Real life data: follow-up assessment on Spanish Gaucher disease patients treated with eliglustat. TRAZELGA project.

BACKGROUND: The availability of multiple treatments for type 1 Gaucher disease increases the need for real-life studies to evaluate treatment efficacy and safety and provide clinicians with more information to choose the best personalized therapy for their patients. AIMS: To determine whether treatment with eliglustat produces, in adult GD1 patients, ans optimal response in daily clinical practice. METHODS: We designed a real-life study with 2 years of follow-up (TRAZELGA [GEE-ELI-2017-01]) to uniformly evaluate the response and adverse events to eliglustat treatment. This study, conducted in 30 patients across Spain and previously treated with other therapies, included the evaluation of safety and efficacy by assessing visceral enlargement, bone disease (DEXA and T and Z scores), concomitant treatments and adverse events, as well as a quality of life evaluation (SF-36). In addition, the quantification of classical biomarkers (chitotriosidase activity, CCL18/PARC and glucosylsphingosine (GluSph)) and new candidates for GD biomarkers (YKL-40, cathepsin S, hepcidin and lipocalin-2 determined by immunoassay) were also assessed. Non-parametric statistical analysis was performed and p < 0.05 was considered statistically significant. MAIN RESULTS: Thirty patients were enrolled in the study. The median age was 41.5 years and the male-female ratio was 1.1:1. 84% of the patients had received ERT and 16% SRT as previous treatment. The most common symptoms at baseline were fatigue (42%) and bone pain (38%), no patient had a bone crisis during the study, and two years after switching, 37% had reduced their use of analgesics. Patient-reported outcomes showed a significant increase in physical function scores (p = 0.027) and physical pain scores (p = 0.010). None of the enrolled patients discontinued treatment due to adverse events, which were mild and transient in nature, mainly gastrointestinal and skin dryness. None of the biomarkers show a significant increase or decompensation after switching. CCL18/PARC (p = 0.0012), YKL-40 (p = 0.00004) and lipocalin-2 (p = 0.0155) improved after two years and GluSph after one year (p = 0.0008) and two years (p = 0.0245) of oral therapy. CONCLUSION: In summary, this real-life study, showed that eliglustat maintains stability and can improve quality of life with few side effects. Significant reductions in classic and other novel biomarkers were observed after two years of therapy.

Toxicity of Asciminib in Real Clinical Practice: Analysis of Side Effects and Cross-Toxicity with Tyrosine Kinase Inhibitors.

(1) Background: Despite the prognostic improvements achieved with tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML), a minority of patients still fail TKIs. The recent introduction of asciminib may be a promising option in intolerant patients, as it is a first-in-class inhibitor with a more selective mechanism of action different from the ATP-competitive inhibition that occurs with TKIs. Therefore, our goal was to analyze toxicities shown with asciminib as well as to study cross-toxicity with previous TKIs. (2) Methods: An observational, multicenter, retrospective study was performed with data from 77 patients with CML with therapeutic failure to second-generation TKIs who received asciminib through a managed-access program (MAP) (3) Results: With a median follow-up of 13.7 months, 22 patients (28.5%) discontinued treatment: 32% (7/22) due to intolerance and 45% (10/22) due to resistance. Fifty-five percent of the patients reported adverse effects (AEs) with asciminib and eighteen percent grade 3-4. Most frequent AEs were: fatigue (18%), thrombocytopenia (17%), anemia (12%), and arthralgias (12%). None of the patients experienced cardiovascular events or occlusive arterial disease. Further, 26%, 25%, and 9% of patients required dose adjustment, temporary suspension, or definitive discontinuation of treatment, respectively. Toxicities under asciminib seemed lower than with prior TKIs for anemia, cardiovascular events, pleural/pericardial effusion, diarrhea, and edema. Cross-toxicity risk was statistically significant for thrombocytopenia, anemia, neutropenia, fatigue, vomiting, and pancreatitis. (4) Conclusion: Asciminib is a molecule with a good safety profile and with a low rate of AEs. However, despite its new mechanism of action, asciminib presents a risk of cross-toxicity with classical TKIs for some AEs.

Six months multicentre pilot open label single-arm study to evaluate patient experience, acceptability and satisfaction of switching certolizumab pegol from a prefilled syringe or autoinjection pen to an AVA® e-Device in rheumatoid arthritis, psoriatic arthritis and axial spondyloarthritis patients.

