Search Results (12)

Background: Multiple sclerosis (MS), an autoimmune disease, involves peripheral immune activation followed by CNS inflammation in a compartmentalized manner. Although high-efficacy disease-modifying therapies (HE-DMTs) have been effective in suppressing relapses in MS patients, they fail to effectively target chronic microglial activation and smoldering lesions in MS patients. Bruton’s tyrosine kinase inhibitors (BTKis), which are orally active and capable of crossing the blood–brain barrier, have been found to be effective in modulating B cells and CNS-resident myeloid cells. Objective: The objective was to assess the efficacy and safety of Bruton’s tyrosine kinase inhibitors in patients with relapsing, secondary, and primary progressive MS. Methods: We performed a systematic review and meta-analysis according to the Cochrane and PRISMA guidelines (PROSPERO registration number: 1323474). We included randomized controlled trials (RCTs) that assessed fenebrutinib, evobrutinib, or tolebrutinib in adult MS patient populations. The main outcome measures were annualized relapse rate, MRI lesion activity, disability progression (EDSS), and hepatotoxicity. The quality of the included trials was assessed for bias by the RoB2 tool. Results: Six RCTs with 3616 participants were included. BTK inhibitors significantly reduced ARR compared with control therapy (pooled RR 0.24; 95% CI 0.15–0.39). MRI activity was reduced (mean difference −1.45 new/enlarging T2 lesions; 95% CI −2.08 to −0.82). Disability progression was unchanged in short-term relapsing MS trials. Serious hepatotoxicity was reported in 11.0% of BTKi-treated patients compared with 13.7% of control patients (pooled RR 0.80; 95% CI 0.66–0.96). However, increased transaminase elevations were reported in placebo-controlled trials, which indicates that hepatotoxicity remains a clinically relevant safety concern for the class. Conclusions: BTK inhibitors reduce inflammatory disease activity in relapsing MS and have emerging efficacy in progressive MS phenotypes; however, continued monitoring for hepatotoxicity is warranted. Optimization of CNS penetrance and pharmacologic selectivity may influence long-term clinical positioning. Full article

Multiple sclerosis (MS) reflects a dynamic interplay between peripheral immune activation and compartmentalized inflammation within the central nervous system (CNS). While current disease-modifying therapies effectively reduce relapse activity driven by transient peripheral immune infiltration, their impact on progressive disability remains limited, prompting interest in strategies targeting CNS-resident immune mechanisms. Bruton’s tyrosine kinase (BTK), expressed in B cells and myeloid-derived cells, including microglia, serves as a shared intracellular signaling node linking adaptive and innate immune pathways. Second-generation BTK inhibitors, including evobrutinib, tolebrutinib, fenebrutinib, remibrutinib, and orelabrutinib, have advanced through Phase II-III development in MS. These agents differ in binding mode, selectivity, pharmacokinetics, CNS penetration, and safety profiles, distinctions that may influence stage-specific therapeutic performance. Recent trials across relapsing and progressive phenotypes have yielded heterogeneous outcomes. Divergent signals in primary and secondary progressive MS reflect underlying biological heterogeneity and suggest that therapeutic responsiveness may depend on residual inflammatory activity, lesion biology, and pharmacologic characteristics. Emerging biomarker frameworks further emphasize the importance of stratifying inflammatory activity and degenerative progression when interpreting trial data. This review integrates molecular pharmacology and the most recent clinical evidence available through 2026 to examine how pharmacologic properties translate into stage-dependent therapeutic positioning. We also consider safety constraints within a disease-stage-specific benefit-risk framework, aiming to clarify the evolving role of BTK inhibition in MS. Full article

Background and Objectives: The impact of peripheral below-the-knee (BTK) fractional flow reserve (FFR) on long-term clinical outcomes remains unknown. Materials and Methods: We enrolled 40 patients with severe BTK lesions (Rutherford 4–6). FFR (using 40 mg papaverin) and skin perfusion toe pressure (SPTP) by laser Doppler were measured during the index procedure. The primary outcomes were major adverse limb events (MALEs) (defined as reintervention on the index arterial segment or amputation of the index limb) and death during follow-up. Results: The median follow-up was 7 [IQR 4–8] years. After the index procedure, FFR increased significantly (p < 0.001) and post-revascularization SPTP was significantly higher in the FFR ≥ 0.80 group (p = 0.022). Multivariable regressions showed no association between change in FFR (absolute or percentage) and the risk of death (p = 0.39, p = 0.28) or MALEs (p = 0.83, p = 0.29), but both pre- and post-revascularization FFR values could predict MALEs at follow-up (p = 0.018, p = 0.012). Lower SPTP was also associated with the risk of MALEs (p = 0.027). SPTP > 97.8 mmHg was 100% specific for FFR ≥ 0.80. Conclusions: While there is no association between change in FFR and the risk of death or MALEs, lower FFR values either before or after revascularization were associated with higher long-term risk of MALEs. Moreover, a lower SPTP was associated with a higher risk of MALEs. Aiming for approximately 100 mmHg in SPTP represents a non-invasive surrogate of FFR ≥ 0.80. Larger studies are needed to validate the impact of post-revascularization FFR-SPTP-adjacent values on clinical outcomes. Full article

