Focus on pemphigus treatment publications: A bibliometric and visual analysis (1992-2022).

Pemphigus is a chronic recurrent disease in dermatology. Although it is not very common, its treatment has been an increasing concern in recent years because it is difficult and long-lasting. At present, there are many papers on pemphigus treatment, and to better understand the research trends and research frontiers of pemphigus treatment, it is necessary to conduct a comprehensive systematic review and analysis. We combined bibliometric and visualization methods to analyze 1365 papers published in the Web of Science database from 1992 to 2022, including basic information about countries, institutions and authors, to gain a general understanding of the treatment of pemphigus. Among them, the United States is the country with the most output, Iran's Tehran University of Medical Sciences is the institution with the most published works, and Ahmed, A. Razzaque of Tufts University is the most influential scholar. In addition, we also learned about the research hotspots and frontiers of pemphigus treatment through a series of analyses on the frequency, clustering, keywords bursts and cited literature, and we briefly reviewed the highly cited literature. We found that the current research focuses in the study of pemphigus treatment are the types, pathogenesis, and treatment of pemphigus, including glucocorticoids, immunosuppressants and many other major treatment methods. Hailey-Hailey disease, genetic susceptibility, and traditional Chinese medicine are potential research hotspots. Rituximab is a research frontier. In conclusion, we hope to provide new research ideas for promoting the development of pemphigus treatment.

Biomarkers and coptis chinensis activity for rituximab-resistant diffuse large B-cell lymphoma: Combination of bioinformatics analysis, network pharmacology and molecular docking.

BACKGROUND: Rituximab resistance is one of the great challenges in the treatment of diffuse large B-cell lymphoma (DLBCL), but relevant biomarkers and signalling pathways remain to be identified. Coptis chinensis and its active ingredients have antitumour effects; thus, the potential bioactive compounds and mechanisms through which Coptis chinensis acts against rituximab-resistant DLBCL are worth exploring. OBJECTIVE: To elucidate the core genes involved in rituximab-resistant DLBCL and the potential therapeutic targets of candidate monomers of Coptis chinensis. METHODS: Using the Traditional Chinese Medicine System Pharmacology Database and Analysis Platform (TCMSP), the Similarity Ensemble Approach and Swiss Target Prediction, the main ingredients and pharmacological targets of Coptis chinensis were identified through database searches. Through the overlap between the pharmacological targets of Coptis chinensis and the core targets of rituximab-resistant DLBCL, we identified the targets of Coptis chinensis against rituximab-resistant DLBCL and constructed an active compound-target interaction network. The targets and their corresponding active ingredients of Coptis chinensis against rituximab-resistant DLBCL were molecularly docked. RESULTS: Berberine, quercetin, epiberberine and palmatine, the active components of Coptis chinensis, have great potential for improving rituximab-resistant DLBCL via PIK3CG. CONCLUSION: This study revealed biomarkers and Coptis chinensis-associated molecular functions for rituximab-resistant DLBCL.

Bilateral Scleritis with Heterogeneous Etiologies: A Diagnostic Dilemma.

PURPOSE: To report a patient with bilateral scleritis who was initially treated for infectious scleritis, and subsequently diagnosed as granulomatosis with polyangiitis (GPA). METHOD: Retrospective chart review. RESULT: A 48-year-old female with a known history of diabetes presented with pain, redness, and blurring of vision in the right eye. She was diagnosed as scleritis with retinal detachment and underwent vitrectomy, with silicone oil tamponade and intravitreal injections of antibiotics, and antifungal agents. She presented with active scleritis with additional multiple pus points. Several scleral biopsies failed to yield any microorganism and finally, the painful blind eye was enucleated. The enucleated specimen grew gram-positive bacteria which were identified as Staphylococcus arlettae by polymerase chain reaction (PCR)-based sequencing of the 16S rRNA gene. Nine months after the onset of symptoms in the right eye, the patient developed necrotizing scleritis in the left eye. Laboratory investigation revealed a positive cytoplasmic- anti-neutrophil cytoplasmic autoantibody, which was previously negative during the right eye involvement. She was diagnosed with GPA by a rheumatologist and treated accordingly. CONCLUSION: Retinal detachment may be associated with scleritis, and ANCA testing may not detect GPA in its early stages. Once infection has been excluded, clinicians should not be afraid to use high-dose immunosuppression instead of surgery to treat retinal detachment associated with scleritis.