WHAT IS KNOWN AND OBJECTIVE: The study aimed to assess acceptability and patient experience of Certolizumab (CZP) self-injection with AVA® and clarify patient device preference after switching CZP from the syringe or auto-injection pen to AVA® in rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA) patients. METHOD: A multicentre open-label, cross-sectional and prospective study among four Spanish hospitals was performed. Adult RA, PsA, axSpA patients treated for at least 6 months with the CZP syringe or pen were recruited. At the first visit, patients completed Pre-AVA® questionnaire. Patients were instructed on proper administration of CZP by AVA®. After 2 and 6 months of CZP self-injections using the AVA®, patient experience, adherence, preference and safety of each administration was assessed using post-AVA® questionnaire. RESULTS AND DISCUSSION: Thirty four patients were included (28 women). All patients self-administered CZP AVA® the full dose of CZP was injected. Patients reported >90% adherence to CZP AVA® assessed with the injection log. Pain at the injection site was reduced after switching to AVA®. Twenty nine patients preferred CZP AVA® and five patients preferred the CZP pen. No safety-related findings related to AVA® CZP administration were identified. WHAT IS NEW AND CONCLUSION: The AVA® is an advantageous delivery option for CZP in patients with RA, PsA, axSpA.

Proposed global prognostic score for systemic mastocytosis: a retrospective prognostic modelling study.

BACKGROUND: Several risk stratification models have been proposed in recent years for systemic mastocytosis but have not been directly compared. Here we designed and validated a risk stratification model for progression-free survival (PFS) and overall survival (OS) in systemic mastocytosis on the basis of all currently available prognostic factors, and compared its predictive capacity for patient outcome with that of other risk scores. METHODS: We did a retrospective prognostic modelling study based on patients diagnosed with systemic mastocytosis between March 1, 1983, and Oct 11, 2019. In a discovery cohort of 422 patients from centres of the Spanish Network on Mastocytosis (REMA), we evaluated previously identified, independent prognostic features for prognostic effect on PFS and OS by multivariable analysis, and designed a global prognostic score for mastocytosis (GPSM) aimed at predicting PFS (GPSM-PFS) and OS (GPSM-OS) by including only those variables that showed independent prognostic value (p<0·05). The GPSM scores were validated in an independent cohort of 853 patients from centres in Europe and the USA, and compared with pre-existing risk models in the total patient series (n=1275), with use of Harrells' concordance index (C-index) as a readout of the ability of each model to risk-stratify patients according to survival outcomes. FINDINGS: Our GPSM-PFS and GPSM-OS models were based on unique combinations of independent prognostic factors for PFS (platelet count ≤100 × 109 cells per L, serum ß2-microglobulin ≥2·5 µg/mL, and serum baseline tryptase ≥125 µg/L) and OS (haemoglobin ≤110 g/L, serum alkaline phosphatase ≥140 IU/L, and at least one mutation in SRSF2, ASXL1, RUNX1, or DNMT3A). The models showed clear discrimination between low-risk and high-risk patients in terms of worse PFS and OS prognoses in the discovery and validation cohorts, and further discrimination of intermediate-risk patients. The GPSM-PFS score was an accurate predictor of PFS in systemic mastocytosis (C-index 0·90 [95% CI 0·87-0·93], vs values ranging from 0·85 to 0·88 for pre-existing models), particularly in non-advanced systemic mastocytosis (C-index 0·85 [0·76-0·92], within the range for pre-existing models of 0·80 to 0·93). Additionally, the GPSM-OS score was able to accurately predict OS in the entire cohort (C-index 0·92 [0·89-0·94], vs 0·67 to 0·90 for pre-existing models), and showed some capacity to predict OS in advanced systemic mastocytosis (C-index 0·72 [0·66-0·78], vs 0·64 to 0·73 for pre-existing models). INTERPRETATION: All evaluated risk classifications predicted survival outcomes in systemic mastocytosis. The REMA-PFS and GPSM-PFS models for PFS, and the International Prognostic Scoring System for advanced systemic mastocytosis and GPSM-OS model for OS emerged as the most accurate models, indicating that robust prognostication might be prospectively achieved on the basis of biomarkers that are accessible in diagnostic laboratories worldwide. FUNDING: Carlos III Health Institute, European Regional Development Fund, Spanish Association of Mastocytosis and Related Diseases, Rare Diseases Strategy of the Spanish National Health System, Junta of Castile and León, Charles and Ann Johnson Foundation, Stanford Cancer Institute Innovation Fund, Austrian Science Fund.

Successful use of golimumab in a patient with ulcerative colitis refractory to infliximab and adalimumab.

