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Gut Feb 2023There are numerous biological therapies and small molecules licensed for luminal Crohn's disease (CD), but these are often studied in placebo-controlled trials, meaning... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
There are numerous biological therapies and small molecules licensed for luminal Crohn's disease (CD), but these are often studied in placebo-controlled trials, meaning relative efficacy is uncertain. We examined this in a network meta-analysis.
DESIGN
We searched the literature to 1 July 2022, judging efficacy according to induction of clinical remission, clinical response and maintenance of clinical remission, and according to previous exposure or non-exposure to biologics. We used a random effects model and reported data as pooled relative risks (RRs) with 95% CIs, ranking drugs according to p-score.
RESULTS
We identified 25 induction of remission trials (8720 patients). Based on failure to achieve clinical remission, infliximab 5 mg/kg ranked first versus placebo (RR=0.67, 95% CI 0.56 to 0.79, p-score 0.95), with risankizumab 600 mg second and upadacitinib 45 mg once daily third. However, risankizumab 600 mg ranked first for clinical remission in biologic-naïve (RR=0.66, 95% CI 0.52 to 0.85, p-score 0.78) and in biologic-exposed patients (RR=0.74, 95% CI 0.67 to 0.82, p-score 0.92). In 15 maintenance of remission trials (4016 patients), based on relapse of disease activity, upadacitinib 30 mg once daily ranked first (RR=0.61, 95% CI 0.52 to 0.72, p-score 0.93) with adalimumab 40 mg weekly second, and infliximab 10 mg/kg 8-weekly third. Adalimumab 40 mg weekly ranked first in biologic-naïve patients (RR=0.59, 95% CI 0.48 to 0.73, p-score 0.86), and vedolizumab 108 mg 2-weekly first in biologic-exposed (RR=0.70, 95% CI 0.57 to 0.86, p-score 0.82).
CONCLUSION
In a network meta-analysis, infliximab 5 mg/kg ranked first for induction of clinical remission in all patients with luminal CD, but risankizumab 600 mg was first in biologic-naïve and biologic-exposed patients. Upadacitinib 30 mg once daily ranked first for maintenance of remission.
Topics: Humans; Crohn Disease; Adalimumab; Infliximab; Network Meta-Analysis; Biological Therapy; Remission Induction
PubMed: 35907636
DOI: 10.1136/gutjnl-2022-328052 -
American Family Physician Oct 2019Acne vulgaris is the most prevalent chronic skin disease in the United States, affecting nearly 50 million people per year, mostly adolescents and young adults....
Acne vulgaris is the most prevalent chronic skin disease in the United States, affecting nearly 50 million people per year, mostly adolescents and young adults. Potential sequelae of acne, such as scarring, dyspigmentation, and low self-esteem, may result in significant morbidity. Typical acne lesions involve the pilosebaceous follicles and the interrelated processes of sebum production, Cutibacterium acnes (previously called Propionibacterium acnes) colonization, and inflammation. Acne may be classified as mild, moderate, or severe based on the number and type of skin lesions. Multiple treatment agents and formulations are available, with each agent targeting a specific area within acne pathogenesis. Treatment selection is based on disease severity, patient preference, and tolerability. Topical retinoids are indicated for acne of any severity and for maintenance therapy. Systemic and topical antibiotics should be used only in combination with benzoyl peroxide and retinoids and for a maximum of 12 weeks. Isotretinoin is used for severe, recalcitrant acne. Because of the risk of teratogenicity, patients, pharmacists, and prescribers must register with the U.S. Food and Drug Administration-mandated risk management program, iPledge, before implementing isotretinoin therapy. There is limited evidence for physical modalities (e.g., laser therapy, light therapy, chemical peels) and complementary therapies (e.g., purified bee venom, low-glycemic-load diet, tea tree oil); therefore, further study is required.
