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Advances in Rheumatology (London,... Jun 2024To develop the second evidence-based Brazilian Society of Rheumatology consensus for diagnosis and treatment of lupus nephritis (LN).
OBJECTIVE
To develop the second evidence-based Brazilian Society of Rheumatology consensus for diagnosis and treatment of lupus nephritis (LN).
METHODS
Two methodologists and 20 rheumatologists from Lupus Comittee of Brazilian Society of Rheumatology participate in the development of this guideline. Fourteen PICO questions were defined and a systematic review was performed. Eligible randomized controlled trials were analyzed regarding complete renal remission, partial renal remission, serum creatinine, proteinuria, serum creatinine doubling, progression to end-stage renal disease, renal relapse, and severe adverse events (infections and mortality). The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to develop these recommendations. Recommendations required ≥82% of agreement among the voting members and were classified as strongly in favor, weakly in favor, conditional, weakly against or strongly against a particular intervention. Other aspects of LN management (diagnosis, general principles of treatment, treatment of comorbidities and refractory cases) were evaluated through literature review and expert opinion.
RESULTS
All SLE patients should undergo creatinine and urinalysis tests to assess renal involvement. Kidney biopsy is considered the gold standard for diagnosing LN but, if it is not available or there is a contraindication to the procedure, therapeutic decisions should be based on clinical and laboratory parameters. Fourteen recommendations were developed. Target Renal response (TRR) was defined as improvement or maintenance of renal function (±10% at baseline of treatment) combined with a decrease in 24-h proteinuria or 24-h UPCR of 25% at 3 months, a decrease of 50% at 6 months, and proteinuria < 0.8 g/24 h at 12 months. Hydroxychloroquine should be prescribed to all SLE patients, except in cases of contraindication. Glucocorticoids should be used at the lowest dose and for the minimal necessary period. In class III or IV (±V), mycophenolate (MMF), cyclophosphamide, MMF plus tacrolimus (TAC), MMF plus belimumab or TAC can be used as induction therapy. For maintenance therapy, MMF or azathioprine (AZA) are the first choice and TAC or cyclosporin or leflunomide can be used in patients who cannot use MMF or AZA. Rituximab can be prescribed in cases of refractory disease. In cases of failure in achieving TRR, it is important to assess adherence, immunosuppressant dosage, adjuvant therapy, comorbidities, and consider biopsy/rebiopsy.
CONCLUSION
This consensus provides evidence-based data to guide LN diagnosis and treatment, supporting the development of public and supplementary health policies in Brazil.
Topics: Lupus Nephritis; Humans; Immunosuppressive Agents; Brazil; Societies, Medical; Creatinine; Proteinuria; Mycophenolic Acid; Antibodies, Monoclonal, Humanized; Rheumatology; Rituximab; Biopsy; Cyclophosphamide; Leflunomide; Glucocorticoids; Hydroxychloroquine; Azathioprine; Remission Induction; Cyclosporine; Evidence-Based Medicine; Consensus; Disease Progression; Kidney Failure, Chronic; Randomized Controlled Trials as Topic
PubMed: 38890752
DOI: 10.1186/s42358-024-00386-8 -
BMJ Open Jun 2024There is an unmet need to develop high-quality evidence addressing tuberculosis (TB)-related mental health comorbidity, particularly in the context of...
INTRODUCTION AND OBJECTIVES
There is an unmet need to develop high-quality evidence addressing tuberculosis (TB)-related mental health comorbidity, particularly in the context of lower-middle-income countries. This study aims to examine the effectiveness and cost-effectiveness of cognitive behavioural therapy (CBT) versus enhanced treatment as usual (ETAU) in improving depressive symptoms in people with TB and comorbid depression, enhancing adherence with anti-TB treatment (ATT) and its implementation in the real-world setting of Pakistan.
