A review of Bruton's tyrosine kinase inhibitors in multiple sclerosis.

Bruton's tyrosine kinase (BTK) inhibitors are an emerging class of therapeutics in multiple sclerosis (MS). BTK is expressed in B-cells and myeloid cells, key progenitors of which include dendritic cells, microglia and macrophages, integral effectors of MS pathogenesis, along with mast cells, establishing the relevance of BTK inhibitors to diverse autoimmune conditions. First-generation BTK inhibitors are currently utilized in the treatment of B-cell malignancies and show efficacy in B-cell modulation. B-cell depleting therapies have shown success as disease-modifying treatments (DMTs) in MS, highlighting the potential of BTK inhibitors for this indication; however, first-generation BTK inhibitors exhibit a challenging safety profile that is unsuitable for chronic use, as required for MS DMTs. A second generation of highly selective BTK inhibitors has shown efficacy in modulating MS-relevant mechanisms of pathogenesis in preclinical as well as clinical studies. Six of these BTK inhibitors are undergoing clinical development for MS, three of which are also under investigation for chronic spontaneous urticaria (CSU), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Phase II trials of selected BTK inhibitors for MS showed reductions in new gadolinium-enhancing lesions on magnetic resonance imaging scans; however, the safety profile is yet to be ascertained in chronic use. Understanding of the safety profile is developing by combining safety insights from the ongoing phase II and III trials of second-generation BTK inhibitors for MS, CSU, RA and SLE. This narrative review investigates the potential of BTK inhibitors as an MS DMT, the improved selectivity of second-generation inhibitors, comparative safety insights established thus far through clinical development programmes and proposed implications in female reproductive health and in long-term administration.

A review of Bruton's tyrosine kinase inhibitors in multiple sclerosis Why was this study done? This study was done to find out about current knowledge on a type of drug, called Bruton's tyrosine kinase inhibitors, or BTK inhibitors. There are currently six BTK inhibitors being studied as a possible new drug for treating multiple sclerosis (MS). Some of these six drugs are also being studied as a possible new drug for chronic spontaneous urticaria, rheumatoid arthritis and systemic lupus erythematosus. These are all autoimmune conditions, where the immune system mistakenly attacks parts of the body. Clinician scientists wanted to understand what is currently known about BTK inhibitors, how they work in the laboratory and how safe they could be for treating autoimmune conditions. This could help us understand more about BTK inhibitors in MS.What did the scientists do? The scientists assessed existing research on these six BTK inhibitors, through a process known as a literature review. These were results from ongoing clinical trials, and information collected through studying BTK inhibitors in laboratories. The researchers pieced together all these findings, to produce this paper that summarizes the results.What did the scientists find? The scientists found that most studies of BTK inhibitors for MS are still ongoing. So far, BTK inhibitors seem to show reasonable safety in most studies, but it is too early to know. The researchers also found out about how BTK inhibitors work in the lab, about what could happen if the drugs are taken for a long time and how they could impact female reproductive health.What do these findings mean? These findings will help other scientists learn more about BTK inhibitors in MS. Trials with BTK inhibitors for MS are still ongoing, but piecing together all the current findings gives a picture of what we know and what still needs to be done.

The Development of Ofatumumab, a Fully Human Anti-CD20 Monoclonal Antibody for Practical Use in Relapsing Multiple Sclerosis Treatment.

