Efficacy and safety of pharmacological treatment of psoriatic arthritis: a systematic literature research informing the 2023 update of the EULAR recommendations for the management of psoriatic arthritis.

OBJECTIVES: To obtain an overview of recent evidence on efficacy and safety of pharmacological treatments in psoriatic arthritis (PsA). METHODS: This systematic literature research (SLR) investigated the efficacy and safety of conventional synthetic (cs), biological (b) and targeted synthetic (ts) disease-modifying antirheumatic drugs (DMARDs) in patients with PsA. A systematic database search using Medline, EMBASE, Cochrane CENTRAL was conducted to identify relevant articles published since the previous update in 2019 until 28 December 2022. Efficacy was assessed in trials while for safety observational data were also considered. Adverse events of special interest were infections (including herpes zoster, influenza and tuberculosis), malignancies, major adverse cardiovascular events, venous thromboembolisms, liver disease, laboratory changes and psychiatric adverse events. No meta-analyses were performed. RESULTS: For efficacy, of 3946 articles screened, 38 articles (30 trials) were analysed. The compounds investigated included csDMARDs (leflunomide, methotrexate), bDMARDs inhibiting IL17 (bimekizumab, brodalumab, ixekizumab, izokibep, secukinumab,), IL-23 (guselkumab, risankizumab, tildrakizumab), IL-12/23 (ustekinumab) as well as TNF (adalimumab, certolizumab-pegol, etanercept, infliximab, golimumab) and Janus Kinase inhibitors (JAKi) (brepocitinib, deucravacitinib, tofacitinib, upadacitinib). The compounds investigated were efficacious in improving signs and symptoms of PsA, improving physical functioning and quality of life. For safety, 2055 abstracts were screened, and 24 articles analysed: 15 observational studies and 9 long-term follow-ups of trials, assessing glucocorticoids, TNFi, IL-17i, JAKi, IL-12/23i and PDE4i (apremilast). Safety indicators were generally coherent with the previous SLR in 2019. CONCLUSION: The results of this SLR informed the task force responsible for the 2023 update of the European Alliance of Associations for Rheumatology recommendations for pharmacological management of PsA.

EULAR recommendations for the management of psoriatic arthritis with pharmacological therapies: 2023 update.

OBJECTIVE: New modes of action and more data on the efficacy and safety of existing drugs in psoriatic arthritis (PsA) required an update of the EULAR 2019 recommendations for the pharmacological treatment of PsA. METHODS: Following EULAR standardised operating procedures, the process included a systematic literature review and a consensus meeting of 36 international experts in April 2023. Levels of evidence and grades of recommendations were determined. RESULTS: The updated recommendations comprise 7 overarching principles and 11 recommendations, and provide a treatment strategy for pharmacological therapies. Non-steroidal anti-inflammatory drugs should be used in monotherapy only for mild PsA and in the short term; oral glucocorticoids are not recommended. In patients with peripheral arthritis, rapid initiation of conventional synthetic disease-modifying antirheumatic drugs is recommended and methotrexate preferred. If the treatment target is not achieved with this strategy, a biological disease-modifying antirheumatic drug (bDMARD) should be initiated, without preference among modes of action. Relevant skin psoriasis should orient towards bDMARDs targeting interleukin (IL)-23p40, IL-23p19, IL-17A and IL-17A/F inhibitors. In case of predominant axial or entheseal disease, an algorithm is also proposed. Use of Janus kinase inhibitors is proposed primarily after bDMARD failure, taking relevant risk factors into account, or in case bDMARDs are not an appropriate choice. Inflammatory bowel disease and uveitis, if present, should influence drug choices, with monoclonal tumour necrosis factor inhibitors proposed. Drug switches and tapering in sustained remission are also addressed. CONCLUSION: These updated recommendations integrate all currently available drugs in a practical and progressive approach, which will be helpful in the pharmacological management of PsA.

Risk of Corneal Graft Rejection and Vaccination: A Matched Case-Control Study From a United States Integrated Health Care System.

