Ultrafast folding kinetics of WW domains reveal how the amino acid sequence determines the speed limit to protein folding.

Protein (un)folding rates depend on the free-energy barrier separating the native and unfolded states and a prefactor term, which sets the timescale for crossing such barrier or folding speed limit. Because extricating these two factors is usually unfeasible, it has been common to assume a constant prefactor and assign all rate variability to the barrier. However, theory and simulations postulate a protein-specific prefactor that contains key mechanistic information. Here, we exploit the special properties of fast-folding proteins to experimentally resolve the folding rate prefactor and investigate how much it varies among structural homologs. We measure the ultrafast (un)folding kinetics of five natural WW domains using nanosecond laser-induced temperature jumps. All five WW domains fold in microseconds, but with a 10-fold difference between fastest and slowest. Interestingly, they all produce biphasic kinetics in which the slower phase corresponds to reequilibration over the small barrier (<3 RT) and the faster phase to the downhill relaxation of the minor population residing at the barrier top [transition state ensemble (TSE)]. The fast rate recapitulates the 10-fold range, demonstrating that the folding speed limit of even the simplest all-ß fold strongly depends on the amino acid sequence. Given this fold's simplicity, the most plausible source for such prefactor differences is the presence of nonnative interactions that stabilize the TSE but need to break up before folding resumes. Our results confirm long-standing theoretical predictions and bring into focus the rate prefactor as an essential element for understanding the mechanisms of folding.

Protein Folding Cooperativity and Thermodynamic Barriers of the Simplest ß-Sheet Fold: A Survey of WW Domains.

Theory and experiments have shown that microsecond folding proteins exhibit characteristic thermodynamic properties that reflect the limited cooperativity of folding over marginal barriers (downhill folding). Those studies have mostly focused on proteins with large α-helical contents and small size, which tend to be the fastest folders. A key open question is whether such properties are also present in the fastest all-ß proteins. We address this issue by investigating the unfolding thermodynamics of a collection of WW domains as representatives of the simplest ß-sheet fold. WW domains are small microsecond folders, although they do not fold as fast as their α-helical counterparts. In previous work on the NEDD4-WW4 domain, we reported deviations from two-state thermodynamics that were less apparent and thus suggestive of an incipient downhill scenario. Here we investigate the unfolding thermodynamics of four other WW domains (NEDD4-WW3, YAP65-WW1(L30K), FBP11-WW1, and FBP11-WW2) by performing all of the thermodynamic tests for downhill folding that have been previously developed on α-helical proteins. This set of five WW domains shares low sequence identity and include examples from two specificity classes, thus providing a comprehensive survey. Thermodynamic analysis of the four new WW domains consistently reveals all of the properties of downhill folding equilibria, which are in all cases more marked than what we found before in NEDD4-WW4. Our results show that fast-folding all-ß proteins do share limited cooperativity and gradual unfolding thermodynamics with fast α-helical proteins and suggest that the free energy barrier to folding of natural proteins is mostly determined by size and fold topology and much less by the specific amino acid sequence.

Probing the free energy landscape of the fast-folding gpW protein by relaxation dispersion NMR.

The topographic features of the free energy landscapes that govern the thermodynamics and kinetics of conformational transitions in proteins, which in turn are integral for function, are not well understood. This reflects the experimental challenges associated with characterizing these multidimensional surfaces, even for small proteins. Here we focus on a 62-residue protein, gpW, that folds very rapidly into a native structure with an α/ß topology in which α-helices are at the N- and C-terminal ends of the molecule with a central ß-hairpin positioned orthogonally to the helices. Using relaxation dispersion NMR spectroscopy to probe the conformational fluctuations in gpW at 1 °C, we found that the native state interconverts with a transiently formed, sparsely populated second state with a lifetime of 250 µs, consistent with the global folding-unfolding rate under these conditions. In this low-populated state, the ß-hairpin is unfolded whereas the α-helices remain predominantly formed. Our results argue for a hierarchical stability of secondary structural elements and demonstrate the existence of a complex free energy landscape even in this small, fast-folding single-domain protein.