The importance of B cells in multiple sclerosis (MS) has been demonstrated through the advent of B-cell-depleting anti-CD20 antibody therapies. Ofatumumab is the first fully human anti-CD20 monoclonal antibody (mAb) developed and tested for subcutaneous (SC) self-administration at monthly doses of 20 mg, and has been approved in the US, UK, EU, and other regions and countries worldwide for the treatment of relapsing MS. The development goal of ofatumumab was to obtain a highly efficacious anti-CD20 therapy, with a safety and tolerability profile that allows for self-administration by MS patients at home and a positive benefit-risk balance for use in the broad relapsing MS population. This development goal was enabled by the unique binding site, higher affinity to B cells, and higher potency of ofatumumab compared to previous anti-CD20 mAbs; these properties of ofatumumab facilitate rapid B-cell depletion and maintenance with a low dose at a low injection volume (20 mg/0.4 ml). The high potency in turn enables the selective targeting of B cells that reside in the lymphatic system via subcutaneous (SC) administration. Through a comprehensive dose-finding program in two phase 2 studies (one intravenous and one SC) and model simulations, it was found that safety and tolerability can be further improved, and the risk of systemic injection-related reactions (IRRs) minimized, by avoiding doses ≥ 30 mg, and by reaching initial and rapid B-cell depletion via stepwise weekly administration of ofatumumab at Weeks 0, 1, and 2 (instead of a single high dose). Once near-complete B-cell depletion is reached, it can be maintained by monthly doses of 20 mg/0.4 ml. Indeed, in phase 3 trials (ASCLEPIOS I/II), rapid and sustained near-complete B-cell depletion (largely independent of body weight, race and other factors) was observed with this dosing regimen, which resulted in superior efficacy of ofatumumab versus teriflunomide on relapse rates, disability worsening, neuronal injury (serum neurofilament light chain), and imaging outcomes. Likely due to its fully human nature, ofatumumab has a low immunogenic risk profile-only 2 of 914 patients receiving ofatumumab in ASCLEPIOS I/II developed anti-drug antibodies-and this may also underlie the infrequent IRRs (20% with ofatumumab vs. 15% with the placebo injection in the teriflunomide arm) that were mostly (99.8%) mild to moderate in severity. The overall rates of infections and serious infections in patients treated with ofatumumab were similar to those in patients treated with teriflunomide (51.6% vs. 52.7% and 2.5% vs. 1.8%, respectively). The benefit-risk profile of ofatumumab was favorable compared to teriflunomide in the broad RMS population, and also in the predefined subgroups of both recently diagnosed and/or treatment-naïve patients, as well as previously disease-modifying therapy-treated patients. Interim data from the ongoing extension study (ALITHIOS) have shown that long-term treatment with ofatumumab up to 4 years is well-tolerated in RMS patients, with no new safety risks identified. In parallel to the phase 3 trials in which SC administration was carried out with a pre-filled syringe, an autoinjector pen for more convenient self-administration of the ofatumumab 20 mg dose was developed and is available for use in clinical practice.

Foot Melanoma Localized to Subungual Toe Location Portends Poorer Prognosis.

Our group previously reported that melanoma of the foot is associated with advanced disease on diagnosis and decreased survival. Lesions localized to the toe appeared to have the worst outcomes. In this study, we both expanded our study to include a 10-year population of patient with invasive melanoma of the foot and ankle and investigated additional factors associated with prognosis. Between January 2007 and December 2016, 211 patients underwent biopsy diagnosis and surgery for invasive melanoma in the BLANK health care system. Demographic, pathologic, staging, and localization characteristics were studied for overall survival. Lesions were localized to dorsal foot, plantar foot, toe (nonsubungual), and toe (subungual) locations. Multivariable analysis found Breslow depth, ulceration, lymph node involvement, and subungual toe location to be associated with poorer survival. Overall survival rate for foot melanoma was 70.6%. Overall survival for nonsubungual toe melanoma was 60.7%, compared to 53.1% for subungual toe melanoma. Of the subungual melanomas, 37.5% of presented as deep lesions with a Breslow depth >4.0 mm. Subungual melanoma was statistically significant for and found to be an independent prognostic factor associated with poorer survival and advanced disease. Based on the results of this study, there should be a low threshold to biopsy suspicious lesions of the toe and foot with particular attention to be dedicated to subungual lesions.

Ponseti Idiopathic and Nonidiopathic Clubfoot Correction With Secondary Surgeries.

