EphA2-specific microvesicles derived from tumor cells facilitate the targeted delivery of chemotherapeutic drugs for osteosarcoma therapy.

Despite advances in surgery and chemotherapy, the survival of patients with osteosarcoma (OS) has not been fundamentally improved over the last two decades. Microvesicles (MVs) have a high cargo-loading capacity and are emerging as a promising drug delivery nanoplatform. The aim of this study was to develop MVs as specifically designed vehicles to enable OS-specific targeting and efficient treatment of OS. Herein, we designed and constructed a nanoplatform (YSA-SPION-MV/MTX) consisting of methotrexate (MTX)-loaded MVs coated with surface-carboxyl Fe3O4 superparamagnetic nanoparticles (SPIONs) conjugated with ephrin alpha 2 (EphA2)-targeted peptides (YSAYPDSVPMMS, YSA). YSA-SPION-MV/MTX showed an effective targeting effect on OS cells, which was depended on the binding of the YSA peptide to EphA2. In the orthotopic OS mouse model, YSA-SPION-MV/MTX effectively delivered drugs to tumor sites with specific targeting, resulting in superior anti-tumor activity compared to MTX or MV/MTX. And YSA-SPION-MV/MTX also reduced the side effects of high-dose MTX. Taken together, this strategy opens up a new avenue for OS therapy. And we expect this MV-based therapy to serve as a promising platform for the next generation of precision cancer nanomedicines.

Effect of combined treatment with prednisone and methotrexate versus prednisone alone over laboratory parameters in giant cell arteritis / Efecto del tratamiento combinado con prednisona y metotrexato versus prednisona sola sobre los parámetros de laboratorio en arteritis de células gigantes

Objective: To compare the effect of combined treatment with prednisone and methotrexate (MTX) versus prednisone alone over laboratory parameters in giant cell arteritis (GCA). Patients and methods: We performed a double-blind, placebo-controlled, randomized clinical trial about usefulness of treatment with prednisone and MTX versus prednisone and placebo in GCA (Ann Intern Med 2001;134:106–114). As a part of follow-up of patients (n=42), we performed laboratory analysis in 20 time points during the two-year period of follow-up. To analyze differences, we calculated the area under the curve (AUC) for erythrocyte sedimentation rate (ESR), hemoglobin, and platelets, and compared the results in both groups adjusting by time of follow-up, existence of relapses and dose of prednisone. Results: A total of 724 laboratory measurements were done. Median value of ESR was 33 [18–56] in patients with placebo and 26 [15–44] in patients with MTX (P=0.0002). No significant differences were observed in ESR during relapses. The mean ESR value followed a parallel course in both groups, but was lower in the group with MTX than in the group with placebo in 18 of 20 time points of follow-up. The AUC of ESR by time of follow-up was 28,461.7±12,326 in the group with placebo and 19,598.4±8,117 in the group with MTX (mean difference 8,863, 95% CI 1.542–16.184; P=0.019). The course of other laboratory parameters paralleled, without statistical significance, those observed for ESR. Conclusions: These data, along with clinical data, suggest that MTX might play a role as a disease-modifying agent in the treatment of GCA.(AU)

Objetivo: Comparar el efecto del tratamiento combinado con prednisona y metotrexato (MTX) versus prednisona sola sobre parámetros de laboratorio en arteritis de células gigantes (ACG). Pacientes y métodos: Realizamos un ensayo clínico aleatorizado, doble ciego, controlado con placebo sobre la utilidad del tratamiento con prednisona y MTX frente a prednisona y placebo en la ACG (Ann Intern Med. 2001;134:106-114). Como parte del seguimiento de los pacientes (n=42), realizamos análisis de laboratorio en 20 puntos temporales durante el período de seguimiento de 2 años. Para analizar diferencias calculamos el área bajo la curva (AUC) de VSG, hemoglobina y plaquetas, y comparamos los resultados en ambos grupos ajustando por tiempo de seguimiento, existencia de recaídas y dosis de prednisona. Resultados: Se realizaron un total de 724 mediciones de laboratorio. El valor medio de la VSG fue de 33 (18-56) en pacientes con placebo y de 26 (15-44) en pacientes con MTX (p=0,0002). No se observaron diferencias significativas en la VSG durante las recaídas. El valor medio de la VSG siguió un curso paralelo en ambos grupos, pero fue menor en el grupo con MTX que en el grupo con placebo en 18 de 20 puntos temporales de seguimiento. El AUC de la VSG por tiempo de seguimiento fue de 28.461,7±12.326 en el grupo con placebo y de 19.598,4±8.117 en el grupo con MTX (diferencia de medias 8.863; IC 95%: 1.542-16.184; p=0,019). La evolución de los demás parámetros de laboratorio fue paralela, sin significación estadística, a la observada para la VSG. Conclusiones: Estos datos, junto con los datos clínicos, sugieren que el MTX podría desempeñar un papel como agente modificador de la enfermedad en el tratamiento de la ACG.(AU)