PURPOSE: Data on vaccine-associated corneal transplant rejections are limited. We examined the association between graft rejection and vaccination. DESIGN: Matched case-control METHODS: We used electronic health records to identify corneal transplant recipients between January 2008 and August 2022 at Kaiser Permanente Southern California. Cases were transplant recipients who experienced a graft rejection (outcome) during the study period. Randomly selected controls who did not experience a corneal graft rejection at their matched cases' index date (rejection date) were matched in a 3:1 ratio to cases. For controls, index date was determined by adding the number of days between transplant and graft rejection of their matched case to the control's transplant date. RESULTS: The study included 601 cases and 1803 matched controls (mean age 66 years [s.d. 17.0], 52% female, 47% non-Hispanic white). Twenty-three% of cases and 22% of controls received ≥1 vaccinations within 12 weeks prior to the index date. The adjusted odds ratio (aOR) for vaccination in the 12 weeks prior to index date, comparing cases to controls was 1.17 (95% CI: 0.91, 1.50]). The aOR was 1.09 (0.84, 1.43) for 1 vaccination, 1.53 (0.90, 2.61) for 2 vaccinations, and 1.79 (0.55, 5.57) for ≥3 vaccinations. The aOR was 1.60 (0.81, 3.14) for mRNA vaccines, and 1.19 (0.80, 1.78) for adjuvanted/high dose vaccines. CONCLUSIONS: We found no evidence to suggest an association between vaccination and graft rejection. Our findings provide support for the completion of recommended vaccinations for corneal transplant recipients, without significantly increasing the risk of graft rejection.

What rheumatologists need to know about mRNA vaccines: current status and future of mRNA vaccines in autoimmune inflammatory rheumatic diseases.

Messenger RNA (mRNA) vaccines as a novel vaccine platform offer new tools to effectively combat both emerging and existing pathogens which were previously not possible. The 'plug and play' feature of mRNA vaccines enables swift design and production of vaccines targeting complex antigens and rapid incorporation of new vaccine constituents as needed. This feature makes them likely to be adopted for widespread clinical use in the future.Currently approved mRNA vaccines include only those against SARS-CoV-2 virus. These vaccines demonstrate robust immunogenicity and offer substantial protection against severe disease. Numerous mRNA vaccines against viral pathogens are in the early to late phase of development. Several mRNA vaccines for influenza are tested in clinical trials, with some already in phase 3 studies. Other vaccines in the early and late phases of development include those targeting Cytomegalovirus, varicella zoster virus, respiratory syncytial virus and Epstein-Barr virus. Many of these vaccines will likely be indicated for immunosuppressed populations including those with autoimmune inflammatory rheumatic diseases (AIIRD). This review focuses on the mechanism, safety and efficacy of mRNA in general and summarises the status of mRNA vaccines in development for common infectious diseases of particular interest for patients with AIIRD.

Cystic Fibrosis Carrier States Are Associated With More Severe Cases of Bronchiectasis.

Background: People with cystic fibrosis (CF) are at increased risk for bronchiectasis, and several reports suggest that CF carriers may also be at higher risk for developing bronchiectasis. The purpose of this study was to determine if CF carriers are at risk for more severe courses or complications of bronchiectasis. Methods: Using MarketScan data (2001-2021), we built a cohort consisting of 105 CF carriers with bronchiectasis and 300 083 controls with bronchiectasis but without a CF carrier diagnosis. We evaluated if CF carriers were more likely to be hospitalized for bronchiectasis. In addition, we examined if CF carriers were more likely to be infected with Pseudomonas aeruginosa or nontuberculous mycobacteria (NTM) or to have filled more antibiotic prescriptions. We considered regression models for incident and rate outcomes that controlled for age, sex, smoking status, and comorbidities. Results: The odds of hospitalization were almost 2.4 times higher (95% CI, 1.116-5.255) for CF carriers with bronchiectasis when compared with non-CF carriers with bronchiectasis. The estimated odds of being diagnosed with a Pseudomonas infection for CF carriers vs noncarriers was about 4.2 times higher (95% CI, 2.417-7.551) and 5.4 times higher (95% CI, 3.398-8.804) for being diagnosed with NTM. The rate of distinct antibiotic fill dates was estimated to be 2 times higher for carriers as compared with controls (95% CI, 1.735-2.333), and the rate ratio for the total number of days of antibiotics supplied was estimated as 2.8 (95% CI, 2.290-3.442). Conclusions: CF carriers with bronchiectasis required more hospitalizations and more frequent administration of antibiotics as compared with noncarriers. Given that CF carriers were also more likely to be diagnosed with Pseudomonas and NTM infections, CF carriers with bronchiectasis may have a phenotype more resembling CF-related bronchiectasis than non-CF bronchiectasis.

Vaccination recommendations for adults receiving biologics and oral therapies for psoriasis and psoriatic arthritis: Delphi consensus from the medical board of the National Psoriasis Foundation.