Arterial diseases (ADs) are a significant health problem, with high mortality and morbidity rates. Endovascular interventions, such as balloon angioplasty (BA), bare-metal stents (BMSs), drug-eluting stents (DESs) and drug-coated balloons (DCBs), have made significant progress in their treatments. However, the issue has not been fully resolved, with restenosis remaining a major concern. In this context, bioresorbable vascular stents (BVSs) have emerged as a promising area of investigation. This manuscript includes articles that assess the use of BVSs. Studies have identified ongoing challenges, such as negative vascular remodeling and elastic recoil post-angioplasty, stent-related injury, and in-stent restenosis following BMS placement. While DESs have mitigated these issues to a considerable extent, their durable structures are unable to prevent late stent thrombosis and delay arterial recovery. BVSs, with their lower support strength and tendency towards thicker scaffolds, increase the risk of scaffold thrombosis. Despite inconsistent study results, the superiority of BVSs over DESs has not been demonstrated in randomized trials, and DES devices continue to be the preferred choice for most cases of arterial disease. Esprit BTK (Abbott Vascular) received approval from the US FDA for below-knee lesions in 2024, offering hope for the use of BVSs in other vascular conditions. Enhancing the design and thickness of BVS scaffolds may open up new possibilities. Large-scale and longer-term comparative studies are still required. This article aims to provide an overview of the use of biodegradable stents in the endovascular treatment of vascular stenosis. Full article

Objectives: Chronic limb-threatening ischemia (CLTI) is the most severe manifestation of peripheral artery disease (PAD) and is associated with high morbidity and mortality. The Naples prognostic score (NPS), a composite marker incorporating serum albumin, total cholesterol, neutrophil-to-lymphocyte ratio (NLR), and lymphocyte-to-monocyte ratio (LMR), has shown prognostic value in various cardiovascular conditions. This study aimed to evaluate the prognostic significance of the NPS in predicting all-cause mortality and any kind of amputation in patients with CLTI undergoing endovascular treatment (EVT) for below-the-knee (BTK) lesions. Methods: In this retrospective analysis, 191 patients diagnosed with CLTI and treated with EVT for BTK lesions between 2017 and 2023 were stratified into three groups based on the NPS: low (0–1), intermediate (2), and high (3–4). The primary endpoint was all-cause mortality, while the secondary endpoint was any kind of amputation. Results: A higher NPS was significantly associated with increased all-cause mortality (hazard ratio: 3.66; 95% confidence interval: 1.72–7.78; p < 0.001), while no significant association was observed between the NPS and major amputation. Independent predictors of mortality included a high NPS, reduced left ventricular ejection fraction, and impaired renal function. Conclusions: The NPS is an independent predictor of long-term mortality in CLTI patients undergoing EVT for BTK lesions. Full article

Background/Objectives: Type 2 diabetes mellitus (T2DM) represents a major risk factor for peripheral artery disease (PAD). We aimed to evaluate the impact of T2DM on lesion localization and complexity, clinical presentation by Rutherford categories, and limb outcomes in elderly patients with symptomatic PAD undergoing endovascular revascularization. Methods: Five hundred consecutive patients with symptomatic infra-inguinal PAD who underwent rotational atherectomy-assisted endovascular revascularization were included. PAD clinical presentation and lesion localization were recorded. The primary endpoints were clinically driven target lesion revascularization (CD-TLR) and major amputation rates during follow-up. Results: Overall, 245/500 (49.0%) patients had T2DM, whereas 179 (35.8%) presented with lifestyle limiting claudication and 321 (64.2%) with critical limb-threatening ischemia (CLTI). Median age was 78.0 (IQR = 70.0–84.0) years, and 201 (40.2%) patients were female. The presence of T2DM was significantly more frequent in patients with CLTI vs. those with claudication (58.6 vs. 31.8%; p < 0.001). Furthermore, the percentage of patients with below-the-knee (BTK) lesions was significantly higher in patients with vs. without T2DM (40.7 vs. 27.5%, p = 0.0002). During median follow-up of 21.9 (IQR = 12.8–28.8) months, CD-TLR rates were similar in patients with vs. without T2DM (HR = 1.2, 95%CI = 0.8–2.0, p = 0.39). However, patients with T2DM had a ~5.5-fold increased risk for major above-the-ankle amputation (HR = 5.5, 95%CI = 1.6–19.0, p = 0.007). After adjustment for age, gender, lesion complexity, and calcification, T2DM remained predictive for major amputation (p = 0.04). Conclusions: T2DM is more frequently associated with CLTI, BTK-PAD, and amputations despite successful endovascular revascularization. More stringent surveillance of patients with PAD and T2DM is warranted to prevent atherosclerosis-related complications. Full article

