Monotherapy is a relevant option in rheumatoid arthritis treatment: a literature review.

The latest revision of the European League Against Rheumatism (EULAR) recommendations for rheumatoid arthritis (RA) treatment maintains the indication for the combined therapy of biological disease-modifying antirheumatic drugs (bDMARDs) and targeted synthetic DMARDs (tsDMARDs), namely Jak-inhibitors as tofacitinib and baricitinib, with conventional synthetic DMARDs (csDMARDs). Moreover, the use of bDMARDs and tsDMARDs should be restricted to patients who failed to achieve an adequate response to one or more csDMARDs, in accordance with the current evidence showing the superiority of combination therapy over monotherapy. In patients who cannot use csDMARDs as comedication, IL-6 inhibitors and tsDMARDs should be preferred to other bDMARDs because they are apparently more effective as monotherapy. Registry and real-world data demonstrate that monotherapy is far more commonly used than expected based on treatment recommendations, currently being about 30% of patients with RA on bDMARD monotherapy. We review here the literature on most commonly used DMARDs in monotherapy for RA. Our review points at an increasing evidence of the potential of some bDMARDs and tsDMARDs in monotherapy, which may become a considerable and realistic option in RA patients.

Real-world experience with tofacitinib for the treatment of rheumatoid arthritis.

OBJECTIVES: Oral targeted synthetic disease-modifying anti-rheumatic drugs (DMARDs), including the Janus kinase inhibitors tofacitinib and baricitinib, are the latest addition to the therapeutic options for rheumatoid arthritis (RA). Tofacitinib 5 mg, twice daily, is approved for treatment, with or without methotrexate, of moderate to severe active RA in adults not adequately responding to, or not tolerating one or more DMARDs. In this narrative review we aimed to provide an overview of the real-world evidence for tofacitinib in RA. METHODS: The literature was reviewed up to March 2018 for studies regarding the efficacy and safety of tofacitinib for the treatment of RA. The focus was mainly on real-world studies with implications for every day clinical practice. RESULTS: The efficacy and safety of tofacitinib have been comprehensively assessed in a wide programme of randomised controlled trials. Extensive observational research on tofacitinib in RA is also ongoing worldwide and a substantial body of post-marketing real-world data from clinical practice is becoming available. There was a degree of consistency across the real-world studies reviewed. Tofacitinib tends to be used as monotherapy more frequently than bDMARDS and appears to be effective without background methotrexate. The data show a manageable safety profile, with no new safety signals and a discontinuation rate from safety issues <10%. Patients initiating tofacitinib usually have longer disease duration and have been exposed to longer bDMARDs than patients initiating a bDMARD. CONCLUSIONS: Real-world data are a key component of the evidence supporting the effectiveness of this novel drug and are of interest to all stakeholders. Treatment persistence and adherence to tofacitinib are good overall and similar to those seen for bDMARDs.

Vaccinations in adults with rheumatoid arthritis in an era of new disease-modifying anti-rheumatic drugs.

Patients with rheumatoid arthritis are at greater risk of infectious morbidity and mortality due to disease-related abnormalities and use of immunosuppressive medications. Vaccinations are recommended by international guidelines among infection control strategies, but vaccination rates are reported to be still suboptimal in both America and Europe. Furthermore, with the increasing number of immunomodulatory medications used in RA patients, safety and efficacy of vaccinations in RA patients on such therapies have been questioned. This paper reviews current data about the safety of the most relevant vaccinations for RA adult patients and on the extent to which RA treatment can affect vaccine efficacy. Although it is recognised that immunological and pathological reactions can occur following vaccination, especially in genetically susceptible hosts, early data in RA patients under treatment with bDMARDs or tsDMARDs indicate that vaccines might be safer in the setting of immunosuppression than previously thought. Reviewing safety and immunogenicity data about influenza, pneumococcal, HZ, HPV, and HBV vaccines, we here try to summarise updated, practical suggestions for rheumatologists. Improving the knowledge of the vaccination practice both in patients and physicians is of crucial importance. In RA patients, vaccination status should be assessed in the initial patients' work-up and vaccination strategies should be planned and then implemented ideally during stable disease, as recommended by international guidelines.

Accumulation of oocytes from a few modified natural cycles to improve IVF results: a pilot study.