Evaluación de la eficacia del tratamiento con rituximab asociado a ciclofosfamida en pacientes con miopatía inflamatoria idiopática refractaria / Evaluation of the effectiveness of treatment with rituximab associated to cyclophosphamide in patients with resistant idiopathic inflammatory myopathy

Fundamento y objetivo: Comunicamos nuestra experiencia con rituximab más ciclofosfamida en el tratamiento de pacientes con miopatía inflamatoria idiopática refractaria. Pacientes y método: Estudio prospectivo abierto no controlado sobre 17 pacientes.Resultados: Evaluación cumplimentada tras 1, 6 y 12 meses en el 95,2, el 85,7 y el 52,4% de los ciclos, respectivamente. Remisión total o parcial tras 1, 6 y 12 meses en el 65, el 100 y el 63,6% de los ciclos evaluados, respectivamente. Depleción absoluta de linfocitos B en sangre periférica en los 18 casos con datos disponibles, con tendencia a la normalización tras 6 a 12 meses. Hubo 5 recaídas; la mediana de tiempo hasta la recaída fue de 11 meses; hubo repetición del tratamiento en 4 casos. Cuatro pacientes tenían afectación respiratoria; uno (etiología multifactorial) no mejoró, pero sí los otros 3, con neumopatía intersticial aislada o asociada a debilidad muscular respiratoria. Hubo 5 pacientes con anticuerpos anti-Jo-1 positivos (6 ciclos), con respuesta al tratamiento superponible al resto. Se observaron escasos efectos adversos; solo cabe destacar un caso de meningitis por Corynebacterium, con buena evolución.Conclusiones: El rituximab parece una alternativa válida en el tratamiento de pacientes con polimiositis o dermatomiositis resistentes (AU)

Background and objective: We report our experience with rituximab plus cyclophosphamide in the treatment of patients with resistant idiopathic inflammatory myopathies. Patients and method: Open-label uncontrolled prospective sudy on 17 patients.Results: Evaluation was completed after 1, 6 and 12 months in 95’2, 85’7 y 52’4% of cycles, respectively. Total or partial remission was achieved after 1, 6 and 12 months in 65, 100 y 63’6% of evaluated cycles, respectively. Absolute depletion of B lymphocites from peripheral blood was found in the 18 cases with available data. There were 5 relapses; median of time to relapse: 11 months; treatment was repeated in 4. Four patients (6 cycles) had impaired pulmonary function; one (with a multifactorial etiology) did not improve but the other 3, with interstitial pneumonia associated or not with respiratory muscle weakness, did. Five patients with positive anti-Jo-1 antibodies (6 cycles) displayed similar results. The only adverse event observed was a case of meningitis caused by Corynebacterium, with good results. Conclusion: Rituximab seems a valid alternative for the treatment of patients with resistant polymyositis or dermatomyosytis (AU)

[Evaluation of the effectiveness of treatment with rituximab associated to cyclophosphamide in patients with resistant idiopathic inflammatory myopathy]. / Evaluación de la eficacia del tratamiento con rituximab asociado a ciclofosfamida en pacientes con miopatía inflamatoria idiopática refractaria.

BACKGROUND AND OBJECTIVE: We report our experience with rituximab plus cyclophosphamide in the treatment of patients with resistant idiopathic inflammatory myopathies. PATIENTS AND METHOD: Open-label uncontrolled prospective study on 17 patients. RESULTS: Evaluation was completed after 1, 6 and 12 months in 95'2, 85'7 y 52'4% of cycles, respectively. Total or partial remission was achieved after 1, 6 and 12 months in 65, 100 y 63'6% of evaluated cycles, respectively. Absolute depletion of B lymphocites from peripheral blood was found in the 18 cases with available data. There were 5 relapses; median of time to relapse: 11 months; treatment was repeated in 4. Four patients (6 cycles) had impaired pulmonary function; one (with a multifactorial etiology) did not improve but the other 3, with interstitial pneumonia associated or not with respiratory muscle weakness, did. Five patients with positive anti-Jo-1 antibodies (6 cycles) displayed similar results. The only adverse event observed was a case of meningitis caused by Corynebacterium, with good results. CONCLUSION: Rituximab seems a valid alternative for the treatment of patients with resistant polymyositis or dermatomyosytis.

