D in affected joints may contribute to the maintenance of joint inflammation. TRIAL REGISTRATION: (j.nr NCT00209859).
Asunto(s)
Artritis Reumatoide/sangre , Proteína D Asociada a Surfactante Pulmonar/sangre , Adolescente , Adulto , Anciano , Artritis Reumatoide/genética , Artritis Reumatoide/fisiopatología , Artrografía , Femenino , Genotipo , Estado de Salud , Humanos , Masculino , Metalotioneína/genética , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Estudios Prospectivos , Valores de Referencia , Encuestas y Cuestionarios , Adulto JovenRESUMEN
OBJECTIVE: To study the association between polymorphisms in the mannose-binding lectin gene (MBL2) and disease activity, physical disability, and joint erosions in patients with newly diagnosed rheumatoid arthritis (RA). METHODS: Patients with early RA (n=158) not previously treated with disease modifying antirheumatic drugs, participating in a treatment trial (CIMESTRA study) were examined at inclusion for MBL2 pooled structural genotypes (O/O, A/O, A/A), regulatory MBL2 promoter polymorphism in position -221 (XX, XY, YY), anti-cyclic citrullinated peptide 2 antibodies (anti-CCP2), disease activity by Disease Activity Score-28 (DAS28 score), physical disability by Health Assessment Questionnaire (HAQ) score, and erosive changes in hands and feet (Sharp-van der Heijde score). RESULTS: Eight patients were homozygous MBL2 defective (O/O), 101 belonged to an intermediate group, and 49 were MBL2 high producers (YA/YA). Anti-CCP was present in 93 patients (59%). High scores of disease activity, C-reactive protein-based DAS28 (p=0.02), and physical disability by HAQ (p=0.01) were associated with high MBL2 expression genotypes in a gene-dose dependent way, but only in anti-CCP-positive patients. At this early stage of the disease there was no association with erosion score from radiographs. CONCLUSION: The results point to a synovitis-enhancing effect of MBL in anti-CCP-positive RA, whereas such an effect was not demonstrated for joint erosions.
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Artritis Reumatoide/genética , Artritis Reumatoide/fisiopatología , Autoanticuerpos/inmunología , Lectina de Unión a Manosa/genética , Péptidos Cíclicos/inmunología , Polimorfismo Genético , Adulto , Anciano , Artritis Reumatoide/inmunología , Artritis Reumatoide/patología , Autoanticuerpos/sangre , Evaluación de la Discapacidad , Método Doble Ciego , Femenino , Humanos , Persona de Mediana Edad , Regiones Promotoras Genéticas/genética , Índice de Severidad de la Enfermedad , Encuestas y Cuestionarios , Adulto JovenRESUMEN
OBJECTIVE: To investigate whether disease control can be achieved in early active rheumatoid arthritis (RA) by treatment with methotrexate and intraarticular betamethasone, and whether the addition of cyclosporine to the regimen has any additional effect. METHODS: Patients (n = 160) were randomized to receive methotrexate 7.5 mg/week plus cyclosporine 2.5 mg/kg of body weight/day (combination therapy) or methotrexate plus placebo-cyclosporine (monotherapy). At weeks 0, 2, 4, 6, and 8 and every 4 weeks thereafter, betamethasone was injected into swollen joints (maximum 4 joints or 4 ml per visit). Beginning at week 8, if synovitis was present, the methotrexate dosage was increased stepwise up to 20 mg/week, with a subsequent stepwise increase in the cyclosporine or placebo-cyclosporine dosage up to 4 mg/kg. RESULTS: At 52 weeks, 20% improvement according to the American College of Rheumatology criteria (ACR20) was achieved in 85% of the combination therapy group versus 68% of the monotherapy group (P = 0.02). The median individual overall ACR response (ACR-N) in the 2 groups was 80.0% (interquartile range 40.1-91.8%) and 54.5% (interquartile range 2.4-87.8%), respectively (P = 0.025). At 48 and 52 weeks, ACR remission criteria were met in 35% of the combination therapy group and 28% of the monotherapy group. Progression in the Larsen score at 52 weeks was -0.2 +/- 6.5 and 0.4 +/- 6.9 (mean +/- SD) in the combination therapy and monotherapy groups, respectively. Serum creatinine levels increased by 7%, and hypertrichosis was more prevalent, in the combination therapy group. CONCLUSION: Combined treatment with methotrexate and intraarticular glucocorticoid showed excellent disease control and stopped the progression of erosions in patients with early active RA, who had a poor prognosis. Addition of cyclosporine improved the ACR20 and ACR-N responses, whereas the ACR50 and ACR70 responses, remission rates, and radiographic changes did not differ between the 2 study groups.