PURPOSE: To evaluate the role of co-transfer of embryos derived from vitrified oocytes accumulated during the previous modified natural cycles and an embryo developed from the last one as an alternative to repetitive single embryo transfer ina fresh modified natural cycle. METHODS: Thirty-six patients underwent ICSI procedure with three frozen natural oocytes supplemented by a fresh one obtained from the fourth modified natural cycle. Thirty-one controls received at least three consecutive single embryo transfer in a fresh modified natural cycle. RESULTS: In the study group the oocyte retrieval, survival and total fertilization rate were 73.0 %, 78.1 %, and 64.5 %, respectively. Fifty-two embryos were transferred in 29 transfers. In the control group the oocyte retrieval and fertilization rate was 77.4 % and 83.7 %, respectively. Fifty single embryo transfers were performed. Of a total 14 pregnancies obtained in the study group 10 were defined as clinical and 4 as abortions. In the control group a total of 8 single clinical pregnancies and 2 miscarriages were encountered. The overall (20.0 % vs 48.2 %) and the clinical (16.0 % vs 34.4 %) pregnancy rate were significantly higher in the study group having cumulative embryo transfer following the oocyte accumulation. CONCLUSIONS: These data demonstrate that the co-transfer of embryos derived from vitrified oocytes accumulated during the previous modified natural cycles and an embryo developed from the last fresh modified natural cycle assure an excellent clinical outcome with the overall and clinical pregnancy rate significantly higher compared to the repetitive single embryo transfer in a fresh modified natural cycle.

Sperm vacuoles negatively affect outcomes in intracytoplasmic morphologically selected sperm injection in terms of pregnancy, implantation, and live-birth rates.

OBJECTIVE: To retrospectively evaluate whether sperm vacuoles influence clinical results, with a particular focus on live-birth rates, in 101 intracytoplasmic morphologically selected sperm injection (IMSI) cycles. DESIGN: Retrospective, observational study. SETTING: Medical center. PATIENT(S): A total of 101 couples with at least two failed intracytoplasmic sperm injection (ICSI) attempts and impaired sperm morphology. INTERVENTION(S): Patients divided into two groups according to sperm morphology and vacuolization pattern: group A comprising patients with good quality spermatozoa (type I and/or type II spermatozoa) (n = 63 patients); group B comprising patients with low quality spermatozoa (type III and/or IV spermatozoa) (n = 38 patients). MAIN OUTCOME MEASURE(S): Fertilization rate, embryo quality, pregnancy, implantation, and live-birth rates. RESULT(S): No statistically significant differences were observed between group A and B with regard to "early" assisted reproduction outcomes (fertilization rate and embryo quality). However, the "late" outcomes (pregnancy, implantation, and live-birth rates) were statistically significantly higher in group A. CONCLUSION(S): These results confirm a correlation between sperm vacuoles and a negative IMSI outcome, suggesting that sperm vacuoles are related to the late paternal effect.

Identification and characterization of adult stem/progenitor cells in the human bladder (bladder spheroids): perspectives of application in pediatric surgery.

There is evidence that tissue-specific stem cells reside in certain adult tissues. Their specific properties remain elusive, because they are rare in parent tissues and heterogeneous; furthermore, technical difficulties have been encountered in their identification and the characterization of their progeny. The aim of this study was to isolate stem/progenitor cells from the human bladder. We have devised a method for isolating stem/progenitor cells from the human bladder. This is based on the enzymatic digestion of fresh surgical bladder specimens, followed by culture of cells in the presence of EGF and bFGF. We also used markers that identified and finally characterized these cells. Spheroids with self-replicative potential were obtained from all bladder specimens. The isolated population contained a subset of CD34+ CD45- cells. These spheroids represent a predominant functional type of stem/progenitor cells within the human bladder. This envisage their potential use for the treatment of animal models in pediatric surgery.

Pelvic floor reconstruction in female exstrophic complex patients: different results from males?