High-Dose Methotrexate as CNS Prophylaxis in High-Risk Aggressive B-Cell Lymphoma.

PURPOSE: CNS progression or relapse is an uncommon but devastating complication of aggressive B-cell lymphoma. There is no consensus regarding the optimal approach to CNS prophylaxis. This study was designed to determine whether high-dose methotrexate (HD-MTX) is effective at preventing CNS progression in patients at high risk of this complication. PATIENTS AND METHODS: Patients age 18-80 years with aggressive B-cell lymphoma and high risk of CNS progression, treated with curative-intent anti-CD20-based chemoimmunotherapy, were included in this international, retrospective, observational study. Cause-specific hazard ratios (HRs) and cumulative risks of CNS progression were calculated according to use of HD-MTX, with time to CNS progression calculated from diagnosis for all patients (all-pts) and from completion of frontline systemic lymphoma induction therapy, for patients in complete response at completion of chemoimmunotherapy (CR-pts). RESULTS: Two thousand four hundred eighteen all-pts (HD-MTX; n = 425) and 1,616 CR-pts (HD-MTX; n = 356) were included. CNS International Prognostic Index was 4-6 in 83.4% all-pts. Patients treated with HD-MTX had a lower risk of CNS progression (adjusted HR, 0.59 [95% CI, 0.38 to 0.90]; P = .014), but significance was not retained when confined to CR-pts (adjusted HR, 0.74 [95% CI, 0.42 to 1.30]; P = .29), with 5-year adjusted risk difference of 1.6% (95% CI, -1.5 to 4.4; all-pts) and 1.4% (95% CI, -1.5 to 4.1; CR-pts). Subgroups were underpowered to draw definitive conclusions regarding the efficacy of HD-MTX in individual high-risk clinical scenarios; however, there was no clear reduction in CNS progression risk with HD-MTX in any high-risk subgroup. CONCLUSION: In this large study, high-risk patients receiving HD-MTX had a 7.2% 2-year risk of CNS progression, consistent with the progression risk in previously reported high-risk cohorts. Use of HD-MTX was not associated with a clinically meaningful reduction in risk of CNS progression.

Periocular methotrexate versus periocular triamcinolone injections for active thyroid-associated orbitopathy: a randomized clinical trial.

PURPOSE: To assess the efficacy and safety of periocular injections of methotrexate versus triamcinolone in the management of active thyroid-associated orbitopathy. STUDY DESIGN: Prospective, double-masked, randomized clinical trial. METHODS: Participants with bilateral active, moderate-to-severe thyroid-associated orbitopathy were randomly assigned to receive three periocular injections of 7.5 mg methotrexate in one orbit and three periocular injections of 20 mg triamcinolone in the contralateral orbit. RESULTS: Among the enrolled 25 patients, 18 patients completed the study. A statistically significant reduction of the mean clinical activity score was detected in both arms (from 5.2 ± 0.89 at baseline to 0.9 ± 1.7 at study endpoint, p-value < 0.001 in the methotrexate arm, and from 5.1 ± 0.9 at baseline to 1 ± 1.7 at study endpoint, p-value < 0.001 in the triamcinolone arm), mean proptosis also decreased in both arms (from 25.2 ± 3.4 mm at baseline to 23.8 ± 3.7 mm at study endpoint, p-value = 0.01 in the methotrexate arm, and from 24.2 ± 3.06 mm at baseline to 23.2 ± 3.3 mm at study endpoint, p-value = 0.049 in the triamcinolone arm). Lid aperture and soft tissue signs improved significantly in both arms in comparison to baseline. A statistically significant reduction in the intraocular pressure was observed in the methotrexate arm but not in the triamcinolone arm. 88.9% of patients in both arms were overall responders at 6 months. There was no significant difference in mean CAS, proptosis, lid aperture or rate of responders between the two arms at any visit. Both drugs were found to be safe with minimal local and systemic complications. CONCLUSION: Periocular injections of methotrexate represent an effective and safe alternative option for the management of active, moderate-to-severe thyroid-associated orbitopathy. Although no serious complications occurred during the 6-month follow-up, the possibility of late complications such as orbital fat atrophy cannot be ruled out.