Disfunción tiroidea en pacientes con hipertensión arterial pulmonar. Estudio de una cohorte de 58 pacientes / Thyroid dysfunction in patients with pulmonary arterial hipertensión. A cohort study of 58 patients

Fundamento y objetivo: La patología tiroidea (PT) es más frecuente en pacientes con hipertensión arterial pulmonar (HAP) que en la población general. No están bien establecidas la frecuencia ni la causa de esta asociación. El objetivo de este trabajo es cuantificar y analizar la incidencia y las características de la PT en una cohorte de pacientes con HAP (idiopática o asociada preferentemente a enfermedades sistémicas) y realizar una revisión de la literatura científica. Pacientes y método: Se estudió a 58 pacientes con HAP prospectivamente según un protocolo preestablecido (incluido cateterismo cardíaco derecho) y se determinaron la tirotropina (TSH), la tiroxina libre (T4l) y los anticuerpos antitiroglobulínicos y anticuerpos antiperoxidasa. Se definió la PT como alteración de la TSH o elevación de cualquiera de los 2 anticuerpos antitiroideos (AcAT). Se compararon las variables clínicas, biológicas y hemodinámicas entre los grupos con y sin PT. Resultados: Había PT en 30 pacientes (51%): TSH elevada en 21 (36,21%), hipertiroidismo en 2 pacientes (3,45%) y AcAT elevados en 16 de los 54 pacientes (27,59%), 7 de los cuales eran eutiroideos. En el grupo con PT el tiempo de evolución de la HAP fue mayor (4,62 frente a 2,61 años; intervalo de confianza [IC] del 95%: 0,63 a 3,38; p=0,005), hubo más pacientes en clase funcional iv (13 frente a 5, el 43,3 frente al 15,8%; IC del 95%: 0,05 a 11,75; p=0,046), el gasto cardíaco fue menor (IC del 95%: 3,16 a 4,89; p=0,032) y fue más frecuente el tratamiento con epoprostenol (14 frente a 4, el 46 frente al 14,3%; IC del 95%: 1,46 a 18,85; odds ratio de 5,25; p=0,008) que en el grupo sin PT (AU)

Background and objective: Thyroid disease (TD) is more prevalent in patients with pulmonary arterial hypertension (PAH) than in the general population. The frequency and the cause of this association are not well established. We aimed to quantify and analyze the incidence and characteristics of TD in a cohort of PAH patients (idiopathic or preferentially associated with systemic diseases) and review the literature. Patients and method: Fifty eight PAH patients were prospectively studied, according to a previously established protocol (that included right heart catheterization); TSH, T4, and antithyroglobulin and antiperoxidase antibodies were determined. TD was defined as an abnormal TSH level and/or elevated antithyroid antibodies (TAbs). Clinical, biological and hemodynamic variables were compared between patients with and without TD. Results: TD was detected in 30 patients (51%): high TSH levels were observed in 21 (36,21%); hyperthyroidism in 2 (3,45%); and TAbs in 16 of 54 (27,59%), 7 of whom were euthyroid. In the TD group, PAH evolution time was longer (4,62 vs 2,61 years; P=.005, CI 95%, 0,63–3,38), more patients were in functional class IV (13;43,3% vs 5;15,8%, P=.046, CI 95% ,0,05–11,75), cardiac output was lower (P=.032, CI 95%, 3,16–4,89) and epoprostenol treatment was more frequently used (14;46,6% vs 4;14,3%, P=.008, CI 95%, 1,46–18,85; OR=5,25). Conclusions: The frequency of TD detected in this PAH cohort reaches 51% and it was associated with a longer evolution time of PAH and worse hemodynamic situation. Although epoprostenol was used more frequently in TD patients, a causal relationship with TD could not be established (AU)

[Thyroid dysfunction in patients with pulmonary arterial hypertension. A cohort study of 58 patients]. / Disfunción tiroidea en pacientes con hipertensión arterial pulmonar. Estudio de una cohorte de 58 pacientes.