BACKGROUND: For psoriatic patients who need to receive nonlive or live vaccines, evidence-based recommendations are needed regarding whether to pause or continue systemic therapies for psoriasis and/or psoriatic arthritis. OBJECTIVE: To evaluate literature regarding vaccine efficacy and safety and to generate consensus-based recommendations for adults receiving systemic therapies for psoriasis and/or psoriatic arthritis receiving nonlive or live vaccines. METHODS: Using a modified Delphi process, 22 consensus statements were developed by the National Psoriasis Foundation Medical Board and COVID-19 Task Force, and infectious disease experts. RESULTS: Key recommendations include continuing most oral and biologic therapies without modification for patients receiving nonlive vaccines; consider interruption of methotrexate for nonlive vaccines. For patients receiving live vaccines, discontinue most oral and biologic medications before and after administration of live vaccine. Specific recommendations include discontinuing most biologic therapies, except for abatacept, for 2-3 half-lives before live vaccine administration and deferring next dose 2-4 weeks after live vaccination. LIMITATIONS: Studies regarding infection rates after vaccination are lacking. CONCLUSION: Interruption of antipsoriatic oral and biologic therapies is generally not necessary for patients receiving nonlive vaccines. Temporary interruption of oral and biologic therapies before and after administration of live vaccines is recommended in most cases.

Safety profile of baricitinib for the treatment of rheumatoid arthritis over a median of 3 years of treatment: an updated integrated safety analysis.

BACKGROUND: Baricitinib is an oral selective inhibitor of Janus kinase (JAK) 1 and JAK2, approved for the treatment of patients with active rheumatoid arthritis. Because baricitinib, like other disease-modifying antirheumatic drugs, is used chronically, continuous assessment of its long-term safety profile is important. Here we provide updated data supporting the existing safety profile of baricitinib in this patient population. METHODS: In this safety analysis, integrated data were included from nine phase 3, phase 2, and phase 1b clinical trials, and one long-term extension study with data up to 360 weeks, ending Feb 13, 2018. We analysed three integrated datasets, the largest of which was the all-bari-RA dataset, which includes patients who received any dose of baricitinib. We compared the safety of baricitinib with placebo on the basis of data from seven studies with baricitinib 4 mg and placebo and four studies with baricitinib 2 mg, including placebo to week 24 (placebo-controlled dataset). We did a dose-response assessment based on four studies with baricitinib 2 mg and 4 mg, including long-term extension data (2-4 mg extended dataset). We did an exploratory analysis of deaths and venous thromboembolic events in a subset of data from the all-bari-RA dataset that included patients who had ever taken baricitinib 2-mg or baricitinib 4-mg. We did an analysis for malignancies (excluding non-melanoma skin cancer) in the as-randomised population (patients not censored at rescue or dose change). FINDINGS: We collected data for 3770 patients who were given baricitinib for 10 127 patient-years of exposure in the all-bari-RA dataset (median 1115 days [IQR 426-1441], maximum 2520 days). The placebo-controlled dataset comprised 2836 patients, with 1215 in the placebo group, with 451 patient-years of exposure data; 479 in the baricitinib 2 mg group, with 186 patient-years of exposure data; and 1142 in the baricitinib 4 mg group, with 472 patient-years of exposure data. The 2-4 mg extended dataset comprised 958 patients, with 479 in both the 2 mg and 4 mg groups. No significant differences were seen for baricitinib 4 mg or 2 mg versus placebo, or for 4 mg versus 2 mg in the incidence of death, malignancy, serious infection, or major adverse cardiovascular events. Incidence of herpes zoster per 100 patient-years was higher for baricitinib (4 mg: 4·4 [95% CI 2·7-6·7]; 2 mg: 3·1 [1·1-6·8]) versus total placebo group (1·1 [0·4-2·5]), as were treatment-emergent infections (4 mg: 89·7 [81·3-98·6]; 2 mg: 84·0 [71·3-98·2] vs placebo 75·4 [67·6-83·9]). Consistent with previous reports, incidences in the all-bari-RA dataset for venous thromboembolic events was 0·5 (95% CI 0·4-0·6) per 100 patient-years, deep-vein thrombosis was 0·3 (0·2-0·5) per 100 patient-years, and pulmonary embolism was 0·2 (0·2-0·4) per 100 patient-years. Incidences of malignancy (excluding non-melanoma skin cancer) in the 2-4 mg extended dataset were 0·8 (0·4-1·5) per 100 patient-years for baricitinib 2 mg and 1·0 (0·5-1·7) per 100 patient-years for baricitinib 4 mg, without censoring patients who had dose changes or received rescue treatment. We found no indication of higher incidence of venous thromboembolic events in the baricitinib 4 mg group compared with the 2 mg group in the 2-4 mg extended dataset. INTERPRETATION: In this updated integrated analysis of patients with active rheumatoid arthritis exposed to baricitinib for a maximum of almost 7 years, baricitinib 2 mg and 4 mg maintained a similar safety profile to earlier analyses. No new safety signals were identified. Patients in the long-term extension study continue to be followed up to date. FUNDING: Eli Lilly and Company, under license from Incyte Corporation.