Topics: Acne Vulgaris; Adolescent; Adult; Anti-Bacterial Agents; Benzoyl Peroxide; Chronic Disease; Complementary Therapies; Curriculum; Dermatologic Agents; Education, Medical, Continuing; Female; Humans; Isotretinoin; Laser Therapy; Male; Phototherapy; United States; Young Adult
PubMed: 31613567
DOI: No ID Found -
Haematologica Sep 2023The last decade has seen steadfast progress in drug development in acute myeloid leukemia (AML) which has moved progressively towards genomic-based therapy. With these... (Review)
Review
The last decade has seen steadfast progress in drug development in acute myeloid leukemia (AML) which has moved progressively towards genomic-based therapy. With these advances, outcomes in AML have improved but remains far from satisfactory. One approach towards preventing relapse in AML is to use maintenance therapy in patients, after attaining remission. Allogeneic hematopoietic stem cell transplantation (HSCT) is an effective post-remission therapy that has been proven to reduce the risk of relapse. However, in patients who are ineligible for HSCT or have a high risk of relapse, other effective measures to prevent relapse are needed. There is also a need for post-HSCT maintenance to reduce relapse in high-risk subsets. Over the last 3 decades maintenance therapy in AML has evolved from the use of chemotherapeutic agents to more targeted therapies and better modulation of the immune system. Unfortunately, improvements in survival outcomes as a result of using these agents have not been consistently demonstrated in clinical trials. To derive the optimum benefit from maintenance therapy the time points of therapy initiation need to be defined and therapy must be selected precisely with respect to the AML genetics and risk stratification, prior treatment exposure, transplant eligibility, expected toxicity and the patient's clinical profile and desires. The far-reaching goal is to facilitate patients with AML in remission to achieve a normal quality of life while improving remission duration and overall survival. The QUAZAR trial was a welcome step towards a safe maintenance drug that is easy to administer and showed survival benefit but leaves many open issues for discussion. In this review we will discuss these issues, highlighting the development of AML maintenance therapies over the last 3 decades.
Topics: Humans; Quality of Life; Leukemia, Myeloid, Acute; Hematopoietic Stem Cell Transplantation; Recurrence
PubMed: 37139599
DOI: 10.3324/haematol.2022.281810 -
Cell Stem Cell Nov 2022Mesenchymal stem/stromal cells (MSCs) exist in almost all tissues and participate in tissue regeneration and homeostasis. In-vitro-expanded MSCs are employed as... (Review)
Review
Mesenchymal stem/stromal cells (MSCs) exist in almost all tissues and participate in tissue regeneration and homeostasis. In-vitro-expanded MSCs are employed as therapeutics for autoimmune diseases, organ failures, and many other chronic disorders. Remarkably, the reparative and homeostatic maintenance functions of MSCs rely on their interaction with the inflammatory microenvironment. Here, we discuss the characteristics and functions of MSCs under different pathophysiological conditions and highlight how the immunomodulatory functions of MSCs are altered in accordance with the inflammatory cues. We hope to provide new insights into the diverse immunoregulatory properties of MSCs during tissue regeneration and therapy.
Topics: Humans; Mesenchymal Stem Cells; Immunomodulation; Wound Healing; Autoimmune Diseases; Immunity; Mesenchymal Stem Cell Transplantation
PubMed: 36332569
DOI: 10.1016/j.stem.2022.10.001 -
Nature Reviews. Immunology May 2023Allergen immunotherapy is a form of therapeutic vaccination for established IgE-mediated hypersensitivity to common allergen sources such as pollens, house dust mites... (Review)
Review
Allergen immunotherapy is a form of therapeutic vaccination for established IgE-mediated hypersensitivity to common allergen sources such as pollens, house dust mites and the venom of stinging insects. The classical protocol, introduced in 1911, involves repeated subcutaneous injection of increasing amounts of allergen extract, followed by maintenance injections over a period of 3 years, achieving a form of allergen-specific tolerance that provides clinical benefit for years after its discontinuation. More recently, administration through the sublingual route has emerged as an effective, safe alternative. Oral immunotherapy for peanut allergy induces effective 'desensitization' but not long-term tolerance. Research and clinical trials over the past few decades have elucidated the mechanisms underlying immunotherapy-induced tolerance, involving a reduction of allergen-specific T helper 2 (T2) cells, an induction of regulatory T and B cells, and production of IgG and IgA 'blocking' antibodies. To better harness these mechanisms, novel strategies are being explored to achieve safer, effective, more convenient regimens and more durable long-term tolerance; these include alternative routes for current immunotherapy approaches, novel adjuvants, use of recombinant allergens (including hypoallergenic variants) and combination of allergens with immune modifiers or monoclonal antibodies targeting the T2 cell pathway.