Treatment of systemic lupus erythematosus: new therapeutic options.

Systemic lupus erythematosus (SLE) is a systemic autoimmune inflammatory disease of unknown cause, with heterogeneity in its clinical presentation, as well as variability in its clinical course and prognosis. The current goal of treatment is to achieve disease remission or a state of low activity, and thereby improve the patient's quality of life. Biological therapy in lupus, unlike other entities, although it has not been fully established, in recent years it has burst onto the scene with important therapeutic novelties. This review aims to update the therapeutic tools for the treatment of SLE focusing on the new molecules that have achieved the objectives of their clinical trials.

Biological therapy in polymyalgia rheumatica.

INTRODUCTION: Polymyalgia rheumatica (PMR) is an inflammatory rheumatic disease of the elderly, treated mainly with systemic corticosteroids. The frequency of side effects of steroids is high in this aged population and increased due to comorbidities. The use of biological treatments could be of interest in this condition. AREAS COVERED: This review takes into account literature data from the PubMed and clinical trial databases concerning the results of the use of biological treatments in PMR, in terms of efficacy and safety of these treatments. EXPERT OPINION: Current data do not allow us to identify any particular efficacy of the various anti-TNF agents used in the treatment of PMR. Anti-interleukin 6 agents (tocilizumab, sarilumab) have shown consistent efficacy results, suggesting a particularly interesting steroid-sparing effect in the population under consideration. The safety profile appears acceptable. Other biologic targeted treatments are currently being evaluated. Anti-interleukin-6 agents may well have a place in the therapeutic strategy for PMR, particularly for patients with steroid-resistant disease or at high risk of complications of corticosteroid therapy.

Development and External Validation of a Nomogram for Predicting the Effect of RTX on the Treatment of Membranous Nephropathy.

Introduction: Rituximab (RTX) has been shown to be effective in inducing immunological remission in patients with membranous nephropathy (MN). Some patients required more than one course of RTX to achieve immunological remission. Identifying patients who need more courses of RTX to achieve immunological remission is beneficial for better physician-patient communication, the assessment of treatment course, and the evaluation of medical costs. This study aims to establish a practical model to predict the probability of immunological remission after receiving one cycle of RTX. Methods: This study enrolled 106 patients from the First Affiliated Hospital of Zhengzhou University in the modeling group and 30 patients from Henan Provincial Hospital of Traditional Chinese Medicine in the external validation group. Patients in the modeling group were divided into responders or nonresponders according to whether they achieved immunological remission or not after following up for 6 months. A nomogram was established based on the results of logistic regression analysis. The predictive performance of the nomogram was evaluated by the area under the receiver operating characteristic curve (AUC), calibration curves, and decision curve analysis (DCAs). Results: In the modeling group, 75 (70.8%) patients achieved immunological remission within 6 months after receiving one cycle of RTX. Significant differences were observed between nonresponders and responders. Risk factors used in nomogram included PLA2R antibody, hemoglobin, and gender. The AUC value of nomogram was 0.797 (95% CI 0.701-0.894, P<0.001). The calibration curves demonstrated acceptable agreement between the predicted outcomes by the nomogram and the actual values. DCA curves showed good positive net benefits in the predictive model. The external validation also demonstrated the reliability of the prediction nomogram. Conclusion: A predictive nomogram including PLA2R antibody, hemoglobin, and gender may provide a basis to predict the doses of RTX needed in MN patients.

Vitamin D Enhances Immune Effector Pathways of NK Cells Thus Providing a Mechanistic Explanation for the Increased Effectiveness of Therapeutic Monoclonal Antibodies.