OBJECTIVES: To present the surgical, functional, and cosmetic results of anterior pelvic floor reconstruction in female exstrophic patients who underwent single-stage surgical repair. To verify differences in outcome from male exstrophic patients. METHODS: Among the 31 exstrophy-epispadias complex (EEC) patients treated in 10 yr, 13 (42%) were females. We studied 10 of them (9 classic exstrophies and 1 prolapsing epispadia), aged 2 d to 6 yr, who received one-stage repair with pelvic floor reconstruction. The reconstructive steps were posterior pelvic osteotomy, en bloc mobilisation of bladder neck-urethra/vagina within the midline pelvic floor, symmetrical reassembly of the muscular complex that constitutes the pelvic diaphragm (using a bipolar stimulator), tubularisation and elongation of the bladder neck and urethra, and genitoplasty. At 2- to 3-yr follow-up, bladder capacity and dry intervals were evaluated by cystogram and urodynamic study, respectively. Surgical complications and cosmetic appearance were also assessed. Results were compared with a group of 18 male EEC patients treated in the same period with similar technique. Fisher exact test and chi-square test were used for statistical analysis. RESULTS: No bladder/urethra dehiscence, exstrophy relapse, or uterine procidentia were observed. Cosmesis was fully satisfying in all. Bladder capacity ranged from 35 to 137 ml (mean: 87). Cyclic voiding with 45- to 90-min dry intervals was achieved in 7 patients (70%), but stress incontinence was present in 5 patients. Volitional micturition control was achieved in 5 of 6 (83.3%) girls aged 4-8 yr. In the male group, we observed two surgical complications (glans disruption and urethrocutaneous fistula) and one poor cosmetic outcome. Mean bladder capacity was 70 ml (range: 25-140). Dry intervals were present in 6 patients (33%). Volitional voiding was achieved in 5 of 12 (40%) male exstrophic patients older than 4 yr, with little stress incontinence. Female and male EEC patients presented significantly different outcomes (p<0.05) regarding both surgical complications and functional bladder behaviour. CONCLUSIONS: Pelvic floor reconstruction and its correct relationship with the lower genitourinary tract may facilitate the development of volitional micturition control. Female patients behaved slightly better than males concerning dry intervals and coordinated bladder activity achievement.

Anterior perineal reconstruction in exstrophy-epispadias complex.

OBJECTIVES: To assess the role of correct anatomical reconfiguration of the anterior perineal musculature in exstrophy-epispadias (E-E) patients. To stress the use of a bipolar stimulator to detect the perineal muscular complex intraoperatively, and to increase the functional results of reconstruction in E-E patients. METHODS: A total of 22 patients with E-E complex were treated in a 7-year period: 17 patients presenting classic bladder extrophy (aged 3 days to 6 years) and 5 incontinent male epispadias (aged 9 months to 16 years). An electric bipolar stimulator was used to identify and reapproximate at the midline the muscular fibers that constitute the periurethral muscular complex, as a part of the anterior perineal membrane. Outcome was evaluated at 24 months from surgery, considering bladder capacity, dry intervals, urinary infections (UTI's), upper tract deterioration and surgical complications (fistula, obstruction, dehiscence). Results were compared with a matched group of 19 E-E patients treated in the previous 5-year period, without the presented technique (control group). Student T-test was used for statistical analysis, considering p

The stability of lidocaine and epinephrine solutions exposed to electric current and comparative administration rates of the two drugs into pig bladder wall.

Intravesical electromotive administration of local anesthetics is clinically successful but electrochemistry, cost and effectiveness limit the choice of drugs to diluted lidocaine HCl 4% mixed with epinephrine. These studies address the stability of lidocaine and epinephrine both over time and when exposed to electric current, i.e. transport rates with passive diffusion and electromotive administration. The drug mixture used was 50 ml lidocaine 4%, 50 ml H2O and 1 ml epinephrine 1/1000. For stability, the solution was placed either in bowls for 7 days or in a two chamber cell with the donor compartment (drugs) separated from the receptor compartment (NaCl solution) by a viable pig bladder wall. This was subjected to 30 mA for 45 min. Stability was measured with mass spectrometry. The cell was also used to determine transport rates with passive diffusion and currents of 20 mA and 30 mA, over 20, 30 and 45 min. Drug measurements in both compartments and bladder were made with HPLC. Lidocaine remained stable throughout the 7 days, epinephrine on day 1 only and both drugs were stable with 30 mA for 45 min. Comparing 20 mA and 30 mA with passive diffusion, there were significant differences in 6/6 donor compartment lidocaine levels, 4/6 receptor compartment levels and 6/6 bladder tissue levels and also in 6/6 epinephrine donor levels and 6/6 tissue levels. The combination lidocaine and epinephrine remains stable for 1 day and when exposed to 30 mA for 45 min. Electric current accelerates the transport of lidocaine and epinephrine.