The aim of the study is to evaluate the safety and effectiveness of rotational atherectomy-assisted balloon angioplasty (BTK-RA) for the treatment of isolated below the knee (BTK) atherosclerotic lesions and to compare the outcomes to plain old balloon angioplasty (POBA). Between January 2020 and September 2023, 96 consecutive patients with chronic limb threatening ischemia (CTLI) and isolated BTK-lesions underwent POBA (group A) or BTK-RA (group B). The primary outcome measures were: periprocedural technical success, primary patency, postoperative increase of the ankle branchial index (ABI), target lesion revascularization (TLR), limb salvage, minor amputation and death. Both techniques had similar technical success, operative time, intraprocedural complications and bailout stent implantations, independently of the operator’s experience. Group B had significantly higher primary patency rates (93.5% vs. 72.0%, respectively, p = 0.006), TLR (2.1% vs. 24%, p = 0.057), lower in-hospital stay (2.0–3.0 vs. 4.0–6.0 days, respectively, p < 0.001) and higher postoperative ABI (0.8–0.2 vs. 0.7–0.1, respectively, p = 0.008), compared to group A. Significant differences (POBA n: 20, 40%, BTK-RA n = 3, 6.5%) were found in minor amputation rates between the two groups (p < 0.001), while the respective limb salvage rates were similar in both groups (94.0% vs. 97.8%, p = 0.35). The use of BTK-RA for the treatment of BTK-lesions in patients with CTLI showed significant clinical advantages in comparison to POBA. Full article

Severe mucormycosis is a fatal disease rarely complicating chronic lymphoproliferative disorders. We present a fulminant and fatal case of a 74-year-old Caucasian woman suffering from CLL treated with second-generation BTK inhibitor zanubrutinib. After a first septic episode a month prior, originating from the lung with later systemic involvement by an unidentified agent and treated with large-spectrum antibiotics and fluconazonle, a slow-onset enlarging tender warm and erythematous nodular swollen cutaneous lesion appeared in her lower limbs and spread subsequently to her upper limbs, progressing towards central ulceration with a necrotic core. Suspecting a mycotic dissemination from an unknown agent, a skin punch biopsy was performed, and intraconazole was started. Due to spread of the skin lesions, the patient was hospitalized and intravenous liposomal ampthotericin B was started. Histopathology showed an atypical sporangium-rich mycotic angioinvasion of the small vessels. Only the increase of BDG and GM could corroborate the hypothesis of mycotic infection. However, long-term CLL, immunosuppressive therapies, neutropenia, and prior use of azoles and other antimycotic agents were risk factors for mucormycosis; BTK inhibitor could also be added as another novel risk factor. Despite all therapeutic efforts, the patient died. Post-mortem molecular exams confirmed the diagnosis of disseminated mucormycosis. Full article

Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. Despite its indolent clinical course, therapy refractoriness and disease progression still represent an unmet clinical need. Before the advent of pathway inhibitors, chemoimmunotherapy (CIT) was the commonest option for CLL treatment and is still widely used in areas with limited access to pathway inhibitors. Several biomarkers of refractoriness to CIT have been highlighted, including the unmutated status of immunoglobulin heavy chain variable genes and genetic lesions of TP53, BIRC3 and NOTCH1. In order to overcome resistance to CIT, targeted pathway inhibitors have become the standard of care for the treatment of CLL, with practice-changing results obtained through the inhibitors of Bruton tyrosine kinase (BTK) and BCL2. However, several acquired genetic lesions causing resistance to covalent and noncovalent BTK inhibitors have been reported, including point mutations of both BTK (e.g., C481S and L528W) and PLCG2 (e.g., R665W). Multiple mechanisms are involved in resistance to the BCL2 inhibitor venetoclax, including point mutations that impair drug binding, the upregulation of BCL2-related anti-apoptotic family members, and microenvironmental alterations. Recently, immune checkpoint inhibitors and CAR-T cells have been tested for CLL treatment, obtaining conflicting results. Potential refractoriness biomarkers to immunotherapy were identified, including abnormal levels of circulating IL-10 and IL-6 and the reduced presence of CD27⁺CD45RO⁻ CD8⁺ T cells. Full article