Post-Transplantation Cyclophosphamide-Based Graft-versus-Host Disease Prophylaxis.

BACKGROUND: In patients undergoing allogeneic hematopoietic stem-cell transplantation (HSCT), a calcineurin inhibitor plus methotrexate has been a standard prophylaxis against graft-versus-host disease (GVHD). A phase 2 study indicated the potential superiority of a post-transplantation regimen of cyclophosphamide, tacrolimus, and mycophenolate mofetil. METHODS: In a phase 3 trial, we randomly assigned adults with hematologic cancers in a 1:1 ratio to receive cyclophosphamide-tacrolimus-mycophenolate mofetil (experimental prophylaxis) or tacrolimus-methotrexate (standard prophylaxis). The patients underwent HSCT from an HLA-matched related donor or a matched or 7/8 mismatched (i.e., mismatched at only one of the HLA-A, HLA-B, HLA-C, and HLA-DRB1 loci) unrelated donor, after reduced-intensity conditioning. The primary end point was GVHD-free, relapse-free survival at 1 year, assessed in a time-to-event analysis, with events defined as grade III or IV acute GVHD, chronic GVHD warranting systemic immunosuppression, disease relapse or progression, and death from any cause. RESULTS: In a multivariate Cox regression analysis, GVHD-free, relapse-free survival was significantly more common among the 214 patients in the experimental-prophylaxis group than among the 217 patients in the standard-prophylaxis group (hazard ratio for grade III or IV acute GVHD, chronic GVHD, disease relapse or progression, or death, 0.64; 95% confidence interval [CI], 0.49 to 0.83; P = 0.001). At 1 year, the adjusted GVHD-free, relapse-free survival was 52.7% (95% CI, 45.8 to 59.2) with experimental prophylaxis and 34.9% (95% CI, 28.6 to 41.3) with standard prophylaxis. Patients in the experimental-prophylaxis group appeared to have less severe acute or chronic GVHD and a higher incidence of immunosuppression-free survival at 1 year. Overall and disease-free survival, relapse, transplantation-related death, and engraftment did not differ substantially between the groups. CONCLUSIONS: Among patients undergoing allogeneic HLA-matched HSCT with reduced-intensity conditioning, GVHD-free, relapse-free survival at 1 year was significantly more common among those who received cyclophosphamide-tacrolimus-mycophenolate mofetil than among those who received tacrolimus-methotrexate. (Funded by the National Heart, Lung, and Blood Institute and others; BMT CTN 1703 ClinicalTrials.gov number, NCT03959241.).

Problemas clínicos en Micología Médica: problema número 56 / Clinical problems in Medical Mycology: Problem number 56

We present the case of a twenty six year-old woman with rheumatoid arthritis, treated with certolizumab. She sought medical attention due to cough, fever and night sweats. X-ray exam showed a miliary pneumonia. She was treated for tuberculosis and 50days later she presented with aphasia. Magnetic nuclear resonance revealed brain lesions. Histoplasma capsulatum PCR test and urinary antigen were positive, so an antifungal treatment with voriconazole was started. Visual adverse effects forced to change the antifungal schedule in both the length of treatment and the antifungal drug. With this measure the patient progressed favorably. The test of urinary Histoplasma capsulatum antigen and PCR amplification were key to make a diagnosis and also for a follow-up.(AU)