METHODS
We will conduct a pragmatic parallel arm randomised control trial with an internal pilot. A brief psychological intervention based on CBT has been developed using a combination of qualitative and ethnographic studies. The inbuilt pilot trial will have a sample size of 80, while we plan to recruit 560 (280 per arm) participants in the definitive trial. Participants who started on ATT within 1 month of diagnosis for pulmonary and extrapulmonary TB or multidrug resistant TB (MDR-TB) and meeting the criteria for depression on Patient Health Questionnaire-9 (PHQ-9) will be randomised with 1:1 allocation to receive six sessions of CBT (delivered by TB healthcare workers) or ETAU. Data on the feasibility outcomes of the pilot will be considered to proceed with the definitive trial. Participants will be assessed (by a blinded assessor) for the following main trial primary outcomes: (1) severity of depression using PHQ-9 scale (interviewer-administered questionnaire) at baseline, weeks 8, 24 and 32 postrandomisation and (2) ATT at baseline and week 24 at the end of ATT therapy.
ETHICS AND DISSEMINATION
Ethical approval has been obtained from Keele University Research Ethics Committee (ref: 2023-0599-792), Khyber Medical University Ethical Review Board (ref: DIR/KMU-EB/CT/000990) and National Bioethics Committee Pakistan (ref: No.4-87/NBC-998/23/587). The results of this study will be reported in peer-reviewed journals and academic conferences and disseminated to stakeholders and policymakers.
TRIAL REGISTRATION NUMBER
ISRCTN10761003.
Topics: Humans; Cognitive Behavioral Therapy; Pilot Projects; Pakistan; Depression; Pragmatic Clinical Trials as Topic; Tuberculosis; Multicenter Studies as Topic; Cost-Benefit Analysis; Antitubercular Agents; Adult
PubMed: 38889941
DOI: 10.1136/bmjopen-2023-083483 -
Frontiers in Immunology 2024The assessment of tuberculosis (TB) treatment outcomes predominantly relies on sputum culture conversion status. To enhance treatment management, it is crucial to...
INTRODUCTION
The assessment of tuberculosis (TB) treatment outcomes predominantly relies on sputum culture conversion status. To enhance treatment management, it is crucial to identify non-sputum-based biomarkers that can predict unfavorable outcomes. Cytokines are widely studied as diagnostic biomarkers for active TB. However, their potential as indicators for unfavorable treatment outcomes remains uncertain.
METHODOLOGY
This study was conducted within a well-characterized cohort comprising newly diagnosed patients with drug-sensitive pulmonary TB, confirmed through sputum smear and culture positivity. Our objective was to elucidate the TB antigen-stimulated cytokine profile at pre-treatment and at 2 months into anti-TB treatment (ATT) in patients with unfavorable treatment outcomes (cases, = 27) in comparison to recurrence-free, microbiologically cured controls ( = 31). Whole blood was stimulated with TB antigens using the QuantiFERON In-tube gold method, and plasma supernatants were subjected to a panel of 14 cytokine measurements.
RESULTS
In our study, pre-treatment analysis revealed that eight cytokines (IL-2, IFN-γ, TNF-α, IL-6, IL-10, IL-17A, IL-18, and GM-CSF) were significantly elevated at baseline in cases compared to cured controls, both in unstimulated conditions and following TB antigen (CFP10, ESAT6, and TB7.7) stimulation. A similar pattern was observed at the 2-month mark of ATT, with eight cytokines (IL-2, IL-10, IL-13, IFN-γ, IL-6, IL-12p70, IL-17A, and TNF-α) showing significant differences between the groups. Importantly, no variations were detected following mitogen stimulation, underscoring that these distinctive immune responses are primarily driven by TB-specific antigens.
CONCLUSION
Our findings indicate that individuals with unfavorable TB treatment outcomes display a characteristic cytokine profile distinct from TB-cured patients, even before commencing ATT. Therefore, the levels of specific cytokine pre-treatment and at the 2-month point in the course of treatment may serve as predictive immune markers for identifying individuals at risk of unfavorable TB treatment outcomes, with these responses being predominantly influenced by TB-specific antigens.