Patients with diffuse large cell lymphoma who have an adequate vitamin D supply derive significantly more benefit from immuno-chemotherapy with rituximab than patients with vitamin D deficiency; this is especially true for female patients. We have already been able to show that vitamin D increases the antibody-dependent cytotoxicity (ADCC) of NK cells in a sex-dependent manner, but it is unclear how vitamin D makes NK cells more efficient. METHODS: Healthy individuals with vitamin D deficiency were supplemented with vitamin D to sufficient levels. NK cells were isolated from blood samples before and after vitamin D saturation. For transcriptome analysis, we used the Affymetrix Gene-Chip 2.0™. Gene expression analysis as well as supervised and unsupervised pathway analysis were performed. RESULTS: Among others the "NK cell-associated cytotoxicity pathway" increased after vitamin D substitution. Five IFN-α subtypes (2, 4, 6, 7 and 10) and IFN-κ were more highly expressed and are mainly responsible in these pathways. In contrast, the pathway "interferon-gamma response", as well as other sets in cytokine production and chemotaxis showed a reduction. Toll-like receptor genes (TLR-8, TLR-7, TLR-2) were downregulated and, therefore, are responsible for the decline of these pathways. The same could be shown for the "ubiquitin-ligase" pathway. CONCLUSIONS: Increased expression of several IFN-α subtypes may explain the increased ADCC of NK cells in vitamin D-replenished and otherwise healthy subjects. Other regulators of interferon production and ADCC are compensatory upregulated in compensation, such as Toll-like receptors and those of the ubiquitin ligase, and normalize after vitamin D substitution.

Changes in bone turnover markers after discontinuing long-term glucocorticoid administration in children with idiopathic nephrotic syndrome: a multicenter retrospective observational study.

BACKGROUND: Glucocorticoids affect bone turnover. Little is known about how bone turnover changes when glucocorticoids are discontinued following long-term administration. METHODS: This retrospective observational study was conducted on the relationship between discontinuation of long-term administration of glucocorticoid and bone turnover markers (BTMs) in patients with childhood-onset idiopathic nephrotic syndrome. Serum bone alkaline phosphatase (BAP), intact procollagen type 1 N-terminal propeptide (P1NP), and tartrate-resistant acid phosphatase-5b (TRACP-5b) were evaluated as BTMs. RESULTS: Thirty-eight pairs of BTMs at glucocorticoid administration and after discontinuation were analyzed in 29 patients. The median age at baseline was 12.4 (interquartile range, 9.0-14.5) years, and the median time from the onset of nephrotic syndrome was 5.9 (3.3-9.7) years. The mean period from prednisolone discontinuation to the measurement of BTMs after glucocorticoid discontinuation was 3.5 ± 1.0 months. Changes in BTMs after glucocorticoid discontinuation were modest when the daily prednisolone dose was < 0.25 mg/kg/day (ln BAP standard deviation [SD] score, p = 0.19; log intact P1NP SD score, p = 0.70; TRACP-5b, p = 0.95). When the daily prednisolone dose was ≥ 0.25 mg/kg/day, all BTMs increased significantly after glucocorticoid discontinuation (ln BAP SD score, p < 0.01; log intact P1NP SD score, p < 0.01; TRACP-5b, p < 0.01). CONCLUSIONS: Decreased BTMs can rise within a few months of discontinuing long-term glucocorticoid administration. When the administered glucocorticoid dose is low, changes in BTMs may be small. A higher resolution version of the Graphical abstract is available as Supplementary information.

Watchful waiting is an acceptable treatment option for asymptomatic primary ocular adnexal mucosa-associated lymphoid tissue lymphoma: A retrospective study.

BACKGROUND: Primary ocular adnexal mucosa-associated lymphoid tissue (MALT) lymphoma (POAML) is the most common subtype of indolent ocular adnexal lymphomas. Although radiotherapy (RT) is the standard of care for localized POAML, it can occasionally lead to permanent side effects. Other treatment strategies, such as rituximab (R) monotherapy and immunochemotherapy, have been used for POAML treatment, but their long-term benefits and relative merits remain unclear. While watchful waiting (WW) is a potential option for some indolent lymphomas, the benefits of WW for POAML patients are also unclear. METHODS: We here retrospectively analyzed 75 patients who were diagnosed with POAML between 2008 and 2019 in the institutions of the Kyoto Clinical Hematology Study Group. RESULTS: Commonly involved sites were conjunctiva (42.7%), orbit (36.0%), and lacrimal gland (12.0%), and most patients (92.0%) presented with Ann Arbor stage IE disease. The treatment strategy was selected at the physicians' discretion. More patients without subjective symptoms by tumor mass were subjected to WW (29 patients), while more patients with tumor-derived subjective symptoms were treated by tumor-directed therapy (24 received focal RT, and 19 received R monotherapy). Complete response rates were 79.2% and 42.1% in the RT and R groups, respectively. At 60 months of follow-up, the estimated proportions of POAML patients not requiring new treatment were 69.4%, 85.2%, and 53.8% in the WW, RT, and R groups, respectively. There were no significant differences in the time to start a new treatment between WW and RT groups (median: both not reached [NR], p = 0.187) and between WW and R groups (median: NR vs. 69.0 months, p = 0.554). No specific predictive factor for the future need of treatment was identified in the WW group. CONCLUSION: Our results demonstrate WW may be an acceptable treatment option for POAML, especially for asymptomatic patients.