OBJECTIVE: To report a case of successful use of golimumab (GLB) in a patient with ulcerative colitis (UC) refractory to infliximab (IFX) and adalimumab (ADA). CASE SUMMARY: A 60-year-old man was diagnosed with left UC and was given azathioprine 2.5 mg/kg to control UC symptoms and decrease corticosteroid patient dependence. Four years later, he developed adverse reaction to azathioprine and began treatment with mercaptopurine 1.5 mg/kg/day. Despite this treatment, he developed a severe relapse (Truelove-Witts modified: 15 points). Treatment with IFX 5 mg/kg at weeks 0, 2, 6, and every 8 weeks was started. After 1 year in clinical remission, the patient developed an infusion reaction to IFX, and IFX was suspended. The patient started treatment with ADA 40 mg every other week. After 2 years in clinical remission, ADA was suspended. 20 months after ADA discontinuation, the patient developed an acute episode of UC with a Truelove-Witts modified score of 16 points. ADA plus corticosteroid therapy was restarted. Despite these treatments, the patient's clinical condition did not improved. ADA 40 mg per week was started with not clinical improvement and with corticosteroid dependence after 4 months of ADA intensive therapy. The patient denied surgery, and cyclosporine was discarded because of its inability to be used as a maintenance drug. The patient started GLB with an induction dosage regimen of 200 mg subcutaneous at week 0, followed by 100 mg at week 2, and then maintenance therapy with 100 mg every 4 weeks (patient's weight = 84 kg), combined with mercaptopurine and corticosteroids. After 6 weeks of treatment, the patient achieved clinical remission, with just three non-bleeding stools per day, without stomach ache, apyretic, and no urgency or tenesmus rectal symptoms. One year later, the patient continued to be asymptomatic with a Truelove-Witts modified score of 2 points, corticoid-free treatment, and a complete clinical and endoscopic remission and normal calprotectin levels (< 15 µg/g). We decided to suspend mercaptopurine in order to avoid side effects derived from the combined treatment. After 1 year on GLB therapy, the patient continued in clinical remission. CONCLUSIONS: Based on our case, GLB could be selected as an effective approach for patients with UC refractory to IFX and ADA. However, further studies need to be performed to evaluate the efficacy of GLB therapy as a rescue treatment.

Legionella pneumophila pneumonia possibly due to ustekinumab therapy in a patient with Crohn's disease.

PURPOSE: A case report of Legionella pneumophila pneumonia associated with off-label use of ustekinumab in a patient with Crohn's disease (CD) is presented. SUMMARY: A 57-year-old man with longstanding CD was hospitalized with a four-day history of fever (38.5 °C), dyspnea, left pleuritic pain, and weight loss (more than 6 kg) about six weeks after beginning treatment with ustekinumab, a human monoclonal antibody approved in the United States for two indications (plaque psoriasis and psoriatic arthritis) and currently under investigation as a potential treatment for CD and other inflammatory disorders. During the preceding 25 years, the man had been treated for severe CD with a number of agents (e.g., infliximab, adalimumab, certolizumab); ultimately, off-label ustekinumab therapy (90 mg subcutaneously weekly) was initiated due to persistent severe CD symptoms. Chest x-ray studies at the time of admission demonstrated left upper lobar consolidation, and a urine antigen test was positive for L. pneumophila. The patient was treated with i.v. levofloxacin and methylprednisolone and discharged after two weeks. Ustekinumab was reintroduced (45 mg subcutaneously every two weeks), and the patient continued to receive the drug for 16 months, with clinical remission of CD symptoms and no further adverse events. A literature search identified two case reports of pneumonia associated with ustekinumab use, but neither case involved L. pneumophila. CONCLUSION: Pneumonia caused by L. pneumophila developed in a patient with CD treated with ustekinumab. Pneumonia symptoms resolved after ustekinumab was discontinued.

Successful use of infliximab and tacrolimus combination therapy in a patient with ulcerative colitis refractory to infliximab dose intensification plus azathioprine.