Topics: Humans; Tuberculosis, Pulmonary; Cytokines; Male; Female; Adult; Middle Aged; Biomarkers; Antigens, Bacterial; Treatment Outcome; Antitubercular Agents; Mycobacterium tuberculosis; Aged
PubMed: 38887283
DOI: 10.3389/fimmu.2024.1392256 -
BMJ Case Reports Jun 2024We present the case of a patient with HIV and tuberculosis (TB) coinfection who initially developed paradoxical TB immune reconstitution inflammatory syndrome (TB-IRIS)...
We present the case of a patient with HIV and tuberculosis (TB) coinfection who initially developed paradoxical TB immune reconstitution inflammatory syndrome (TB-IRIS) post-antituberculous treatment and post-antiretroviral therapy initiation. Despite being managed effectively, lymphadenitis recurred as many as three times over the course of several years. Due to consistent culture-negative lymph node biopsies, the recurring lymphadenitis was eventually deemed inflammatory rather than microbiological recurrences. Cessation of anti-TB treatment led to symptom remission followed by a long asymptomatic period, corroborating the immunological nature of the episodes. However, 5 and 6 years after cessation of anti-TB treatment, respectively, lymphadenitis returned. In both instances, her symptoms regressed without treatment with anti-TB drugs. This case underscores the complexities of managing TB-IRIS and the necessity of differentiating between paradoxical TB-IRIS and other paradoxical reactions for appropriate treatment decisions. Recognition of such distinctions is crucial in guiding effective therapeutic interventions in TB-HIV coinfection scenarios.
Topics: Humans; Immune Reconstitution Inflammatory Syndrome; Female; Antitubercular Agents; HIV Infections; Lymphadenitis; Recurrence; Adult; Coinfection; Tuberculosis, Lymph Node
PubMed: 38885999
DOI: 10.1136/bcr-2023-259211 -
The Journal of the Association of... Jun 2024The modified Ponticelli regimen (mPR) is a first-line therapy in patients with idiopathic membranous nephropathy (IMN); however, it has a less favorable safety profile.... (Randomized Controlled Trial)
Randomized Controlled Trial
Mycophenolate Mofetil with Steroid, a Reasonable Alternative to Current First-line Therapy, for Idiopathic Membranous Nephropathy in Resource-constrained Settings: A Randomized, Open-label Study.
BACKGROUND
The modified Ponticelli regimen (mPR) is a first-line therapy in patients with idiopathic membranous nephropathy (IMN); however, it has a less favorable safety profile. Though mycophenolate mofetil (MMF) + steroid (S) is not recommended by Kidney Disease Improving Global Outcomes guidelines, it can be used as an alternative to mPR due to higher tolerability and steroid-sparing effect. Thus, we compared the safety and effectiveness of MMF + S and mPR regimens in patients with IMN.
METHODS
This randomized, open-label study enrolled patients with adult-onset nephrotic syndrome (NS) and biopsy-proven IMN. Forty-two patients were allocated to MMF + S group (MMF 1 gm twice daily + oral prednisolone 0.5 mg/kg/day; = 21) and mPR group [methylprednisolone (1 gm intravenous) for 3 days followed by alternating monthly cycles of oral prednisolone (0.5 mg/kg/day) for the next 27 days and cyclophosphamide (2 mg/kg/day) for 6 months; = 21]. The primary outcome measure was change in urinary protein creatinine ratio (UPCR).
RESULTS
At 6 months, both groups demonstrated a significant increase in serum albumin levels and estimated glomerular filtration rate (eGFR) (both -values <0.0001) as well as a decrease in 24-hour proteinuria (MMF + S group: -value = 0.003, and mPR group: -value <0.0001) and UPCR (both -values <0.0001). However, the groups did not differ in any of these parameters at any of the monthly follow-up visits. Moreover, the groups did not differ significantly in terms of the composite remission rates (61.91% for MMF + S group and 71.43% for mPR group).