Drug-survival profiling of second-line biologic therapy in rheumatoid arthritis: Choice of another tumour necrosis factor inhibitor or a biologic of different mode of action?

OBJECTIVES: To assess the best choice of second-line therapy between tumour necrosis factor-inhibitor (TNFi) and biologics of different-mode-of-action (BDMA-rituximab/tocilizumab/abatacept) in rheumatoid arthritis (RA) by evaluating drug-survival following discontinuation of the first-line TNFi. METHODS: This retrospective drug-survival study was performed across two different hospitals by conventional-statistics and machine-learning approach. RESULTS: From a total of 435 patients, 213 (48.9%; TNFi = 122, BDMA = 91) discontinued their second-line biologic {median drug-survival: TNFi, 27 months [95% confidence interval (95%CI) 22-32] vs BDMA, 37 months (95%CI 32-52)}. As a second-line biologic, BDMA was likely to reduce the risk of treatment-discontinuation [hazard-ratio (HR) 0.63, 95%CI 0.48-0.83] compared to TNFi, but only in seropositive-patients (HR 0.52, 95%CI 0.38-0.73), not in seronegative-RA. Drug-survival benefit of BDMA over TNFi was not observed if the seropositive-patients were previously exposed to monoclonal-TNFi (HR 0.77, 95%CI 0.49-1.22) versus soluble-TNFi (etanercept/biosimilars) or if the first-line TNFi was terminated within 23.9 months of initiation (HR 0.97, 95%CI 0.56-1.68). CONCLUSIONS: BDMA, as a second-line biologic, is more likely to be sustained in seropositive-patients, particularly without prior exposure to monoclonal-TNFi. The drug-survival benefit of BDMA was not observed in seronegative-patients or if the first-line TNFi was stopped within 2 years.

Management of Graves ophthalmopathy - 2022 update.

Graves ophthalmopathy (GO) occurs in 25-50% cases of Graves disease. Most cases are just mild, only 5% represents eye threatening diseases. About 5-10% of cases could be euthyroid and 10% hypothyroid, respectively. All patients with GO should be assessed for activity (clinical activity score - CAS) and severity of the disease. Essential conditions of the successful treatment are well controlled thyroid dysfunction, smoking cessation and to refer patients with moderate to severe and sight threatening GO to specialized thyroid eye centers as soon as possible. Local therapy to maintain wet eye (lubricants) and supplementation of selenium deficiency is adequate in mild cases of GO. In cases of moderate to severe and sight threatening GO, administration of intravenous glucocorticoids in thyroid eye centers is first line treatment and a combination with mycophenolate or radiotherapy could be considered. When the first-line treatment fails or a contraindication/intolerance to them is present, non-steroid immunosuppressive drugs (mycophenolate, ciclosporin), rituximab, or radiotherapy could be considered. In rare cases of sight threatening GO urge surgical orbital decompression or tarsorrhaphy is warranted.

Acquired B-cell deficiency secondary to B-cell-depleting therapies.