Serum Cell-free DNA-based Detection of Mycobacterium Avium Complex Infection.

RATIONALE: Mycobacterium avium complex (MAC) is the most common cause of nontuberculous mycobacterial pulmonary disease (NTM-PD), which exhibits increasing global incidence. Current microbiologic methods routinely used in clinical practice lack sensitivity and have long latencies, leading to delays in diagnosis and treatment initiation and evaluation. A CRISPR-based assay that measures MAC cell-free DNA (MAC-cfDNA) levels in serum could provide a rapid means to detect MAC infection and monitor response to antimicrobial treatment. OBJECTIVES: To develop and optimize a CRISPR-MAC assay for MAC infection detection and to evaluate its diagnostic and prognostic performance in two MAC disease cohorts. METHODS: MAC-cfDNA serum levels were measured in individuals diagnosed with MAC disease or who had bronchiectasis or COPD diagnoses without a history of NTM-PD or NTM-positive sputum cultures. Diagnostic performance was analyzed with pre-treatment serum from two cohorts. Serum MAC-cfDNA changes during MAC-PD treatment were evaluated in a subset of MAC-PD patients who received macrolide-based multi-drug regimens. MEASUREMENTS AND MAIN RESULTS: CRISPR-MAC assay detected MAC-cfDNA in MAC-PD with 97.6% (91.6 - 99.7%) sensitivity and 97.6% (91.5 - 99.7%) specificity overall. Serum MAC-cfDNA levels markedly decreased after MAC-directed treatment initiation in MAC-PD patients that demonstrated MAC culture conversion. CONCLUSIONS: This study provides preliminary evidence for the utility of a serum-based CRISPR-MAC assay to rapidly detect MAC infection and monitor their response to treatment.

Unmet need in rheumatology: reports from the Advances in Targeted Therapies meeting, 2023.

The Advances in Targeted Therapies meets annually, convening experts in the field of rheumatology to both provide scientific updates and identify existing scientific gaps within the field. To review the major unmet scientific needs in rheumatology. The 23rd annual Advances in Targeted Therapies meeting convened with more than 100 international basic scientists and clinical researchers in rheumatology, immunology, infectious diseases, epidemiology, molecular biology and other specialties relating to all aspects of immune-mediated inflammatory diseases. We held breakout sessions in five rheumatological disease-specific groups including: rheumatoid arthritis (RA), psoriatic arthritis (PsA), axial spondyloarthritis (axSpa), systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and vasculitis, and osteoarthritis (OA). In each group, experts were asked to identify and prioritise current unmet needs in clinical and translational research. An overarching theme across all disease states is the continued need for clinical trial design innovation with regard to therapeutics, endpoint and disease endotypes. Within RA, unmet needs comprise molecular classification of disease pathogenesis and activity, pre-/early RA strategies, more refined pain profiling and innovative trials designs to deliver on precision medicine. Continued scientific questions within PsA include evaluating the genetic, immunophenotypic, clinical signatures that predict development of PsA in patients with psoriasis, and the evaluation of combination therapies for difficult-to-treat disease. For axSpA, there continues to be the need to understand the role of interleukin-23 (IL-23) in pathogenesis and the genetic relationship of the IL-23-receptor polymorphism with other related systemic inflammatory diseases (eg, inflammatory bowel disease). A major unmet need in the OA field remains the need to develop the ability to reliably phenotype and stratify patients for inclusion in clinical trials. SLE experts identified a number of unmet needs within clinical trial design including the need for allowing endpoints that reflect pharmacodynamic/functional outcomes (eg, inhibition of type I interferon pathway activation; changes in urine biomarkers). Lastly, within SSc and vasculitis, there is a lack of biomarkers that predict response or disease progression, and that allow patients to be stratified for therapies. There remains a strong need to innovate clinical trial design, to identify systemic and tissue-level biomarkers that predict progression or response to therapy, endotype disease, and to continue developing therapies and therapeutic strategies for those with treatment-refractory disease. This document, based on expert consensus, should provide a roadmap for prioritising scientific endeavour in the field of rheumatology.