Se presenta el caso de una paciente de 26años de edad, profesora de educación física. Nació y vive en Burzaco, conurbano sur de la Provincia de Buenos Aires, República Argentina. Debido a su trabajo había realizado diversos viajes y acampado en diferentes provincias de nuestro país (Misiones, Corrientes, San Juan y Mendoza). En el extranjero solo había visitado Orlando (EE.UU.). Desde hacía 10años padecía artritis reumatoide juvenil. Por esta patología recibió metotrexato 15mg/semana, prednisona 5mg/día e hidroxicloroquina 400mg/día durante 7años. Posteriormente le fue prescrito certolizumab 200mg cada dos semanas y, posteriormente, 400mg cada cuatro semanas. Tras dos años con esta medicación le fue suspendida por la aparición de tos seca, fiebre, astenia, adinamia y sudores nocturnos. Debido a estas manifestaciones se le realizó una radiografía de tórax (fig. 1) y se suspendió inmediatamente el tratamiento con el inmunomodulador (certolizumab).(AU)

Imaging in gynecological disease (25): clinical and ultrasound characteristics of intramural pregnancy.

OBJECTIVE: To describe the clinical and sonographic characteristics of intramural pregnancy, as well as the available management options and treatment outcomes. METHODS: This was a retrospective single-center study of consecutive patients with a sonographic diagnosis of intramural pregnancy between November 2008 and November 2022. An intramural pregnancy was diagnosed on ultrasound when a pregnancy was implanted within the uterine corpus, above the level of the internal cervical os and separate from the interstitial section of the Fallopian tube, and extended beyond the decidual-myometrial junction. Clinical, ultrasound, relevant surgical and histological information and outcomes were retrieved from each patient's record and analyzed. RESULTS: Eighteen patients were diagnosed with an intramural pregnancy during the study period. Their median age was 35 (range, 28-43) years and the median gestational age at diagnosis was 8 + 1 (range, 5 + 5 to 12 + 0) weeks. Vaginal bleeding with or without abdominal pain was the most common presenting symptom, recorded in eight patients. Nine (50%) patients had a partial and nine (50%) had a complete intramural pregnancy. Embryonic cardiac activity was present in eight (44%) pregnancies. The majority of pregnancies (n = 10 (56%)) were initially managed conservatively, including expectant management in eight (44%) cases, local injection of methotrexate in one (6%) and embryocide in one (6%). Conservative management was successful in nine of the 10 (90%) pregnancies, with a median time to serum human chorionic gonadotropin resolution of 71 (range, 35-143) days. One patient with an ongoing live pregnancy had an emergency hysterectomy for a major vaginal bleed at 20 weeks' gestation. No other patient managed conservatively experienced any significant complication. The remaining eight (44%) patients had primary surgical treatment, comprising transcervical suction curettage in seven (88%) of these cases, while one patient presented with uterine rupture and underwent emergency laparoscopy and repair. CONCLUSIONS: We describe the ultrasound features of partial and complete intramural pregnancy, demonstrating key diagnostic features. Our series suggests that, when intramural pregnancy is diagnosed before 12 weeks' gestation, it can be managed either conservatively or by surgery, with preservation of reproductive function in most women. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Análise das gestações ectópicas íntegras tratadas com o protocolo de dose única de metotrexato / Analysis of unruptured ectopic pregnancies treated with single-dose methotrexate protocol

Objetivo: Avaliar o índice de sucesso do tratamento da gravidez ectópica com o protocolo de dose única do metotrexato e verificar sua correlação com variáveis clínicas e dados dos exames complementares. Métodos: É um estudo epidemiológico observacional, analítico, retrospectivo, de delineamento transversal. Foi realizado de janeiro de 2014 a agosto de 2020 em um hospital público, de ensino, em nível terciário, do Sul do Brasil. Em 73 casos com diagnóstico de gestação ectópica íntegra, foi utilizado o protocolo de dose única de metotrexato intramuscular, com a dose de 50 mg/m2 de superfície corporal. As variáveis do estudo foram relacionadas ao sucesso do tratamento e abordaram as características clínicas na admissão, dos exames complementares e do tratamento realizado. As variáveis foram comparadas por análise de regressão de Poisson. O nível de significância estabelecido foi de p < 0,05. Resultados: O índice de sucesso foi de 83,6%, e em nove casos foi necessária uma segunda dose da medicação. Nível de ß-hCG inicial superior a 5.000 mUI/mL foi relacionado a menor chance de sucesso (odds ratio ajustado de 0,20 [0,05-0,95]). Tamanho da imagem anexial, presença de líquido livre na cavidade abdominal e demais variáveis estudadas não afetaram a chance de sucesso do tratamento. Conclusão: O protocolo de dose única de metotrexato mostrou-se uma opção válida para o tratamento da gestação ectópica íntegra, notadamente quando o nível de ß-hCG inicial é inferior 5.000 mUI/mL.