BACKGROUND AND OBJECTIVE: Thyroid disease (TD) is more prevalent in patients with pulmonary arterial hypertension (PAH) than in the general population. The frequency and the cause of this association are not well established. We aimed to quantify and analyze the incidence and characteristics of TD in a cohort of PAH patients (idiopathic or preferentially associated with systemic diseases) and review the literature. PATIENTS AND METHOD: Fifty eight PAH patients were prospectively studied, according to a previously established protocol (that included right heart catheterization); TSH, T(4), and antithyroglobulin and antiperoxidase antibodies were determined. TD was defined as an abnormal TSH level and/or elevated antithyroid antibodies (TAbs). Clinical, biological and hemodynamic variables were compared between patients with and without TD. RESULTS: TD was detected in 30 patients (51%): high TSH levels were observed in 21 (36,21%); hyperthyroidism in 2 (3,45%); and TAbs in 16 of 54 (27,59%), 7 of whom were euthyroid. In the TD group, PAH evolution time was longer (4,62 vs 2,61 years; P=.005, CI 95%, 0,63-3,38), more patients were in functional class IV (13;43,3% vs 5;15,8%, P=.046, CI 95% ,0,05-11,75), cardiac output was lower (P=.032, CI 95%, 3,16-4,89) and epoprostenol treatment was more frequently used (14;46,6% vs 4;14,3%, P=.008, CI 95%, 1,46-18,85; OR=5,25). CONCLUSIONS: The frequency of TD detected in this PAH cohort reaches 51% and it was associated with a longer evolution time of PAH and worse hemodynamic situation. Although epoprostenol was used more frequently in TD patients, a causal relationship with TD could not be established.

Eficacia de rituximab combinado con ciclofosfamida en una paciente con lupus eritematoso sistémico y vasculitis peritoneal resistente a tratamiento inmunosupresor convencional / Efficacy of rituximab combined with cyclophosphamide in a patient with systemic lupus erythematosus and peritoneal vasculitis refractory to conventional inmunosupressive therapy

La vasculitis peritoneal es una manifestación clínica infrecuente y grave del lupus eritematoso sistémico. Se presenta el caso de una paciente con ascitis por vasculitis peritoneal y afección cutánea, articular, hemática y renal. El tratamiento con glucocorticoides e inmunosupresores resultó ineficaz para el control de la ascitis. Dada la resistencia al tratamiento convencional, se administró rituximab en cuatro infusiones semanales de 375mg/m2, potenciado con pulsos de ciclofosfamida las semanas 1 y 3. Con esta estrategia se consiguió una respuesta completa, que se repitió en brotes posteriores (el segundo y el tercero, multisistémicos y de nuevo con ascitis significativa, y el cuarto con nefritis) (AU)

Peritoneal vasculitis is a rare and severe clinical manifestation of systemic lupus erythematosus. We report a patient who presented with ascites due to peritoneal vasculitis and cutaneous, articular, hematological and renal inflammatory activity. Treatment with glucocorticoids and immunosuppressive drugs was ineffective. In view of the resistance to different therapies, 4 weekly infusions of 375mg/m2 of rituximab (RTX) were started, in association with cyclophosphamide pulses during the first and the third weeks. With this treatment strategy, the patient reached a complete response which was achieved in later flares of inflammatory activity (the second and third flares were multisystemic and with ascites again, and the fourth flare with nephritis) (AU)

[Efficacy of rituximab combined with cyclophosphamide in a patient with systemic lupus erythematosus and peritoneal vasculitis refractory to conventional inmunosupressive therapy]. / Eficacia de rituximab combinado con ciclofosfamida en una paciente con lupus eritematoso sistémico y vasculitis peritoneal resistente a tratamiento inmunosupresor convencional.