The advantage of the newer biological therapies is that the immunosuppressive effect is targeted, in contrast, to the standard, traditional immunomodulatory agents, which have a more global effect. However, there are unintended targets and consequences, even to these "precise" therapeutics, leading to acquired or secondary immunodeficiencies. Besides depleting specific cellular immune subsets, these biological agents, which include monoclonal antibodies against biologically relevant molecules, often have broader functional immune consequences, which become apparent over time. This review focuses on acquired B-cell immunodeficiency, secondary to the use of B-cell depleting therapeutic agents. Among the many adverse consequences of B-cell depletion is the risk of hypogammaglobulinemia, failure of B-cell recovery, impaired B-cell differentiation, and risk of infections. Factors, which modulate the outcomes of B-cell depleting therapies, include the intrinsic nature of the underlying disease, the concomitant use of other immunomodulatory agents, and the clinical status of the patient and other co-existing morbidities. This article seeks to explore the mechanism of action of B-cell depleting agents, the clinical utility and adverse effects of these therapies, and the relevance of systematic and serial laboratory immune monitoring in identifying patients at risk for developing immunological complications, and who may benefit from early intervention to mitigate the secondary consequences. Though these biological drugs are gaining widespread use, a harmonized approach to immune evaluation pre-and post-treatment has not yet gained traction across multiple clinical specialties, because of which, the true prevalence of these adverse events cannot be determined in the treated population, and a systematic and evidence-based dosing schedule cannot be developed. The aim of this review is to bring these issues into focus, and initiate a multi-specialty, data-driven approach to immune monitoring.

The prognostic value of IPI in patients with primary breast lymphoma, a multicenter retrospective study.

BACKGROUND: Due to the rarity of PBL and the lack of large-scale studies, the prognostic value of IPI in PBL was controversial. Especially in the rituximab era, the ability of IPI to stratify prognosis in patients receiving immunochemotherapy was severely reduced. Then revised IPI (R-IPI) and National Comprehensive Cancer Network IPI (NCCN-IPI) were introduced. The present study aimed to evaluate the prognostic value of IPI and the other IPIs in patients with PBL in a Chinese population. METHODS: We performed a multicenter retrospective study of 71 patients with PBL from 3 institutions in China. The Kaplan-Meier method and log-rank tests were used for the survival analysis. Cox regression analysis was performed to evaluate the prognostic factors. Subgroup analysis was performed to assess the prognostic significance of IPI scores, R-IPI scores, and NCCN-IPI scores. RESULTS: The median follow-up was 4.7 years (0.7-21.8 years). The 5-year progression-free survival (PFS) and overall survival (OS) rates were 90.2% and 96.3%. In the multivariate analysis, only IPI scores and radiotherapy were significantly associated with OS and PFS (P < 0.05). Applying the R-IPI in our patient cohort indicates a significant difference in PFS between the two groups of R-IPI (P = 0.034) but not for OS (P = 0.072). And the NCCN-IPI was prognostic for OS (P = 0.025) but not for PFS (P = 0.066). Subgroup analyses of IPI showed that survival analysis of IPI scores for the PFS and OS of patients using rituximab were not significantly different (P > 0.05). CONCLUSIONS: Our study confirms the prognostic value of IPI in patients with PBL, but the predictive value of IPI proved to be relatively low with the addition of the rituximab. The R-IPI and NCCN-IPI can accurately assess the high and low-risk groups of PBL patients but were insufficient to evaluate the intermediate risk group.

Systemic lupus erythematosus in the light of the COVID-19 pandemic: infection, vaccination, and impact on disease management.

Patients with systemic lupus erythematosus (SLE) form a vulnerable group in terms of the impact of the COVID-19 pandemic on disease management. We conducted this overview by searches through Medline/PubMed, Scopus, and the Directory of Open Access Journals (DOAJ). The prevalence and severity of COVID-19, efficacy of COVID-19 vaccination, impact on the management of SLE, and the attitudes of SLE patients to COVID-19 and vaccination were explored. After screening and due exclusions, 198 studies were included for the final review. Patients with SLE have a greater risk of acquiring COVID-19 (0.6-22%) and related hospitalization (30%), severe disease (13.5%), and death (6.5%) than the general population. Older age, male gender, comorbidities, moderate or high disease activity, and glucocorticoid, rituximab, and cyclophosphamide use are associated with unfavorable outcomes, whereas methotrexate and belimumab use showed no association with outcomes. COVID-19 vaccines are safe in SLE with minimal risk of severe flares (< 2%). Vaccine efficacy is negatively associated with glucocorticoids. The overall attitude of patients towards vaccination is positive (54-90%). The pandemic has negatively affected access to medical care, hospitalizations, procurement of drugs, employment, and the mental health of patients which need to be addressed as part of holistic care in SLE. Key Points • Lupus patients are at a greater risk of acquiring COVID-19, related hospitalization,  severe  disease, and death than the general population. • COVID-19 vaccines are relatively safe for lupus patients with minimal risk of severe flares. • Lupus patients' attitude towards COVID-19 vaccination is predominantly positive.