CONCLUSION
MMF + S and mPR had comparable tolerability and effectiveness, with MMF-associated advantage of reduced steroid exposure.
Topics: Humans; Glomerulonephritis, Membranous; Mycophenolic Acid; Male; Female; Adult; Immunosuppressive Agents; Drug Therapy, Combination; Prednisolone; Middle Aged; Glucocorticoids; Cyclophosphamide; Methylprednisolone; Treatment Outcome
PubMed: 38881128
DOI: 10.59556/japi.72.0558 -
Frontiers in Immunology 2024Autoimmune cytopenias (AICs) are a group of disorders characterized by immune-mediated destruction of blood cells. In children, they are often secondary to immune...
INTRODUCTION
Autoimmune cytopenias (AICs) are a group of disorders characterized by immune-mediated destruction of blood cells. In children, they are often secondary to immune dysregulation that may require long-lasting immunosuppression. Mycophenolate mofetil and sirolimus represent two well-tolerated options to treat these disorders, often as a steroid-sparing option. However, no data are available on the infection risk for patients undergoing long-lasting treatments.
PATIENTS AND METHODS
The rate of severe infective events was calculated in episodes per 100 persons/months at risk (p/m/r) documented by the analysis of hospitalization charts between January 2015 and July 2023 of patients treated with mycophenolate mofetil or sirolimus given for isolated AIC or AICs associated with autoimmune lymphoproliferative syndrome (ALPS)/ALPS-like syndromes in two large Italian pediatric hematology units.
RESULTS
From January 2015 to July 2023, 13 out of 96 patients treated with mycophenolate mofetil or sirolimus developed 16 severe infectious events requiring hospitalization. No patients died. Overall infection rate was 0.24 person/*100 months/risk (95% CI 0.09-0.3). Serious infectious events incidence was higher in patients with ALPS-like compared to others (0.42 versus 0.09; = 0.006) and lower in patients who underwent mycophenolate treatment alone compared to those who started sirolimus after mycophenolate failure (0.04 versus 0.29, = 0.03). Considering only patients who started treatment at the beginning of study period, overall cumulative hazard was 18.6% at 60 months (95% CI 3.4-31.4) with higher risk of infectious events after 5 years in ALPS-like patients (26.1%; 95% CI 3.2-43.5) compared to other AICs (4%; 95% CI 0-11.4; = 0.041).
DISCUSSION
To the best of our knowledge, this is the first study to describe the infectious risk related to mycophenolate and sirolimus chronic treatment in patients with AICs and immune dysregulation. Our data highlight that infection rate is very low and mainly related to the underlying hematological condition.
CONCLUSIONS
Mycophenolate and sirolimus represent a safe immunosuppressive therapy in AICs and immune dysregulation syndromes.
Topics: Humans; Mycophenolic Acid; Sirolimus; Female; Male; Child; Immunosuppressive Agents; Child, Preschool; Adolescent; Infant; Autoimmune Diseases; Infections; Risk Factors; Retrospective Studies; Incidence; Cytopenia
PubMed: 38873600
DOI: 10.3389/fimmu.2024.1415389 -
Frontiers in Immunology 2024Mycobacterium tuberculosis (Mtb) is an intracellular pathogen capable of adapting and surviving within macrophages, utilizing host nutrients for its growth and... (Review)
Review
Mycobacterium tuberculosis (Mtb) is an intracellular pathogen capable of adapting and surviving within macrophages, utilizing host nutrients for its growth and replication. Cholesterol is the main carbon source during the infection process of Mtb. Cholesterol metabolism in macrophages is tightly associated with cell functions such as phagocytosis of pathogens, antigen presentation, inflammatory responses, and tissue repair. Research has shown that Mtb infection increases the uptake of low-density lipoprotein (LDL) and cholesterol by macrophages, and enhances cholesterol synthesis in macrophages. Excessive cholesterol is converted into cholesterol esters, while the degradation of cholesterol esters in macrophages is inhibited by Mtb. Furthermore, Mtb infection suppresses the expression of ATP-binding cassette (ABC) transporters in macrophages, impeding cholesterol efflux. These alterations result in the massive accumulation of cholesterol in macrophages, promoting the formation of lipid droplets and foam cells, which ultimately facilitates the persistent survival of Mtb and the progression of tuberculosis (TB), including granuloma formation, tissue cavitation, and systemic dissemination. Mtb infection may also promote the conversion of cholesterol into oxidized cholesterol within macrophages, with the oxidized cholesterol exhibiting anti-Mtb activity. Recent drug development has discovered that reducing cholesterol levels in macrophages can inhibit the invasion of Mtb into macrophages and increase the permeability of anti-tuberculosis drugs. The development of drugs targeting cholesterol metabolic pathways in macrophages, as well as the modification of existing drugs, holds promise for the development of more efficient anti-tuberculosis medications.