Peritoneal vasculitis is a rare and severe clinical manifestation of systemic lupus erythematosus. We report a patient who presented with ascites due to peritoneal vasculitis and cutaneous, articular, hematological and renal inflammatory activity. Treatment with glucocorticoids and immunosuppressive drugs was ineffective. In view of the resistance to different therapies, 4 weekly infusions of 375mg/m2 of rituximab (RTX) were started, in association with cyclophosphamide pulses during the first and the third weeks. With this treatment strategy, the patient reached a complete response which was achieved in later flares of inflammatory activity (the second and third flares were multisystemic and with ascites again, and the fourth flare with nephritis).

[Experience with imatinib to treat pulmonary arterial hypertension]. / Experiencia en el tratamiento de la hipertensión arterial pulmonar con imatinib.

Despite advances in the treatment of patients with pulmonary arterial hypertension (PAH), survival has not improved greatly (is still very affected). Imatinib, an antagonist of platelet-derived growth factor with antiproliferative activity, has been effective in experimental models and clinically in several published reports. We report the results of imatinib therapy in 4 patients with PAH (functional class IV) who were refractory to treatment with drug combinations for this condition. The final outcome was favorable in only 1 of the 4 cases. In this case, the patient was in functional class III and his hemodynamic parameters had improved significantly within 5 months after starting therapy. However, the patient died as a result of severe toxic hepatitis in which imatinib may have played a role. The present report adds to the few already in the literature (4 cases) and suggests that care should continue to be shown when using imatinib to treat PAH.

Experiencia en el tratamiento de la hipertensión arterial pulmonar con imatinib / Experience with imatinib to treat pulmonary arterial hypertension

A pesar de los avances en el tratamiento de los pacientescon hipertensión arterial pulmonar (HAP), su supervivenciasigue estando muy afectada. El imatinib, un antagonista delfactor de crecimiento derivado de las plaquetas con acciónantiproliferativa, ha sido eficaz en modelos experimentales yen algunos casos comunicados. Se describe el resultado deltratamiento con imatinib en 4 pacientes con HAP en clasefuncional IV y refractarios al tratamiento con asociacionesde medicamentos para la HAP. La respuesta final fue favorablesólo en uno de los 4 casos, que 5 meses después de iniciadoel tratamiento estaba en clase funcional III y con mejoríasignificativa de los parámetros hemodinámicos. Sinembargo, el paciente falleció por hepatitis tóxica grave en laque el imatinib pudo haber participado. Estos resultados seañaden a la escasa experiencia clínica comunicada (sólootros 4 casos) e indican que debemos mantener la cautela sobrela utilidad del imatinib en el tratamiento de la HAP

Despite advances in the treatment of patients withpulmonary arterial hypertension (PAH), survival has notimproved greatly (is still very affected). Imatinib, an antagonistof platelet-derived growth factor with antiproliferative activity,has been effective in experimental models and clinically inseveral published reports. We report the results of imatinibtherapy in 4 patients with PAH (functional class IV) whowere refractory to treatment with drug combinations for thiscondition. The final outcome was favorable in only 1 of the4 cases. In this case, the patient was in functional class III andhis hemodynamic parameters had improved significantlywithin 5 months after starting therapy. However, the patientdied as a result of severe toxic hepatitis in which imatinib mayhave played a role. The present report adds to the few alreadyin the literature (4 cases) and suggests that care shouldcontinue to be shown when using imatinib to treat PAH

[Rituximab for treatment of patients with systemic autoimmune diseases]. / Utilidad del rituximab en el tratamiento de pacientes con enfermedades sistémicas autoinmunitarias.