OBJECTIVE: To report of a case successful use of infliximab (IFX) and tacrolimus (TAC) in a patient with ulcerative colitis (UC). CASE SUMMARY: A 22-year-old woman diagnosed with UC started treatment with azathioprine 2.5 mg/kg. After 3 years of therapy, she developed a severe relapse. A colonoscopy was performed showing diffuse continuous mucosal disease and multiple erosions (< 5 mm) with no signs of spontaneous bleeding. Treatment with IFX 5 mg/kg at weeks 0, 2, and 6 was started. After IFX induction, she remained with symptoms: six stools per day, as well as presenting bloody diarrhea, tenesmus, and no abdominal pain. An IFX dose intensification of 5 mg/kg every 6 weeks was prescribed. After 6 months of azathioprine plus IFX therapy, patient's clinical condition was improved: 3 - 4 stools per day, 20% of bloody diarrhea, tenesmus, and no abdominal pain. Her Mayo endoscopic subscore was 6.3 months later, and a severe relapse of ulcerative colitis was presented. The patient refused a surgical treatment. Azathioprine 2.5 mg/kg/day was suspended and TAC 0.2 mg/kg/day (12 mg/day) as a compassionate use was added to IFX dose intensification of 10 mg/kg every 8 weeks and mesalamine 800 mg 3 times daily. After the first month of combined therapy, the patient's clinical condition improved with no bloody stools and abdominal pain. After 6 months of combination therapy, the patient was in remission, with two stools per day, no tenesmus and no abdominal pain. Due to the patient's clinical remission, IFX was suspended. Tacrolimus was continued on 10 mg/day. After 6 months of TAC monotherapy, the patient continued without symptoms (1 - 2 normal stools per day). CONCLUSIONS: Based on our case, the combination therapy of IFX and TAC could be selected as an effective approach for the patients with UC refractory to IFX dose intensification plus AZA. However, further studies need to be performed to evaluate the efficacy of this combination therapy.

Dealing with the high cost of biological therapies: developing and implementing a biological therapy prioritization protocol for ankylosing spondylitis patients in a tertiary hospital.

OBJECTIVE: In January 2011, a biological therapies commission was created in our hospital to fully address the management of biological drugs. A biological therapy prioritization protocol was developed for ankylosing spondylitis (AS) patients. Here, we describe it and report on its economic impact to illustrate how we are optimizing the use of these expensive new drugs. METHODS: The biological therapies commission established several procedures for the rational use of biological drugs such as cost-efficiency therapeutic protocols, pharmacovigilance, and therapeutic drug monitoring programs. The AS protocol was based on clinical and economic aspects. We estimated the economic impact of the protocol by comparing the cost of treating AS patients with biological drugs in the pre-commission (2009 - 2010) vs. post-commission period (2011 - 2013). AS patients treated with adalimumab (ADA), etanercept (ETN) or infliximab (IFX) for at least 6 months in the 2009 - 2013 period were included. RESULTS: 107 patients were included. In the pre-commission period, total expenses increased by +30,944 Euro (+4%). After protocol implementation, total expenses decreased by 11,441 Euro (-1%) during 2011, and by an additional 36,781 Euro (-4%) and 53,872 Euro (-8%) in 2012 and 2013, respectively. In the 2010 - 2013 period the cost of biological therapy per patient-year decreased by 869 €, suggesting the positive effects of the biological therapy prioritization protocol instauration. CONCLUSION: We describe the establishment of a multidisciplinary biological therapy commission to optimize the use of biological therapies. We illustrate its work in developing a protocol for the management of AS patients with such therapies. We show that after 3-years of implementation, the biological therapy prioritization protocol allowed us to steadily decrease the direct cost of biological drug therapies per patient, up to 869 Euro.

Successful use of infliximab and tacrolimus in a patient with Crohn's disease.

OBJECTIVE: To report a case of successful use of infliximab (IFX) and tacrolimus (TAC) in a patient with Crohn's disease (CD). CASE SUMMARY: A 42-year-old man with no significant previous medical history was referred to our emergency department because of a 3-month history of weight loss, severe abdominal pain, and bloody diarrhea. His Harvey Bradshaw Index was 39. Ileocolonoscopic revealed severe Crohn colitis. Treatment with IFX 5 mg/kg, azathioprine 2.5 mg/kg/day and corticosteroids was started. After a second IFX infusion, he remained with symptoms with a Harvey Bradshaw Index of 17. An IFX dose intensification of 10 mg/kg every 8 weeks was prescribed. After 16 weeks, a new colonoscopic examination revealed multiple deep ulcerations in sigma and rectum. IFX was intensified to 10 mg/kg every 6 weeks. After 4 doses of IFX intensified dose, the patient's clinical condition was not improved, with a Harvey Bradshaw Index of 10. Azathioprine (AZA) 2.5 mg/kg/day was suspended. Tacrolimus 0.2 mg/kg/day as a compassionate use was added to IFX 10 mg/kg every 6 weeks. After 6 months of combination therapy, the patient was in clinical remission. His Harvey Bradshaw Index was 3. After 1 year on combination IFX and TAC therapy, the patient continued in clinical remission. CONCLUSIONS: This case documents that the combination therapy of IFX and TAC could be selected as an effective approach for patients with CD refractory to IFX dose-intensification plus AZA. However, further studies need to be performed to evaluate the efficacy of this combination therapy.