Tolerability Outcomes of ATS/IDSA Guideline-Recommended Multidrug Antibiotic Treatment for Mycobacterium avium Complex Pulmonary Disease in US Medicare Beneficiaries With Bronchiectasis.

BACKGROUND: Nontuberculous mycobacteria are environmental organisms that are increasingly causing chronic and debilitating pulmonary infections, of which Mycobacterium avium complex (MAC) is the most common pathogen. MAC pulmonary disease (MAC-PD) is often difficult to treat, often requiring long-term multidrug antibiotic therapy. RESEARCH QUESTION: Is there an association between various guideline-based three-drug therapy (GBT) regimens and therapy-associated adverse events or regimen change/discontinuation, within 12 months of therapy initiation? STUDY DESIGN AND METHODS: In a retrospective cohort study, we examined tolerability outcomes of GBT regimens for MAC-PD in 4,626 US Medicare beneficiaries with bronchiectasis, who were prescribed a GBT as initial antibiotic treatment for presumed MAC-PD during 2006 to 2014. Using multivariable Cox proportional hazard regression, we estimated adjusted hazard ratios (aHRs) to compare the risk of adverse events and regimen change/discontinuations within 12 months of therapy initiation in various GBT regimens. RESULTS: The cohort had a mean age ± SD of 77.9 ± 6.1 years at treatment start, were mostly female (77.7%), and were mostly non-Hispanic White (87.2%). The risk of regimen change/discontinuation within 12 months of therapy was higher for clarithromycin-based regimens than azithromycin-based regimens (aHR, 1.12; 95% CI, 1.04-1.20 with rifampin; aHR, 1.11; 95% CI, 0.93-1.32 with rifabutin as the companion rifamycin), and for rifabutin-containing regimens than rifampin-containing regimens (aHR, 1.49; 95% CI, 1.33-1.68 with azithromycin; aHR, 1.47; 95% CI, 1.27-1.70 with clarithromycin as the companion macrolide). The aHR comparing regimen change/discontinuation with clarithromycin-ethambutol-rifabutin and azithromycin-ethambutol-rifampin was 1.64 (95% CI, 1.43-1.64). INTERPRETATION: Overall, an azithromycin-based regimen was less likely to be changed or discontinued than a clarithromycin-based regimen, and a rifampin-containing regimen was less likely to be changed or discontinued than a rifabutin-containing regimen within 12 months of therapy start. Our work provides a population-based assessment on the tolerability of multidrug antibiotic regimens used for the treatment of MAC-PD.

Impact of SARS-CoV-2 infection on patients with systemic lupus erythematosus in England prior to vaccination: a retrospective observational cohort study.

OBJECTIVES: Determine the prevaccination healthcare impact of COVID-19 in patients with systemic lupus erythematosus (SLE) in England. DESIGN: Retrospective cohort study of adult patients with SLE from 1 May to 31 October 2020. SETTING: Clinical Practice Research Datalink (CPRD) Aurum and Hospital Episode Statistics (HES) databases from general practitioners across England combining primary care and other health-related data. PARTICIPANTS: Overall, 6145 adults with confirmed SLE diagnosis ≥1 year prior to 1 May 2020 were included. Most patients were women (91.0%), white (67.1%), and diagnosed with SLE at age <50 (70.8%). Patients were excluded if they had a COVID-19 diagnosis before 1 May 2020. PRIMARY AND SECONDARY OUTCOME MEASURES: Demographics and clinical characteristics were compared. COVID-19 severity was determined by patient care required and procedure/diagnosis codes. COVID-19 cumulative incidence, hospitalisation rates, lengths of stay and mortality rates were determined and stratified by SLE and COVID-19 severity. RESULTS: Of 6145 patients, 3927 had mild, 1288 moderate and 930 severe SLE at baseline. The majority of patients with moderate to severe SLE were on oral corticosteroids and antimalarial treatments. Overall, 54/6145 (0.88%) patients with SLE acquired and were diagnosed with COVID-19, with 45 classified as mild, 6 moderate and 3 severe COVID-19. Cumulative incidence was higher in patients with severe SLE (1.4%) compared with patients classified as mild (0.8%) or moderate (0.8%). Ten COVID-19-specific hospital admissions occurred (n=6 moderate; n=4 severe). Regardless of COVID-19 status, hospital admission rates and length of stay increased with SLE severity. Of 54 patients with SLE diagnosed with COVID-19, 1 (1.9%) COVID-19-related death was recorded in a patient with both severe SLE and severe COVID-19. CONCLUSIONS: SLE severity did not appear to impact COVID-19 outcomes in this study. The COVID-19 pandemic is evolving and follow-up studies are needed to understand the relationship between COVID-19 and SLE.