Objective: The purpose of the present study is to evaluate the success rate of treatment of ectopic pregnancy with the single-dose methotrexate protocol and to verify its correlation with clinical variables and complementary exam data. Methods: This is a retrospective epidemiological observational analytical cross-sectional study. It was carried out from January 2014 to August 2020 in a tertiary level teaching hospital in southern Brazil. In 73 cases with a diagnosis of intact ectopic pregnancy, the intramuscular methotrexate single-dose protocol was applied with a dose of 50 mg/m2 of body surface. The study variables were related to the success of the treatment and addressed the clinical characteristics on admission, the complementary exams and the treatment performed. The variables were compared by Poisson regression analysis. The level of significance was set at p < 0.05. Results: The success rate was 83.6%, and in nine cases a second dose of the medication was necessary. An initial ß-hCG level greater than 5,000 mIU/mL was related to a lower chance of success (adjusted odds ratio of 0.20 [0.05- 0.95]). The size of the adnexal image, the presence of free fluid in the abdominal cavity and other variables studied did not affect the chance of a successful treatment. Conclusion: The methotrexate single-dose protocol proved to be a valid option for the treatment of intact ectopic pregnancy, notably when the initial ß-hCG level is below 5,000 mIU/mL.

EMACO for treatment of gestational trophoblastic neoplasia: A multinational multicenter study.

OBJECTIVE: To investigate the efficacy and toxicity of etoposide, methotrexate, actinomycin D alternating with cyclophosphamide, and vincristine (EMACO) for treatment of gestational trophoblastic neoplasia, and for factors independently associated with EMACO resistance and disease-specific death in an international cohort. METHODS: Medical records of GTN patients who received EMACO during 1986-2019 from gestational trophoblastic disease centers from four countries including the USA, Thailand, Hungary, and Brazil, were retrospectively reviewed. Among 335 GTN patients, 266 patients who received EMACO as primary chemotherapy were included in the primary treatment group, and 69 patients who received EMACO after relapse/resistance to single-agent chemotherapy were included in the prior treatment group. RESULTS: Three-quarters (76.1%) of all patients achieved remission, and the survival rate was 89%. The prior treatment group had better outcomes than the primary treatment group relative to remission rate (87.0% vs. 73.3%, p = 0.014) and number of EMACO cycles to achieve remission (3 vs. 6 cycles, p < 0.001). Sustained remission increased to 87.2% in EMACO-resistant patients treated with later-line chemotherapy. Number of metastatic organs ≥2 (adjusted odds ratio [aOR]: 2.33, p = 0.049) was the only independent predictor of EMACO resistance among overall patients. Interval from index pregnancy ≥7 months (aOR: 4.34, p = 0.001), and pretreatment hCG >100,000 IU/L (aOR: 2.85, p = 0.028) were independent predictors of EMACO resistance in the high-risk subgroup. The only factor independently associated with disease-specific death was EMACO resistance (aOR: 176.04, p < 0.001). CONCLUSIONS: EMACO is an effective treatment for GTN. Number of metastatic organs and EMACO resistance were the independent predictors of EMACO resistance and disease-specific death, respectively.

Treatment and biologic maintenance-dosing patterns among pediatric patients with ulcerative colitis or Crohn's disease.