Current concepts regarding Graves' orbitopathy.

Graves' orbitopathy (GO) is an orbital autoimmune disorder and the main extrathyroidal manifestation of Graves' disease, the most common cause of hyperthyroidism. GO affects about 30% of Graves' patients, although fewer than 10% have severe forms requiring immunosuppressive treatments. Management of GO requires a multidisciplinary approach. Medical therapies for active moderate-to-severe forms of GO (traditionally, high-dose glucocorticoids) often provide unsatisfactory results, and subsequently surgeries are often needed to cure residual manifestations. The aim of this review is to provide an updated overview of current concepts regarding the epidemiology, pathogenesis, assessment, and treatment of GO, and to present emerging targeted therapies and therapeutic perspectives. Original articles, clinical trials, systematic reviews, and meta-analyses from 1980 to 2021 were searched using the following terms: Graves' disease, Graves' orbitopathy, thyroid eye disease, glucocorticoids, orbital radiotherapy, rituximab, cyclosporine, azathioprine, teprotumumab, TSH-receptor antibody, smoking, hyperthyroidism, hypothyroidism, thyroidectomy, radioactive iodine, and antithyroid drugs. Recent studies suggest a secular trend toward a milder phenotype of GO. Standardized assessment at a thyroid eye clinic allows for a better general management plan. Treatment of active moderate-to-severe forms of GO still relies in most cases on high-dose systemic-mainly intravenous-glucocorticoids as monotherapy or in combination with other therapies-such as mycophenolate, cyclosporine, azathioprine, or orbital radiotherapy-but novel biological agents-including teprotumumab, rituximab, and tocilizumab-have achieved encouraging results.

High-dose methotrexate and rituximab induction regimen in immunocompetent patients with primary CNS lymphoma: a retrospective single-center study of survival predictors.

PURPOSE: Primary Central Nervous System Lymphoma (PCNSL) is an aggressive tumor that is confined to the CNS. Although the provision of high-dose methotrexate (HD-MTX) has remarkably improved outcomes in PCNSL patients, the optimal treatment regimens and standard MTX dose for induction therapy have been largely controversial. Herein, we sought to explore the impact of adjuvant rituximab and different dosages of induction HD-MTX on survival outcomes of immunocompetent patients with PCNSL. METHODS: In this study, we examined patients with PCNSL treated at a single NCI-designated comprehensive cancer center to evaluate their survival outcomes. We conducted a retrospective analysis of 51 immunocompetent patients with PCNSL who received their induction chemotherapy at the University of Alabama at Birmingham (UAB) between 2001 and 2019. Only adult patients with a confirmed diagnosis of PCNSL who had either HD-MTX alone or in combination with rituximab were included. Patients' demographics, clinical characteristics, and survival data were collected and analyzed. RESULTS: There is no significant difference in survival among patients who received MTX alone versus MTX plus rituximab (HR = 0.996 (95% CI: 0.398-2.493), p = 0.994). Lower doses of MTX were associated with worse survival outcomes (HR = 0.680 (95% CI: 0.530-0.872), p = 0.002); however, this difference in survival was not significant when adjusted to age (HR = 0.797 (95% CI: 0.584-1.088), p = 0.153). CONCLUSION: Our experience challenges the role of rituximab in PCNSL during induction therapy. Our study also highlights the shorter survival in elderly patients with PCNSL which can be related, to some extent, to the relatively lower doses of HD-MTX. There is an unmet need to establish a consensus on the most effective upfront regimen in PCNSL through prospective studies.

Biologic therapy in relapsing polychondritis: navigating between options.

INTRODUCTION: Relapsing polychondritis (RP) is a rare systemic inflammatory disease of unknown etiology, primarily affecting cartilaginous tissue and proteoglycan-rich structures. Clinical manifestations vary from mild symptoms to occasional organ or life-threatening complications. Treatment can be challenging and is mostly based on experience or case reports/series. AREAS COVERED: There is growing literature investigating the role of biologics in the management of RP. TNFα antagonists, abatacept, tocilizumab, rituximab, anakinra and tofacitinib have been prescribed in several RP patients, mainly as second-line treatment, after conventional immunosuppressive agents' failure. EXPERT OPINION: Glucocorticoids represent the gold standard treatment of RP. Conventional immunosuppressants should be administered in refractory patients or when a glucocorticoid-sparing effect is needed. Biologic therapy should be used after failure of conventional treatments or in severe manifestations. TNFα inhibitors are the most prescribed biologic agent, with partial or complete response in several cases, but loss of efficacy may occur over time. Infliximab and adalimumab should be preferred among TNFα antagonists. Abatacept and tocilizumab proved to be effective as second-line biologic agents, but infections are reported with the former. Data on anakinra and rituximab are controversial, therefore they are not recommended as first-line biologic drugs. The use of JAK inhibitors is still anecdotal.