Topics: Mycobacterium tuberculosis; Cholesterol; Humans; Macrophages; Tuberculosis; Animals; Host-Pathogen Interactions; Antitubercular Agents; Lipid Metabolism
PubMed: 38873598
DOI: 10.3389/fimmu.2024.1402024 -
Mathematical Biosciences and... Mar 2024Tuberculosis has affected human beings for thousands of years, and until today, tuberculosis still ranks third among 29 infectious diseases in China. However, most of...
Tuberculosis has affected human beings for thousands of years, and until today, tuberculosis still ranks third among 29 infectious diseases in China. However, most of the existing mathematical models consider a single factor, which is not conducive to the study of tuberculosis transmission dynamics. Therefore, this study considers the combined effects of vaccination, treatment, and contaminated environments on tuberculosis, and builds a new model with seven compartments of $ SVEITRW $ based on China's tuberculosis data. The study shows that when the basic reproduction number $ R_{0} $ is less than 1, the disease will eventually disappear, but when $ R_{0} $ is greater than 1, the disease may persist. In the numerical analysis part, we use Markov-chain Monte-Carlo method to obtain the optimal parameters of the model. Through the next generation matrix theory, we calculate that the $ R_{0} $ value of tuberculosis in China is $ 2.1102 $, that is, if not controlled, tuberculosis in China will not disappear over time. At the same time, through partial rank correlation coefficients, we find the most sensitive parameter to the basic reproduction number $ R_{0} $. On this basis, we combine the actual prevalence of tuberculosis in China, apply Pontryagin's maximum principle, and perform cost-effectiveness analysis to obtain the conditions required for optimal control. The analysis shows that four control strategies could effectively reduce the prevalence of TB, and simultaneously controlling $ u_{2}, u_{3}, u_{4} $ is the most cost-effective control strategy.
Topics: Humans; Basic Reproduction Number; China; Tuberculosis; Vaccination; Markov Chains; Monte Carlo Method; Computer Simulation; Prevalence; Models, Theoretical; Algorithms; Antitubercular Agents
PubMed: 38872537
DOI: 10.3934/mbe.2024234 -
Bioorganic Chemistry May 2024Tuberculosis is a global serious problem that imposes major health, economic and social challenges worldwide. The search for new antitubercular drugs is extremely...