OBJECTIVES: To assess treatment patterns and initial and maintenance dosing of biologics over 3 years in pediatric patients with ulcerative colitis (UC) or Crohn's disease (CD), utilizing data from the ImproveCareNow registry. METHODS: Pediatric patients diagnosed with UC or CD and aged 2-17 years were included in the study. Descriptive statistics were employed to summarize baseline demographics. The proportion of patients on medication for UC or CD were analyzed at the baseline visit, 1-year, and 3-year time points (Cohort 1). Biologic maintenance dosage was calculated only for patients who had data for dose and weight at all-time points (Cohort 2). RESULTS: In Cohort 1 (UC = 1784; CD = 4720), baseline treatment in UC included corticosteroid, 5-ASA, and 6-MP/AZA; at 1-year and 3-year time points, treatment with 5-ASA and corticosteroid decreased, whereas 6-MP/AZA and anti-TNFs increased. In CD, baseline treatment included corticosteroid, anti-TNF, 6-MP/AZA, and methotrexate; use of corticosteroids decreased, whereas the use of methotrexate and anti-TNFs increased over 3 years. In Cohort 2 (UC = 350; CD = 1537), at first maintenance dose, UC patients on infliximab received a mean dose of 10.5 mg/kg/8 wk, adalimumab (weight < 40 kg and ≥40 kg) 1.3 mg/kg/2 wk and 0.8 mg/kg/2 wk, and vedolizumab 6.9 mg/kg/8 wks. At the first maintenance dose, CD patients on infliximab received a mean dose of 8.1 mg/kg/8 wk, adalimumab (weight < 40 kg) 1.1 mg/kg/2 wk, adalimumab (weight ≥ 40 kg) 0.8 mg/kg/2 wk, and vedolizumab 10.5 mg/kg/8 wks. CONCLUSION: The use of corticosteroids was common at the initial visit in patients. Anti-TNFs remain the most used class of biologics, however, reported doses in our study were substantially higher than the standard dosing guidelines.

Coriorretinopatia de Birdshot: relato de caso e perspectivas sobre o tratamento / Birdshot chorioretinopathy: a case report and perspectives on its treatment

RESUMO A coriorretinopatia de Birdshot é uma uveíte posterior bilateral crônica rara que acomete, preferencialmente, mulheres de meia-idade. O quadro clínico é composto de pouco ou nenhum processo inflamatório de segmento anterior, associado a vitreíte e lesões coriorretinianas ovoides branco-amareladas de característica hiperfluorescente na angiofluoresceinografia e hipofluorescente na angiografia com indocianina verde. O tratamento se dá por meio de corticoides e outras drogas imunossupressoras. Todavia, em alguns casos, a doença é refratária a tal terapêutica, sendo necessário lançar mão de outras drogas, como os agentes biológicos. O presente artigo busca relatar um caso de coriorretinopatia de Birdshot em ajuste de terapia imunossupressora que evoluiu com má resposta às drogas iniciais e bom controle após uso de imunobiológico e discutir as opções terapêuticas disponíveis atualmente.

ABSTRACT Birdshot chorioretinopathy is a rare chronic bilateral posterior uveitis that preferentially affects middle-aged women. The clinical picture is composed of little or no anterior segment inflammatory process, associated with vitritis and yellowish-white ovoid chorioretinal lesions with hyperfluorescent characteristics on fluorescein angiography and hypofluorescent characteristics on green indocyanine green angiography. Treatment is with corticosteroids and other immunosuppressive drugs. However, in some cases, the disease is refractory to such therapy, making it necessary to resort to other drugs such as biological agents. The present article seeks to report a case of Birdshot chorioretinopathy in an adjustment of immunosuppressive therapy that evolved with poor response to the initial drugs and good control after the use of immunobiologicals and discuss the currently available therapeutic options.

Olokizumab versus Placebo or Adalimumab in Rheumatoid Arthritis.