Nontuberculous Mycobacterial Pulmonary Disease in the Immunocompromised Host.

The immunocompromised host is at an increased risk for pulmonary and extrapulmonary NTM infections. Where data are available in these specific populations, increased mortality is observed with NTM disease. Prior to starting therapy for NTM disease, providers should ensure diagnostic criteria are met as treatment is long and often associated with significant side effects and toxicities. Treatment should involve 2 to 4 agents and be guided by cultures and antimicrobial susceptibilities. Drug interactions are important to consider, especially in those with HIV or transplant recipients. Whenever possible, immunosuppression should be reduced or changed.

Nontuberculous mycobacterial pulmonary disease and the potential role of SPR720.

INTRODUCTION: Nontuberculous mycobacteria infect patients who have structural lung disease or those who are immunocompromised. Nontuberculous mycobacterial pulmonary disease (NTM-PD) is increasing in prevalence. Treatment guidelines for Mycobacterium avium complex (MAC) pulmonary disease involve a three-drug regimen with azithromycin, ethambutol, and rifampin, and those of Mycobacterium abscessus complex (MAB) pulmonary disease involve a combination of three or more antimicrobials including macrolides, amikacin, and a ß-lactam or imipenem. However, these regimens are poorly tolerated and generally ineffective. AREAS COVERED: SPR720 is a novel therapeutic agent that has demonstrated activity against a range of NTM species, including MAC and MAB. Encouraging in vitro and pre-clinical data demonstrate that SPR720 is active both alone and in combination with standard-of-care agents, with no evidence of cross-resistance to such agents. It is generally well tolerated with mainly gastrointestinal and headache adverse events of mild or moderate severity. EXPERT OPINION: Management of NTM-PD is challenging for many reasons including length of therapy, poor efficacy, drug intolerance, recurrence, and resistance development. The current antimicrobial management options for NTM-PD are limited in number and there exists a large unmet need for new treatments. SPR720 has encouraging data that warrant further study in the context of a multidrug regimen.

Epidemiology of Mycobacterium abscessus.

BACKGROUND: Nontuberculous mycobacteria (NTM) are highly abundant in soil, dust, and water sources, making human-pathogen contact frequent and recurrent. NTM represents over 200 species/subspecies; some are considered strict or opportunistic pathogens. Mycobacterium abscessus, often regarded as one of the most antibiotic-resistant mycobacteria, is the second most frequent NTM pulmonary disease pathogen. OBJECTIVES: To describe the epidemiology of M. abscessus through a literature review focusing on clinical aspects. SOURCES: We conducted searches on PubMed and Web of Knowledge for articles published from 2010 to the present using the keywords 'Mycobacterium abscessus', 'Nontuberculous mycobacteria', and 'epidemiology'. Our search prioritized original reports on the occurrence of NTM and M. abscessus infection/disease. CONTENT: Advanced molecular and genetic diagnostic techniques have refined the M. abscessus complex (MABC) microbiological classification over the last few decades. MABC can adhere to surfaces and form a biofilm. This characteristic and its resistance to common disinfectants allow these microorganisms to persist in the water distribution systems, becoming a constant reservoir. The frequency and manifestation of NTM species vary geographically because of environmental conditions and population susceptibility differences. MABC lung disease, the most frequent site of NTM infection in humans, is often seen in patients with underlying lung diseases such as bronchiectasis, whereas MABC disseminated disease is related to immunosuppression. Skin and soft tissue infections are associated with surgical or injection procedures. Epidemiological evidence suggests an overall increase in MABC infection and disease in the last decade. IMPLICATIONS: Establishing the burden of this disease is challenging because of varying measures of incidence and prevalence, referral bias, and differences in medical practices and reporting. Furthermore, environmental and structural determinants, infection routes, and MABC pulmonary disease mechanisms require additional investigation. This review contributes to a better understanding of the epidemiology of MABC, which could inform clinical practice and future research.

Nontuberculous mycobacterial (NTM) infections in bronchiectasis patients: A retrospective US registry cohort study.