Biologic therapy in refractory neurobehçet's disease: a multicentre study of 41 patients and literature review.

OBJECTIVES: To assess efficacy and safety of biologic therapy (BT) in neurobehçet's disease (NBD) refractory to glucocorticoids and at least one conventional immunosuppressive drug. METHODS: Open-label, national, multicentre study. NBD diagnosis was based on the International Consensus Recommendation criteria. Outcome variables were efficacy and safety. Main efficacy outcome was clinical remission. Other outcome variables analysed were glucocorticoid-sparing effect and improvement in laboratory parameters. RESULTS: We studied 41 patients [21 women; age 40.6 (10.8) years]. Neurological damage was parenchymal (n = 33, 80.5%) and non-parenchymal (n = 17, 41.5%). First BTs used were infliximab (n = 19), adalimumab (n = 14), golimumab (n = 3), tocilizumab (n = 3) and etanercept (n = 2). After 6 months of BT, neurological remission was complete (n = 23, 56.1%), partial (n = 15, 37.6%) and no response (n = 3, 7.3%). In addition, median (IQR) dose of oral prednisone decreased from 60 (30-60) mg/day at the initial visit to 5 (3.8-10) mg/day after 6 months (P < 0.001). It was also the case for mean erythrocyte sedimentation rate [31.5 (25.6)-15.3 (11.9) mm/1st h, P = 0.011] and median (IQR) C-reactive protein [1.4 (0.2-12.8) to 0.3 (0.1-3) mg/dl, P = 0.001]. After a mean follow-up of 57.5 months, partial or complete neurological remission persisted in 37 patients (90.2%). BT was switched in 22 cases (53.6%) due to inefficacy (n = 16) or adverse events (AEs) (n = 6) and discontinued due to complete prolonged remission (n = 3) or severe AE (n = 1). Serious AEs were observed in two patients under infliximab treatment. CONCLUSIONS: BT appears to be effective and relatively safe in refractory NBD.

Herbal NF-κB Inhibitors Sensitize Rituximab-Resistant B Lymphoma Cells to Complement-Mediated Cytolysis.

BACKGROUND: Drug resistance remains a serious challenge to rituximab therapy in B-NHL (B cell non-Hodgkin's lymphoma). CDC (complement-dependent cytotoxicity) has been proposed as a major antitumor mechanism of rituximab, and direct abrogation of CD59 function partially restores rituximab sensitivity with high efficacy. However, universal blockade of CD59 may have deleterious effects on normal cells. Sp1 regulates constitutive CD59 expression, whereas NF-κB and CREB regulate inducible CD59 expression. METHODS: Immunohistochemistry (IHC) assay was used to detect the expression levels of CD59 and other related molecules. Quantitative Real-time PCR (RT-PCR) analysis was used to explore the levels of transcripts in the original and resistant cells. We chose LY8 cells to test the effects of NF-κB and CBP/p300 inhibition on CD59 expression using flow cytometry (FACS). Immunoblotting analysis was employed to detect the effects of curcumin and POH. The in vitro and in vivo experiments were used to evaluate the toxicity and combined inhibitory effect on tumor cells of curcumin and POH. RESULTS: We demonstrated that herbal (curcumin and perillyl alcohol) blockade of NF-κB specifically suppresses the expression of inducible CD59 but not CD20, thus sensitizing resistant cells to rituximab-mediated CDC. Moreover, activation of NF-κB and CREB is highly correlated with CD59 expression in B-NHL tissues. CONCLUSIONS: Our findings suggest the potential of CD59 expression as a predictor of therapeutic efficacy of NF-κB inhibitors in clinical application as well as the rationality of a NF-κB inhibitor-rituximab regimen in B-NHL therapy.