Tuberculosis is a global serious problem that imposes major health, economic and social challenges worldwide. The search for new antitubercular drugs is extremely important which could be achieved via inhibition of different druggable targets. Mycobacterium tuberculosis enoyl acyl carrier protein reductase (InhA) enzyme is essential for the survival of M. tuberculosis. In this investigation, a series of coumarin based thiazole derivatives was synthesized relying on a molecular hybridization approach and was assessed against thewild typeMtb H37Rv and its mutant strain (ΔkatG) via inhibiting InhA enzyme. Among the synthesized derivatives, compounds 2b, 3i and 3j were the most potent against wild type M. tuberculosis with MIC values ranging from 6 to 8 μg/ mL and displayed low cytotoxicity towards mouse fibroblasts at concentrations 8-13 times higher than the MIC values. The three hybrids could also inhibit the growth of ΔkatGmutant strain which is resistant to isoniazid (INH). Compounds 2b and 3j were able to inhibit the growth of mycobacteria inside human macrophages, indicating their ability to penetrate human professional phagocytes. The two derivatives significantly suppress mycobacterial biofilm formation by 10-15 %. The promising target compounds were also assessed for their inhibitory effect against InhA and showed potent effectiveness with IC values of 0.737 and 1.494 µM, respectively. Molecular docking studies revealed that the tested compounds occupied the active site of InhA in contact with the NAD molecule. The 4-phenylcoumarin aromatic system showed binding interactions within the hydrophobic pocket of the active site. Furthermore, H-bond formation and π -π stacking interactions were also recorded for the promising derivatives.
PubMed: 38870705
DOI: 10.1016/j.bioorg.2024.107511 -
Lumbar Spine Infected by Mycobacterium tuberculosis and Cryptococcus neoformans: a Rare Case Report.Clinical Laboratory Jun 2024In July 2023, our hospital confirmed one case of lumbar spine infected complicated by Mycobacterium tuberculosis and Cryptococcus neoformans. The patient was admitted...
BACKGROUND
In July 2023, our hospital confirmed one case of lumbar spine infected complicated by Mycobacterium tuberculosis and Cryptococcus neoformans. The patient was admitted due to lower back pain for 1 year and a hard lump for 3 months. Symptoms and signs: Dressing can be seen fixed on the lower back, with severe bleeding. When the dressing is removed, a hard and protruding lump with a size of 6 cm x 8 cm, a sinus tract can be seen near the mass, with a slightly red wound and a sinus depth of about 3 cm. Light red fluid can be seen flowing out. There are no symptoms such as redness, swelling, or heat in the rest of the lower back, and the patient has no other underlying diseases or surgical history.
METHODS
Lumbar magnetic resonance imaging and lumbar CT examination; Percutaneous puncture lumbar vertebral biopsy was performed, and the biopsy tissue was subjected to pathological examination, mNGS (metagenomic next-generation sequencing), and acid-fast staining; Extract pus from the lump for fungal culture and ink staining, and identify the fungi through MALDI-TOF MS.
RESULTS
Bone destruction and bone marrow edema in the L5 vertebral body, compression of the spinal canal at the L5 vertebral body level; The pathological results of the biopsy tissue indicate granulomatous lesions. The acid-fast staining of the tissue is positive, and the mNGS of the tissue indicates infection with Mycobacterium tuberculosis. A single fungus was cultured from pus and identified by MALDI-TOF MS as Cryptococcus neoformans. Clinically, isoniazid 0.3 g ivgtt + rifampicin 0.45 g qd po + ethambutol 0.25 g qd po + pyrazinamide 0.75 g qd po + fluconazole 0.3 g qd po was administered for treatment. After 11 days, there was slight pain at the incision site, and the original symptoms were significantly relieved. The wound dressing was fixed in place, dry and without obvious exudation. Improved and discharged, followed up for 3 months with no recurrence of the lesion.
CONCLUSIONS
mNGS is an effective identification technique that can be used to accurately diagnose suspected infection cases. MALDI-TOF MS has significant advantages over traditional detection methods in shortening detection time. This case achieved satisfactory treatment results for patients through a reasonable treatment plan, which is of great significance for exploring the diagnosis and treatment of similar disease infections.
Topics: Humans; Cryptococcus neoformans; Lumbar Vertebrae; Mycobacterium tuberculosis; Cryptococcosis; Male; Tuberculosis, Spinal; Magnetic Resonance Imaging; Antitubercular Agents; Middle Aged; Tomography, X-Ray Computed
PubMed: 38868894
DOI: 10.7754/Clin.Lab.2024.240118