Richter syndrome (RS) represents the occurrence of an aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL), in patients with chronic lymphocytic leukemia (CLL). Most cases of RS originate from the direct transformation of CLL, whereas 20% are de novo DLBCL arising as secondary malignancies. Multiple molecular mechanisms contribute to RS pathogenesis. B-cell receptor (BCR) overreactivity to multiple autoantigens is due to frequent stereotyped BCR configuration. Genetic lesions of TP53, CDKN2A, NOTCH1 and c-MYC deregulate DNA damage response, tumor suppression, apoptosis, cell cycle and proliferation. Hyperactivation of Akt and NOTCH1 signaling also plays a role. Altered expression of PD-1/PD-L1 and of other immune checkpoints leads to RS resistance to cytotoxicity exerted by T-cells. The molecular features of RS provide vulnerabilities for therapy. Targeting BCR signaling with noncovalent BTK inhibitors shows encouraging results, as does the combination of BCL2 inhibitors with chemoimmunotherapy. The association of immune checkpoint inhibitors with BCL2 inhibitors and anti-CD20 monoclonal antibodies is explored in early phase clinical trials with promising results. The development of patient-derived xenograft mice models reveals new molecular targets for RS, exemplified by ROR1. Although RS still represents an unmet medical need, understanding its biology is opening new avenues for precision medicine therapy. Full article

Microglia/astrocyte and B cell neuroimmune responses are major contributors to the neurological deficits after traumatic spinal cord injury (SCI). Bruton tyrosine kinase (BTK) activation mechanistically links these neuroimmune mechanisms. Our objective is to use Ibrutinib, an FDA-approved BTK inhibitor, to inhibit the neuroimmune cascade thereby improving locomotor recovery after SCI. Rat models of contusive SCI, Western blot, immunofluorescence staining imaging, flow cytometry analysis, histological staining, and behavioral assessment were used to evaluate BTK activity, neuroimmune cascades, and functional outcomes. Both BTK expression and phosphorylation were increased at the lesion site at 2, 7, 14, and 28 days after SCI. Ibrutinib treatment (6 mg/kg/day, IP, starting 3 h post-injury for 7 or 14 days) reduced BTK activation and total BTK levels, attenuated the injury-induced elevations in Iba1, GFAP, CD138, and IgG at 7 or 14 days post-injury without reduction in CD45RA B cells, improved locomotor function (BBB scores), and resulted in a significant reduction in lesion volume and significant improvement in tissue-sparing 11 weeks post-injury. These results indicate that Ibrutinib exhibits neuroprotective effects by blocking excessive neuroimmune responses through BTK-mediated microglia/astroglial activation and B cell/antibody response in rat models of SCI. These data identify BTK as a potential therapeutic target for SCI. Full article

Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) is one of the well-recognized extranodal lymphomas commonly addicted to the B-cell receptor-MYD88 superpathway. We aimed to describe the genomic changes in a patient who progressed through treatment with ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor. An 80-year-old woman presented with multiply relapsed PCDLBCL-LT after multiple lines of chemoimmunotherapy and radiotherapy. Pre-treatment testing of the localized cutaneous tumor lesion on a lymphoid amplicon panel demonstrated an MYD88 p.L265P mutation. Ibrutinib therapy was subsequently commenced, resulting in complete resolution of the skin disease. Despite an ongoing skin response, the patient developed progressive nodal disease at two months. Genomic analysis of the cutaneous tumor sample at baseline was compared to that of the inguinal lymph node upon progression, and revealed the acquisition of multiple genomic changes. These included several aberrations expected to bypass BTK inhibition, including two CARD11-activating mutations, and a deleterious mutation in the nuclear factor kappa B (NF-κB) negative regulator, NFKBIE. In addition, an IgH-IRF8 translocation was detected (which brings the IRF8 transcription factor under control of the immunoglobulin heavy chain locus), representing a third plausible mechanism contributing to ibrutinib resistance. Several copy-number changes occurred in both samples, including an amplification of 18q, which encodes the anti-apoptotic protein BCL2. We describe the first case of novel genomic changes of PCDLBCL-LT that occurred while on ibrutinib, providing important mechanistic insights into both pathogenesis and drug resistance. Full article