Topics: Humans; Hypersensitivity; Desensitization, Immunologic; Allergens; Administration, Sublingual; B-Lymphocytes
PubMed: 36253555
DOI: 10.1038/s41577-022-00786-1 -
The Lancet. Gastroenterology &... Dec 2021Data are needed to inform the positioning of biologic therapy in the treatment of moderate-to-severe Crohn's disease, both first line and after previous biologic... (Comparative Study)
Comparative Study Meta-Analysis
BACKGROUND
Data are needed to inform the positioning of biologic therapy in the treatment of moderate-to-severe Crohn's disease, both first line and after previous biologic exposure. We aimed to assess the comparative efficacy and safety of biologics in patients with Crohn's disease.
METHODS
We did a systematic review and network meta-analysis of phase 2 and phase 3 randomised controlled trials done in adults (≥18 years) with moderate-to-severe Crohn's disease (Crohn's Disease Activity Index [CDAI] 220-450) treated with tumour necrosis factor (TNF) antagonists, anti-integrin, anti-interleukin (IL)-12 and IL-23p40, or anti-IL23p19 agents, either alone or in combination with immunosuppressants, as their first-line biologic or after previous biologic exposure, compared with placebo or an active comparator. The minimum duration of therapy was 14 days for trials reporting induction of remission in active disease and 22 weeks in trials reporting maintenance of remission. We searched Medline, EMBASE, the Cochrane CENTRAL Register of Controlled Trials, conference proceedings, trial registries, and unpublished data from inception to June 3, 2021, without any language restrictions. Summary estimates of the primary and secondary outcomes were extracted from the published reports; individual patient-level data were not sought. The primary endpoint was induction of clinical remission in patients with active disease (CDAI <150) and maintenance of remission in patients with response to induction therapy, with data extracted from published reports. A network meta-analysis with multivariate consistency model random-effects meta-regression was done, with rankings based on surface under the cumulative ranking curve (SUCRA) values.
FINDINGS
The search strategy yielded 18 382 citations, of which 31 trials were eligible for inclusion. On the basis of 15 randomised controlled trials including 2931 biologic-naive patients, infliximab monotherapy (odds ratio [OR] 4·53 [95% CI 1·49-13·79]), infliximab combined with azathioprine (7·49 [2·04-27·49]), adalimumab (3·01 [1·25-7·27]), and ustekinumab (2·63 [1·10-6·28]) were associated with significantly higher odds of inducing remission compared to certolizumab pegol (all moderate confidence); infliximab and azathioprine combination therapy was also associated with significantly higher odds of inducing remission than vedolizumab (3·76 [1·01-14·03]; low confidence). On the basis of ten randomised controlled trials including 2479 patients with previous biologic exposure, adalimumab after loss of response to infliximab (OR 2·82 [95% CI 1·20-6·62]; low confidence), and risankizumab (2·10 [1·12-3·92]; moderate confidence), were associated with higher odds of inducing remission than vedolizumab. No differences between active interventions were observed in maintenance trials. Most trials were at low or uncertain risk of bias.
INTERPRETATION
Although biologic treatment choices in patients with moderate-to-severe Crohn's disease must be individualised for each patient, this analysis suggests that either infliximab with azathioprine or adalimumab might be preferred as a first-line therapy, and adalimumab (after infliximab loss of response) or risankizumab might be preferred as a second-line therapy, for induction of clinical remission.
FUNDING
None.