BACKGROUND: The cytokine interleukin-6 is involved in the pathogenesis of rheumatoid arthritis. Olokizumab, a humanized monoclonal antibody targeting the interleukin-6 cytokine directly, is being tested for the treatment of rheumatoid arthritis. METHODS: In a 24-week, phase 3, multicenter, placebo- and active-controlled trial, we randomly assigned (in a 2:2:2:1 ratio) patients with rheumatoid arthritis and an inadequate response to methotrexate to receive subcutaneous olokizumab at a dose of 64 mg every 2 or 4 weeks, adalimumab (40 mg every 2 weeks), or placebo; all patients continued methotrexate therapy. The primary end point was an American College of Rheumatology 20 (ACR20) response (≥20% fewer tender and swollen joints and ≥20% improvement in three of five other domains) at week 12, with each olokizumab dose tested for superiority to placebo. We also tested the noninferiority of each olokizumab dose to adalimumab with respect to the percentage of patients with an ACR20 response (noninferiority margin, -12 percentage points in the lower boundary of the 97.5% confidence interval for the difference between groups). RESULTS: A total of 464 patients were assigned to receive olokizumab every 2 weeks, 479 to receive olokizumab every 4 weeks, 462 to receive adalimumab, and 243 to receive placebo. An ACR20 response at week 12 occurred in 44.4% of the patients receiving placebo, in 70.3% receiving olokizumab every 2 weeks (difference vs. placebo, 25.9 percentage points; 97.5% confidence interval [CI], 17.1 to 34.1), in 71.4% receiving olokizumab every 4 weeks (difference vs. placebo, 27.0 percentage points; 97.5% CI, 18.3 to 35.2), and in 66.9% receiving adalimumab (difference vs. placebo, 22.5 percentage points; 95% CI, 14.8 to 29.8) (P<0.001 for the superiority of each olokizumab dose to placebo). Both olokizumab doses were noninferior to adalimumab with respect to the percentage of patients with an ACR20 response at week 12 (difference, 3.4 percentage points [97.5% CI, -3.5 to 10.2] with olokizumab every 2 weeks and 4.5 percentage points [97.5% CI, -2.2 to 11.2] with olokizumab every 4 weeks). Adverse events, most commonly infections, occurred in approximately 70% of the patients who received olokizumab. Antibodies against olokizumab were detected in 3.8% of the patients receiving the drug every 2 weeks and in 5.1% of those receiving it every 4 weeks. CONCLUSIONS: In patients with rheumatoid arthritis who were receiving maintenance methotrexate, olokizumab was superior to placebo and noninferior to adalimumab in producing an ACR20 response at 12 weeks. Larger and longer trials are required to determine the efficacy and safety of olokizumab in patients with rheumatoid arthritis. (Supported by R-Pharm; CREDO2 ClinicalTrials.gov number, NCT02760407.).

Impact of Methotrexate Discontinuation, Interruption, or Persistence in US Patients with Rheumatoid Arthritis Initiating Tofacitinib + Oral Methotrexate Combination.

PURPOSE: Using data from real-world practice, this analysis compared outcomes in patients with rheumatoid arthritis (RA) initiating treatment with an oral Janus kinase inhibitor, tofacitinib, in combination with persistent, discontinued, or interrupted treatment with oral methotrexate (MTX). METHODS: This retrospective claims analysis (MarketScan® databases) included data from US patients with RA and at least one prescription claim for tofacitinib, dated between January 1, 2013, and April 30, 2017. Eligible patients were continuously enrolled for ≥12 months before and after treatment initiation, and initiated tofacitinib in combination with oral MTX, with at least two prescription claims for each. Patients were grouped according to treatment pattern (MTX-Persistent, MTX-Discontinued, or MTX-Interrupted). Tofacitinib treatment persistence, adherence, and effectiveness, as well as all-cause and RA-related health care costs, were assessed. FINDINGS: A total of 671 patients were eligible for inclusion; 504 (75.1%) were MTX-Persistent; 131 (19.5%), MTX-Discontinued; and 36 (5.4%), MTX-Interrupted. Rates of tofacitinib treatment persistence, adherence, and effectiveness at 12 months were similar between the MTX-Persistent and MTX-Discontinued cohorts. The percentage of patients switched from tofacitinib to another advanced disease-modifying antirheumatic drug within 12 months of tofacitinib initiation was greater in the MTX-Persistent cohort compared with that in the MTX-Discontinued cohort. RA-related health care costs at 12 months post-initiation were significantly greater in the MTX-Persistent cohort compared with those in the MTX-Discontinued cohort. IMPLICATIONS: The findings from this analysis of real-world data indicate that patients who initiate tofacitinib in combination with oral MTX may discontinue MTX and still experience outcomes similar to those in patients who persist with MTX, with lesser RA-related health care costs. These results support those from a previous clinical study on methotrexate withdrawal in patients with RA (NCT02831855).