RATIONALE: Longitudinal epidemiological and clinical data are needed to improve the management of patients with bronchiectasis developing nontuberculous mycobacterial (NTM) pulmonary disease. OBJECTIVES: To describe the epidemiology, patient management, and treatment outcomes of NTM infections in patients with bronchiectasis enrolled in the United States Bronchiectasis and NTM Research Registry (US BRR). METHODS: This was a retrospective cohort study of patients with bronchiectasis and NTM infections enrolled with follow-up in the US BRR in 2008-2019. The study included patients with ≥1 positive NTM respiratory culture in the 24-month baseline period (baseline NTM cohort) and/or during the annual follow-up visits (incident NTM cohort). Incidence, prevalence, baseline patient characteristics, treatment exposure, treatment outcomes, and respiratory clinical outcomes were described in the baseline NTM cohort, incident NTM cohort, and both cohorts combined (prevalent NTM cohort). RESULTS: Between 2008 and 2019, 37.9% (1457/3840) of patients with bronchiectasis in the US BRR met the inclusion criteria for this study and were reported to have Mycobacterium avium complex (MAC) and/or Mycobacterium abscessus complex (MABSC) infections. MAC prevalence increased steadily in the US BRR during 2009-2019; incidence was relatively stable, except for a peak in 2011 followed by a slow decrease. MABSC and mixed MAC/MABSC infections were rare. Most patients with bronchiectasis and NTM infections in the registry were female, White, and aged >65 years. The antibiotics administered most commonly reflected current guidelines. In the prevalent cohort, 44.9% of MAC infections and 37.1% of MABSC infections remained untreated during follow-up, and MAC treatment was initiated with delay (>90 days after positive NTM respiratory culture) twice as frequently as promptly (≤90 days after positive NTM respiratory culture) (68.6% vs 31.4%, respectively). The median time from diagnosis to treatment was shorter for MABSC versus MAC infections (194.0 days [interquartile range (IQR) 8.0, 380.0] vs 296.0 days [IQR 35.0, 705.0], respectively). Among patients with MAC infections who completed treatment, 27.6% were classified as cured and 29.6% as treatment failure during the annual follow-up visit window. For MABSC, these proportions were 25.0% and 28.0%, respectively. CONCLUSIONS: A considerable proportion of MAC and MABSC infections were untreated or treated after initial delay/observation. MABSC infections were more likely to be treated and start treatment sooner than MAC infections. Further longitudinal studies are warranted to evaluate the monitor-with-delay approach and inform clinical guidelines.

Acanthamoeba-associated retinitis successfully treated with intravitreal and systemic antimicrobials.

Purpose: To describe a case of unilateral Acanthamoeba-associated retinitis in the absence of concomitant corneal infection in an immunocompetent host without risk factors. Observations: A 37-year-old woman presented with unilateral multifocal retinitis with minimal vitritis. Anterior segment was normal. Conventional diagnostics of bacterial, fungal, viral, Toxoplasma and Toxocara etiologies all returned negative. Empiric treatments were unsuccessful, including oral valacyclovir, oral fluconazole, as well as intravitreal injection of vancomycin and ceftazidime. Metagenomic deep sequencing (MDS) identified Acanthamoeba genomic fragments in the vitreous sample. Multiple intravitreal voriconazole injections were performed and achieved partial suppression of lesion growth. Subsequent dual therapy of oral voriconazole and trimethoprim-sulfamethoxazole led to resolution of the lesions and vision improvement without further injections. Conclusions and importance: This is an unusual case of unilateral Acanthamoeba-associated retinitis without concomitant corneal infection, diagnosed via unbiased DNA and RNA deep sequencing, with other etiologies ruled out by conventional approaches. Treatment with systemic and intravitreal therapy led to a successful resolution of retinitis and vision improvement. Our case demonstrates the potential of MDS as an unbiased diagnostic tool for rare ocular pathogens and the therapeutic effect of oral voriconazole with trimethoprim-sulfamethoxazole for Acanthamoeba intraocular infection.

Long-term Safety and Tolerability of Omadacycline for the Treatment of Mycobacterium abscessus Infections.