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Antirreumáticos/administración & dosificación , Artritis Reumatoide/tratamiento farmacológico , Betametasona/administración & dosificación , Ciclosporina/administración & dosificación , Glucocorticoides/administración & dosificación , Metotrexato/administración & dosificación , Adulto , Método Doble Ciego , Quimioterapia Combinada , Femenino , Humanos , Inyecciones Intraarticulares , Masculino , Persona de Mediana EdadRESUMEN
INTRODUCTION: This randomised study evaluates the effect of intensive physical therapy on the duration of rehabilitation after hip fracture. MATERIALS AND METHODS: The study comprised 88 patients transferred for rehabilitation after operative treatment for hip fracture. After randomisation, 44 patients received physical therapy 3.6 hours (median) a week, whereas the 44 control patients received physical therapy 1.9 hours a week. The outcome was defined as the duration of physical rehabilitation until the patient was able to 1) walk 50 metres in less than two minutes; 2) manage to climb stairs to the first floor; 3) manage the sit-to-stand transfer; 4) get in and out of bed; 5) manage bathing, dressing, and lavatory visits. RESULTS: In the group randomised to intensive physical therapy, 24 patients dropped out after 15 days (median) whereas 13 patients dropped out of the control group after 22 days. Drop outs were caused by orthopaedic complications, general weakness, and poor co-operation. No difference was found in the duration of physical rehabilitation by analysis per protocol of the patients who completed the trial. DISCUSSION: The considerable number of drop outs suggests that intensive physical therapy may be of limited value in the attempt to reduce the duration of rehabilitation after hip fracture. An altered objective, including enhanced outpatient rehabilitation, may be necessary in order to reduce the length of hospital stay after hip fracture.
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Fracturas del Fémur/rehabilitación , Fracturas de Cadera/rehabilitación , Modalidades de Fisioterapia/métodos , Anciano , Femenino , Fracturas del Fémur/fisiopatología , Fracturas del Fémur/cirugía , Fracturas de Cadera/fisiopatología , Fracturas de Cadera/cirugía , Humanos , Persona de Mediana Edad , Pacientes Desistentes del Tratamiento , Recuperación de la FunciónRESUMEN
INTRODUCTION: This randomised study evaluates the effect of intensive physical therapy on the duration of rehabilitation following hip fracture. METHODS: Eighty-eight patients transferred for rehabilitation after surgical treatment for hip fracture were included in the trial. Forty-four patients were randomised to physical therapy 3.6 hours (median) a week, while the 44 control patients received physical therapy 1.9 hours a week. Outcome was defined as duration of physical rehabilitation until the patient was able to (1) walk 50 metres in less than 2 minutes, (2) manage stair climbing to the first floor, (3) manage sit-to-stand transfer, (4) move in and out of bed, (5) manage bathing, dressing and lavatory visits. RESULTS: In the group randomised to intensive physical therapy 24 patients withdrew after 15 days while 13 patients withdrew from the control group after 22 days (median values). Early withdrawal was due to orthopaedic complications, general weakness and poor co-operation. No difference between the two groups was demonstrated in the duration of physical rehabilitation by a per protocol analysis of the patients who completed the trial. DISCUSSION: The considerable drop-out rate suggests that intensive physical therapy may be of limited value when attempting to reduce the duration of rehabilitation following hip fracture. An altered objective including enhanced out-patient rehabilitation may be necessary in order to reduce the length of hospital stay after hip fracture.