Toxoplasmosis cerebral en paciente con macroglobulinemia de Waldenström / Cerebral toxoplasmosis in a patient with Waldenström's macroglobulinemia

No disponible

Adverse cutaneous reactions induced by TNF-alpha antagonist therapy.

OBJECTIVE: To review adverse cutaneous drug reactions induced by tumor necrosis factor alpha (TNF-alpha) antagonist therapy. METHODS: A literature search was performed using PubMed (1996-March 2009), EMBASE, and selected MEDLINE Ovid bibliography searches. All language clinical trial data, case reports, letters, and review articles identified from the data sources were used. RESULTS: Since the introduction of TNF-alpha antagonist, the incidence of adverse cutaneous drug reactions has increased significantly. A wide range of different skin lesions might occur during TNF-alpha antagonist treatment. New onset or exacerbation of psoriasis has been reported in patients treated with TNF-alpha antagonists for a variety of rheumatologic conditions. TNF-alpha antagonist therapy has been associated with a lupus-like syndrome; most of these case reports occurred in patients receiving either etanercept or infliximab. Serious skin reactions such as erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported rarely with the use of TNF-alpha antagonists. CONCLUSIONS: As the use of TNF-alpha antagonists continues to increase, the diagnosis and management of cutaneous side effects will become an increasingly important challenge. In patients receiving TNF-alpha antagonist treatment, skin disease should be considered, and clinicians need to be aware of the adverse reactions of these drugs.

Severe stomatitis complicating treatment with pegylated-interferon alpha-2a and ribavirin in an HCV-infected patient.

OBJECTIVE: To report a case of severe stomatitis probably induced by peginterferon alpha-2a. METHODS AND RESULTS: A 42-year-old man with chronic hepatitis C genotype 1b commenced treatment with peginterferon alpha-2a 180 microg subcutaneously weekly and ribavirin 1000 mg/d orally. Twenty-eight days after commencing treatment, the patient experienced difficulties with swallowing, dryness of the mouth, stomatitis, and pain. Diagnosis of stomatitis was made. He did not complain of any other adverse effect of peginterferon alpha-2a and ribavirin. Both medications were discontinued. The withdrawal of peginterferon alpha-2a was followed by the resolution of the oral lesions in three weeks. The patient was followed up in the outpatient clinic at one month and at three months, and he was asymptomatic. CONCLUSIONS: Manufacturers of peginterferon alpha-2a suggest that mouth ulceration, stomatitis, dysphagia, and glossitis are considered adverse reactions of this medication. In this case, the most likely cause of the stomatitis was considered to be peginterferon alpha-2a because of the close temporal relationship between exposure to the drug and onset of symptoms, as well as the rapid resolution of the symptoms and signs after peginterferon alpha-2a was discontinued. An objective causality assessment revealed that a adverse drug event was possible. Clinicians should be aware of this potentially adverse effect of a widely used drug.

Hair loss induced by lopinavir-ritonavir.

A 38-year-old Caucasian woman with uncontrolled human immunodeficiency virus (HIV) infection was treated with highly active antiretroviral therapy (HAART) consisting of zidovudine, lamivudine, and nevirapine. Because her therapeutic response was inadequate, the HAART regimen was changed to abacavir, lamivudine, and lopinavir-ritonavir. Three months after this therapy was started, the patient developed progressive and notable hair loss. Her hair became fair and thin, and her appearance deteriorated considerably. Hair loss due to HAART was diagnosed. Lopinavir-ritonavir was stopped, and efavirenz was substituted; abacavir and lamivudine were continued. After 4 weeks, her hair growth substantially improved, as evidenced by rapid growth of new hair. Her general condition also improved. No relapse was observed with the new HAART regimen, and the patient's hair loss completely reversed in 8 weeks. Alopecia is a possible adverse event in HIV-infected patients treated with protease inhibitors, particularly indinavir. Our patient's severe and generalized alopecia was temporally related to the initiation and discontinuation of lopinavir-ritonavir. On the basis of the Naranjo adverse drug reaction probability scale, the adverse reaction was considered probable. Although generalized hair loss due to lopinavir-ritonavir is rare, clinicians should be aware of this potential adverse reaction of this widely used drug. If alopecia is severe or particularly distressing to the patient, the offending drug should be discontinued, and therapy with another HIV drug should be started.