BACKGROUND AND OBJECTIVE: To assess the value of rituximab in systemic autoimmune diseases which are refractory to others treatments. PATIENTS AND METHOD: Prospective study on 12 patients -7 with systemic lupus erythematosus (SLE), 4 with Wegener's granulomatosis (WG), and 1 with overlapping connective disease and autoimmune thrombocytopenia-, controlled in a specialized unit of a tertiary hospital. Four weekly doses of rituximab, 2 biweekly doses of cyclophosphamide, and glucocorticoids were administered to all patients, and other immunosuppressants were also administered as considered necessary in each case. RESULTS: Mean follow up after treatment with rituximab was 12.8 moths for SLE patients and 12.3 for WG patients. In SLE patients, proteinuria was reduced below 1 g daily in 5 cases (83%), with a clear parallel improvement in the urinary sediment. Serositis was resolved in both cases. One patient required 3 treatment cycles to obtain an adequate response and another required a second cycle for relapse. Only one patient with WG had a favorable response. The patient treated for autoimmune thrombocytopenia had a favorable response, with no relapses, and creatine-kinase levels also tended to return to normal. There were 2 serious adverse events (terminal renal failure and serious colitis in a patient with SLE, and death of one patient with WG), that were not adjudicated directly to rituximab. Immunoglobulin levels did not change substantially. There were no infusion reactions or associated infections. CONCLUSIONS: Rituximab was useful in patients with SLE refractory to other immunosuppressants. On the contrary, its efficacy in WG was limited. The response of thrombocytopenia was complete and maintained.

Mielitis transversa en lupus eritematoso sistémico / Transverse myelitis in systemic lupus erythematosus

Objetivo: La mielitis transversa aguda (MTA) es una rara complicación en los pacientes con lupus eritematoso sistémico (LES). Revisamos nuestra serie de pacientes con LES para determinar la prevalencia de MTA y analizar las características clínicas, las pruebas complementarias, la evolución y la respuesta al tratamiento. Pacientes y método: Se identificó a 6 pacientes con MTA que se sometieron a valoración clínico-neurológica, resonancia magnética y estudio electrofisiológico y recibieron el mismo tratamiento. Realizamos un estudio estadístico descriptivo. Resultados: Observamos una prevalencia de MTA del 0,92% de nuestros pacientes con LES. El 83,3% presentaba anticuerpos antifosfolipídicos y/o anticoagulante lúpico. La resonancia magnética confirmó el diagnóstico en 5 de los 6 casos; 3 de los 5 pacientes con anticuerpos antifosfolipídicos fueron anticoagulados o antiagregados, con buena evolución neurológica; 2 de ellos han quedado sin secuelas. Conclusiones: Encontramos una prevalencia similar a la observada en otras series, en torno al 1%. La alta prevalencia de anticuerpos antifosfolipídicos en los pacientes, con buen resultado en los antiagregados o anticoagulados, indica un importante papel patogénico en el desarrollo de la MTA, y nos hace plantearnos la importancia de añadir al tratamiento estándar terapia antiagregante o anticoagulante (AU)

Objective: Transverse myelitis (TM) is a rare complication in patients with systemic lupus erithematosus (SLE). We reviewed a series of our SLE patients to determine the prevalence of TM, and evaluate the clinical characteristics, medical tests, evolution and response to the treatment. Patients and method: Six patients with TM were identified and underwent a neurological evaluation, MRI, electrophysiologic study and were all subjected to the same treatment. A descriptive statistical study was conducted. Results: We observed a prevalence of 0.92% in our patients with SLE. Eighty three point three per cert had antiphospholipid antibodies and/or lupus anticoagulant. The MRI confirmed the diagnosis in 5 cases. Of the 5 patients with antiphospholypid antibodies, 3 were anticoagulated or took aspirin with a good neurological outcome, leaving 2 of them without posterior complications. Conclusions: We found a prevalence similar to that observed in other series, around 1%. The high prevalence of antiphospholypid antibodies in these patients, with good outcome in those anticoagulated or treated with antiplatelet agents suggests an important pathogenic role in the development of TM, and emphasized the possibility of adding to the standard treatment, antiplatelet agents or anticoagulation (AU)