Topics: Adalimumab; Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Azathioprine; Benzene Derivatives; Biological Therapy; Carboxylic Acids; Case-Control Studies; Crohn Disease; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Infliximab; Interleukin-12 Subunit p40; Interleukin-23 Subunit p19; Male; Network Meta-Analysis; Placebos; Randomized Controlled Trials as Topic; Remission Induction; Safety; Severity of Illness Index; Treatment Outcome; Tumor Necrosis Factor Inhibitors; Ustekinumab
PubMed: 34688373
DOI: 10.1016/S2468-1253(21)00312-5 -
American Journal of Hematology Nov 2019Curative treatment in acute myeloid leukemia (AML) depends on successful induction therapy to achieve a complete remission (CR), and subsequent post-remission therapy to... (Review)
Review
Curative treatment in acute myeloid leukemia (AML) depends on successful induction therapy to achieve a complete remission (CR), and subsequent post-remission therapy to prevent relapse. High relapse rates after consolidation therapy and after allogeneic stem cell transplant contribute to suboptimal outcomes in AML patients, and continue to represent a difficult challenge. Effective maintenance therapy could play an important role in prolonging the remission interval in the post-consolidation setting, especially in high risk AML patients. Maintenance treatment approaches based on conventional chemotherapy, immunotherapy, hypomethylating agents, and targeted small molecules have been explored in this setting, but no data so far have been convincing enough to establish this approach as the standard of care. However, ongoing and future studies including novel targeted therapies may demonstrate promising efficacy that could facilitate incorporation of maintenance therapy into clinical practice. In this review we summarize previous and ongoing approaches of maintenance therapy in AML and discuss the most promising strategies.
Topics: Antineoplastic Agents; Clinical Trials as Topic; Combined Modality Therapy; DNA Methylation; Disease-Free Survival; Drug Resistance, Neoplasm; Hematopoietic Stem Cell Transplantation; Humans; Immunotherapy; Interferons; Interleukin-2; Leukemia, Myeloid, Acute; Maintenance Chemotherapy; Molecular Targeted Therapy; Multicenter Studies as Topic; Neoplasm Proteins; Neoplasm, Residual; Recurrence; Remission Induction
PubMed: 31429099
DOI: 10.1002/ajh.25620 -
American Family Physician Oct 2012Acne is a chronic inflammatory skin disease that is the most common skin disorder in the United States. Therapy targets the four factors responsible for lesion... (Review)
Review
Acne is a chronic inflammatory skin disease that is the most common skin disorder in the United States. Therapy targets the four factors responsible for lesion formation: increased sebum production, hyperkeratinization, colonization by Propionibacterium acnes, and the resultant inflammatory reaction. Treatment goals include scar prevention, reduction of psychological morbidity, and resolution of lesions. Grading acne based on lesion type and severity can help guide treatment. Topical retinoids are effective in treating inflammatory and noninflammatory lesions by preventing comedones, reducing existing comedones, and targeting inflammation. Benzoyl peroxide is an over-the-counter bactericidal agent that does not lead to bacterial resistance. Topical and oral antibiotics are effective as monotherapy, but are more effective when combined with topical retinoids. The addition of benzoyl peroxide to antibiotic therapy reduces the risk of bacterial resistance. Oral isotretinoin is approved for the treatment of severe recalcitrant acne and can be safely administered using the iPLEDGE program. After treatment goals are reached, maintenance therapy should be initiated. There is insufficient evidence to recommend the use of laser and light therapies. Referral to a dermatologist should be considered if treatment goals are not met.