Background: Mycobacterium abscessus is a virulent human pathogen. Treatment is complex and often poorly tolerated with suboptimal rates of eradication, highlighting the need for improved therapeutics. This study reports clinical experience with omadacycline for treatment of M abscessus infections at five large nontuberculous mycobacterial (NTM) disease clinics across the United States to better understand long-term safety and tolerability. Methods: We conducted a multicenter retrospective chart review of adults with M abscessus infections. All patients treated with omadacycline as part of a multidrug therapeutic regimen through December 2021 were included. Clinical data from time of omadacycline initiation and up to 12 months of follow-up were collected. Descriptive statistics were performed. Results: Analysis included 117 patients. Among patients with M abscessus isolate subspeciation, 58 of 71 (81.7%) were M abscessus spp abscessus. In isolates with reported drug susceptibility testing, 15 of 70 (21.4%) had confirmed susceptibility to macrolides. The most common site of infection was lungs. Median duration omadacycline treatment was 8 months (range, 0.25-33 months; interquartile range, 4-15 months). Omadacycline was discontinued in 60 patients (51.3%); 20 completed planned treatment course, 23 experienced intolerance or adverse event leading to drug cessation, and 17 stopped due to cost, death (unrelated to NTM infection or therapy), or another reason. In those with pulmonary disease, 44 of 95 (46%) had 1 or more negative cultures at time of final microbiological assessment, with 17 of 95 (18%) achieving culture conversion. Conclusions: This study reports data supporting long-term safety and tolerability of omadacycline along with signal of effectiveness in treatment of M abscessus infections.

Physicians' Agreement on and Implementation of the 2019 European Alliance of Associations for Rheumatology Vaccination Guideline: An International Survey.

Objective: To evaluate the perspective of healthcare professionals towards the 2019 European Alliance of Associations for Rheumatology (EULAR) vaccination guideline in patients with autoimmune inflammatory rheumatic diseases (AIIRD). Methods: Healthcare professionals who care for patients with AIIRD were invited to participate in an online survey regarding their perspective on the 2019 update of the EULAR recommendations for vaccination in adult patients with AIIRD. Level of agreement and implementation of the 6 overarching principles and 9 recommendations were rated on a 5-point Likert scale (1~5). Results: Survey responses of 371 healthcare professionals from Asia (42.2%) and North America (41.6%), Europe (13.8%), and other countries were analyzed. Only 16.3% of participants rated their familiarity with the 2019 EULAR guideline as 5/5 ("very well"). There was a high agreement (≥4/5 rating) with the overarching principles, except for the principles applying to live-attenuated vaccines. There was a high level of agreement with the recommendations regarding influenza and pneumococcal vaccinations; implementation of these recommendations was also high. Participants also reported a high level of agreement with the remaining recommendations but did not routinely implement these recommendations. Conclusion: The 2019 update of EULAR recommendations for the vaccination of adult patients with AIIRD is generally thought to be important by healthcare professionals, although implementation of adequate vaccination is often lacking. Better education of healthcare providers may be important to optimize the vaccination coverage for patients with AIIRD.

Open-Label Trial of Amikacin Liposome Inhalation Suspension in Mycobacterium abscessus Lung Disease.

BACKGROUND: Mycobacterium abscessus is the second most common nontuberculous mycobacterium respiratory pathogen and shows in vitro resistance to nearly all oral antimicrobials. M abscessus treatment success is low in the presence of macrolide resistance. RESEARCH QUESTION: Does treatment with amikacin liposome inhalation suspension (ALIS) improve culture conversion in patients with M abscessus pulmonary disease who are treatment naive or who have treatment-refractory disease? STUDY DESIGN AND METHODS: In an open-label protocol, patients were given ALIS (590 mg) added to background multidrug therapy for 12 months. The primary outcome was sputum culture conversion defined as three consecutive monthly sputum cultures showing negative results. The secondary end point included development of amikacin resistance. RESULTS: Of 33 patients (36 isolates) who started ALIS with a mean age of 64 years (range, 14-81 years), 24 patients (73%) were female, 10 patients (30%) had cystic fibrosis, and nine patients (27%) had cavitary disease. Three patients (9%) could not be evaluated for the microbiologic end point because of early withdrawal. All pretreatment isolates were amikacin susceptible and only six isolates (17%) were macrolide susceptible. Eleven patients (33%) were given parenteral antibiotics. Twelve patients (40%) received clofazimine with or without azithromycin as companion therapy. Fifteen patients (50%) with evaluable longitudinal microbiologic data demonstrated culture conversion, and 10 patients (67%) sustained conversion through month 12. Six of the 33 patients (18%) demonstrated mutational amikacin resistance. All were patients using clofazimine or clofazimine plus azithromycin as companion medication(s). Few serious adverse events occurred for ALIS users; however, reduction of dosing to three times weekly was common (52%). INTERPRETATION: In a cohort of patients primarily with macrolide-resistant M abscessus, one-half of the patients using ALIS showed sputum culture conversion to negative findings. The emergence of mutational amikacin resistance was not uncommon and occurred with the use of clofazimine monotherapy. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT03038178; URL: www. CLINICALTRIALS: gov.