Utilización de fármacos contra el factor de necrosis tumoral en una paciente con afección neurológica por enfermedad de Behçet / No disponible

No disponible

Utilidad del rituximab en el tratamiento de pacientes con enfermedades sistémicas autoinmunitarias / Rituximab for treatment of patients with systemic autoimmune diseases

Fundamento y objetivo: Evaluar la utilidad del rituximab en el tratamiento de enfermedades autoinmunitarias sistémicas refractarias a otros tratamientos. Pacientes y método: Se ha realizado un estudio prospectivo de 12 pacientes: 7 con lupus eritematoso sistémico (LES), 4 con granulomatosis de Wegener (GW) y 1 con conectivopatía de superposición y trombocitopenia autoinmunitaria. Se administraron 4 dosis semanales de rituximab y 2 quincenales de ciclofosfamida, además de glucocorticoides y otros inmunodepresores según se estimó necesario en cada caso. Resultados: El tiempo de seguimiento medio tras finalizar el tratamiento con rituximab fue de 12,8 meses para los pacientes con LES y de 12,3 para los pacientes con GW. Entre los casos de LES, la proteinuria se redujo por debajo de 1 g al día en 5 pacientes (83%), con mejoría paralela evidente en el sedimento urinario. La serositis se resolvió en los 2 casos. Un paciente requirió 3 ciclos de tratamiento antes de obtener una respuesta adecuada y otro requirió un segundo ciclo por recaída. Sólo un paciente con GW tuvo una respuesta favorable. El paciente tratado por trombocitopenia autoinmunitaria tuvo una respuesta favorable, sin recurrencias, y además sus valores de creatincinasa tendieron a normalizarse. Hubo 2 acontecimientos adversos graves (insuficiencia renal terminal y colitis grave en una paciente con LES, y fallecimiento de un paciente con GW), que no se atribuyeron directamente al rituximab. Los valores de inmunoglobulinas no se modificaron sustancialmente. No hubo reacciones infusionales ni infecciones asociadas. Conclusiones: El rituximab resultó útil en pacientes con LES resistente a otros inmunodepresores. Por el contrario, su eficacia en la GW resultó limitada. La respuesta de la trombocitopenia fue completa y mantenida

Background and objective: To assess the value of rituximab in systemic autoimmune diseases which are refractory to others treatments. Patients and method: Prospective study on 12 patients ­7 with systemic lupus erythematosus (SLE), 4 with Wegener's granulomatosis (WG), and 1 with overlapping connective disease and autoimmune thrombocytopenia­, controlled in a specialized unit of a tertiary hospital. Four weekly doses of rituximab, 2 biweekly doses of cyclophosphamide, and glucocorticoids were administered to all patients, and other immunosuppressants were also administered as considered necessary in each case. Results: Mean follow up after treatment with rituximab was 12.8 moths for SLE patients and 12.3 for WG patients. In SLE patients, proteinuria was reduced below 1 g daily in 5 cases (83%), with a clear parallel improvement in the urinary sediment. Serositis was resolved in both cases. One patient required 3 treatment cycles to obtain an adequate response and another required a second cycle for relapse. Only one patient with WG had a favorable response. The patient treated for autoimmune thrombocytopenia had a favorable response, with no relapses, and creatine-kinase levels also tended to return to normal. There were 2 serious adverse events (terminal renal failure and serious colitis in a patient with SLE, and death of one patient with WG), that were not adjudicated directly to rituximab. Immunoglobulin levels did not change substantially. There were no infusion reactions or associated infections. Conclusions: Rituximab was useful in patients with SLE refractory to other immunosuppressants. On the contrary, its efficacy in WG was limited. The response of thrombocytopenia was complete and maintained