The Ponseti method has revolutionized clubfoot treatment for not only idiopathic clubfoot but also non-idiopathic clubfoot. This study aimed to validate the existing literature with respect to the Ponseti method serving as first line treatment for clubfoot. The purpose of this study was to compare clubfoot type and recurrence with secondary surgical procedures following Ponseti method. Kaiser Permanente Northern California database was queried to identify clubfoot children under 3 years old with a consecutive 3-year membership. Associated comorbidities and operative procedure codes were identified. Chart review was performed on all surgical clubfoot patients who completed Ponseti method. Patients' average age at time of surgery, frequency of surgeries, and types of procedures performed were recorded. A logistic regression analysis assessed the adjusted association between surgery status and clubfoot type. Clubfoot incidence was about 1 in 1000 live births. Of the 375 clubfoot children, 334 (89%) were idiopathic and 41 (11%) were non-idiopathic. In the total study population, 82% (n = 309) patients maintained Ponseti correction without a secondary surgery; 66 patients (18%) underwent subsequent secondary surgeries. The non-idiopathic clubfoot underwent surgery more frequently compared to idiopathic clubfoot patients (41.5% vs 14.7%, respectively, p = .0001). Non-idiopathic clubfoot children underwent surgery at a younger age. This study validates the Ponseti method is the first line treatment for clubfoot correction despite etiology. However, patients with recurrent clubfoot may require secondary surgery following Ponseti method. Clubfoot recurrence surveillance is key for identifying early symptomatic recurrence in order to minimize foot rigidity and the need for osseous procedures.

Microorganisms Associated With Osteomyelitis of the Foot and Ankle.

Osteomyelitis of the foot and ankle is a challenge to treat and creates a significant demand on both the patient and the healthcare system. The purposes of this study were to determine the microorganisms associated with foot and ankle osteomyelitis, to evaluate the change in methicillin-resistant Staphylococcus aureus (MRSA) between 2005 and 2010, and to determine the relationship between these infecting organisms and patient comorbidities. The medical records for 302 patients diagnosed with osteomyelitis of the foot and ankle, 151 in 2005 and 151 in 2010, were randomly selected and evaluated. The authors reviewed the demographics, comorbidities, microorganism(s) confirmed with bone biopsy and culture, location, and use of antibiotics before bone biopsy. Gram-positive bacteria were the most prevalent, composing 81.9% of the isolates in 2005 and 59.6% in 2010. Methicillin-sensitive Staphylococcus aureus was the most common in both cohorts. Conversely, the incidence of MRSA statistically decreased from 28.3% to 10.6% from 2005 to 2010 (p < .0001). Gram-negative bacteria were found in 39.5% of the 2005 isolates and 31.8% of those from 2010. Pseudomonas sp. was the most common gram-negative bacteria. Patients with peripheral vascular disease had a significantly higher incidence of gram-negative bacteria (odds ratio 2.1, 95% confidence interval, 1.3 to 3.6, p = .003). The results of this study reveal that MSSA was the most common bacteria, incidence of MRSA decreased between the 2005 to 2010, and patients with peripheral vascular disease have a significantly higher incidence of gram-negative bacteria.

Orthobiologics.

Use of orthobiologics in sports medicine and musculoskeletal surgery has gained significant interest. However, many of the commercially available and advertised products are lacking in clinical evidence. Widespread use of products before fully understanding their true indications may result in unknown adverse outcomes and may also lead to increased health care costs. As more products become available, it is important to remain judicial in use and to practice evidence-based medicine. Likewise, it is important to continue advances in research in hopes to improve surgical outcomes. This article reviews clinical evidence behind common orthobiologics in the treatment of foot and ankle pathology.

Melanoma of the Foot Is Associated With Advanced Disease and Poorer Survival.

The purpose of the present study was to review the outcomes and assess the prognostic factors associated with foot melanoma. We hypothesized that primary melanoma of the foot would be more likely to present at an advanced stage and be associated with poorer outcomes. Both univariate and multivariate analyses were conducted to examine the relationships between patients' demographic, clinical, and pathologic characteristics and deaths within 5 years. Categorical data were summarized as frequencies and percentages and continuous variables as mean ± standard deviation. The primary outcome measure was overall survival. On univariate analysis, the significant prognostic variables found included Breslow thickness, ulceration, sentinel node positivity, and localized presentation on the toe. Age, sex, and race were not prognostically significant in this model. Multivariate Cox proportional hazards analysis resulted in a model of foot melanoma with ulceration and location on the toe as independent prognostic variables. The 5-year survival rate for melanoma of the toe was 50%. The results of the present study have shown that physicians should have a low threshold to biopsy suspicious lesions of the foot and ankle. Advanced disease and poorer survival were noted with toe melanoma. An ulcerative lesion of the foot was also associated with poorer survival.