Topics: Acne Vulgaris; Administration, Topical; Anti-Bacterial Agents; Dermatologic Agents; Diagnosis, Differential; Humans; Phototherapy
PubMed: 23062156
DOI: No ID Found -
Journal of Hematology & Oncology Mar 2023Acute myeloid leukemia (AML) is the most common acute leukemia in adults. While survival for younger patients over the last several decades has improved nearly sixfold... (Review)
Review
Acute myeloid leukemia (AML) is the most common acute leukemia in adults. While survival for younger patients over the last several decades has improved nearly sixfold with the optimization of intensive induction chemotherapy and allogeneic stem cell transplantation (alloHSCT), this effect has been largely mitigated in older and less fit patients as well as those with adverse-risk disease characteristics. However, the last 10 years has been marked by major advances in the molecular profiling of AML characterized by a deeper understanding of disease pathobiology and therapeutic vulnerabilities. In this regard, the classification of AML subtypes has recently evolved from a morphologic to a molecular and genetic basis, reflected by recent updates from the World Health Organization and the new International Consensus Classification system. After years of stagnation in new drug approvals for AML, there has been a rapid expansion of the armamentarium against this disease since 2017. Low-intensity induction therapy with hypomethylating agents and venetoclax has substantially improved outcomes, including in those previously considered to have a poor prognosis. Furthermore, targeted oral therapies against driver mutations in AML have been added to the repertoire. But with an accelerated increase in treatment options, several questions arise such as how to best sequence therapy, how to combine therapies, and if there is a role for maintenance therapy in those who achieve remission and cannot undergo alloHSCT. Moreover, certain subtypes of AML, such as those with TP53 mutations, still have dismal outcomes despite these recent advances, underscoring an ongoing unmet need and opportunity for translational advances. In this review, we will discuss recent updates in the classification and risk stratification of AML, explore the literature regarding low-intensity and novel oral combination therapies, and briefly highlight investigative agents currently in early clinical development for high-risk disease subtypes.
Topics: Adult; Humans; Aged; Leukemia, Myeloid, Acute; Combined Modality Therapy; Hematopoietic Stem Cell Transplantation; Mutation; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36966300
DOI: 10.1186/s13045-023-01424-6 -
Blood Cancer Journal Feb 2020The evolving paradigm of continuous therapy and maintenance treatment approaches in multiple myeloma (MM) offers prolonged disease control and improved outcomes compared... (Review)
Review
The evolving paradigm of continuous therapy and maintenance treatment approaches in multiple myeloma (MM) offers prolonged disease control and improved outcomes compared to traditional fixed-duration approaches. Potential benefits of long-term strategies include sustained control of disease symptoms, as well as continued cytoreduction and clonal control, leading to unmeasurable residual disease and the possibility of transforming MM into a chronic or functionally curable condition. "Continuous therapy" commonly refers to administering a doublet or triplet regimen until disease progression, whereas maintenance approaches typically involve single-agent or doublet treatment following more intensive prior therapy with autologous stem cell transplant (ASCT) or doublet, triplet, or even quadruplet induction therapy. However, the requirements for agents and regimens within these contexts are similar: treatments must be tolerable for a prolonged period of time, should not be associated with cumulative or chronic toxicity, should not adversely affect patients' quality of life, should ideally be convenient with a minimal treatment burden for patients, and should not impact the feasibility or efficacy of subsequent treatment at relapse. Multiple agents have been and are being investigated as long-term options in the treatment of newly diagnosed MM (NDMM), including the immunomodulatory drugs lenalidomide and thalidomide, the proteasome inhibitors bortezomib, carfilzomib, and ixazomib, and the monoclonal antibodies daratumumab, elotuzumab, and isatuximab. Here we review the latest results with long-term therapy approaches in three different settings in NDMM: (1) maintenance treatment post ASCT; (2) continuous frontline therapy in nontransplant patients; (3) maintenance treatment post-frontline therapy in the nontransplant setting. We also discuss evidence from key phase 3 trials. Our review demonstrates how the paradigm of long-term treatment is increasingly well-established across NDMM treatment settings, potentially resulting in further improvements in patient outcomes, and highlights key clinical issues that will need to be addressed in order to provide optimal benefit.
Topics: Hematopoietic Stem Cell Transplantation; Humans; Maintenance Chemotherapy; Multiple Myeloma; Prognosis; Quality of Life
PubMed: 32054831
DOI: 10.1038/s41408-020-0273-x