A comprehensive review of dermatomyositis treatments - from rediscovered classics to promising horizons.

INTRODUCTION: Dermatomyositis (DM) is a rare inflammatory disease with diverse cutaneous and systemic manifestations, often associated with myositis-specific antibodies. Managing patients with refractory DM, or individuals presenting pecific complications, like calcinosis or rapidly progressive interstitial lung disease, presents unique challenges. AREAS COVERED: This review explores current and promising treatment options for DM, drawing from clinical studies, case series, and case reports that consider the underlying disease pathophysiology. EXPERT OPINION: Recent advancements have improved our understanding and management of DM. The discovery of distinct DM autoantibodies and their correlation with specific clinical phenotypes has transformed patient categorization and enhanced our knowledge of the pathogenesis of the disease. Intravenous immunoglobulin, a well-established treatment in dermatomyositis, has regained prominence and a large randomized clinical trial has reaffirmed its efficacy, confirming it as an effective therapeutic option in this group of patients. Identification of the type I interferon pathway as a key pathogenic mechanism in DM has opened up new avenues for more effective treatment strategies. Blocking the JAK/STAT pathway offers potential for improved management of refractory patients and prevention of highly morbid complications. These recent advancements have significantly impacted the management and care of dermatomyositis patients, enabling tailored approaches, targeted interventions, and improved outcomes for individuals affected by this complex condition.

Relapsing polychondritis: Best Practice & Clinical Rheumatology.

Relapsing polychondritis (RP) is an uncommon inflammatory disorder that predominantly targets cartilaginous structures. The disease frequently affects the nose, ears, airways, and joints, but it can also impact organs that aren't primarily cartilage-based, such as blood vessels, skin, inner ear, and eyes. Given its infrequent occurrence and recurrent symptoms, patients often experience delays in proper diagnosis. Lately, based on the organs involved, the disease's diverse manifestations have been categorized into specific clinical groups, based on the most likely organ involvement including auricular, nasal, pulmonary, and musculoskeletal. More recently the discovery of a new disease, called (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) VEXAS syndrome, due to mutations in UBA1 gene, identified the cause of 8 % of the patients with a clinical diagnosis of RP. VEXAS is likely the cause of a previously described "hematologic subgroup" in RP. This discovery is proof of concept that RP is likely more than one disease (Beck et al., Dec 31 2020; Ferrada et al., 2021). People diagnosed with RP face numerous hurdles, with the quality of their lives and overall prognosis being affected. Diagnosing the condition is particularly challenging due to its fluctuating symptoms, the absence of specific markers, and the lack of universally recognized classification criteria. For a correct diagnosis, it's imperative for healthcare professionals to identify its unique clinical patterns. Moreover, there are no approved metrics to gauge the disease's severity, complicating patient management. This review seeks to equip clinicians with pertinent insights to better diagnose and attend to these complex patients.

Successful Treatment of Paecilomyces variotii Pneumonia and Lupus Nephritis With Posaconazole-Cyclophosphamide Co-administration Without Drug Interaction-Induced Toxicity.

Paecilomyces variotii is an opportunistic mold that causes pulmonary infections in immunosuppressed humans that are often treated with triazole therapy. Lupus nephritis is a major cause of progressive kidney disease in patients with systemic lupus erythematosus, often requiring cyclophosphamide-based therapies. Triazole-cyclophosphamide co-administration is challenging as triazoles increase cyclophosphamide concentrations, which can worsen cyclophosphamide toxicity. We describe herein a patient with Paecilomyces variotii pneumonia and concomitant lupus nephritis who was successfully treated with posaconazole and echinocandin-bridged interruptions to allow for cyclophosphamide therapy. This regimen was well-tolerated without cyclophosphamide toxicity and achieved improvements in both fungal pneumonia and renal function.

Coincidence or connection? A patient with concurrent Lane Hamilton Syndrome and idiopathic membranous nephropathy.

Lane Hamilton Syndrome is the rare association of idiopathic pulmonary hemosiderosis and Celiac Disease. The definitive pathophysiologic link is unknown, but the syndrome has been described as co-occurring along with other diseases. We describe the first reported case of Lane Hamilton Syndrome and idiopathic membranous nephropathy. We also hypothesize the possibility of an immune-mediated connection between the pathologies and propose a potential link of the phospholipase A2 receptor.

Increased mTOR activation in idiopathic multicentric Castleman disease.

Idiopathic multicentric Castleman disease (iMCD) is a rare and poorly understood hematologic disorder characterized by lymphadenopathy, systemic inflammation, cytopenias, and life-threatening multiorgan dysfunction. Interleukin-6 (IL-6) inhibition effectively treats approximately one-third of patients. Limited options exist for nonresponders, because the etiology, dysregulated cell types, and signaling pathways are unknown. We previously reported 3 anti-IL-6 nonresponders with increased mTOR activation who responded to mTOR inhibition with sirolimus. We investigated mTOR signaling in tissue and serum proteomes from iMCD patients and controls. mTOR activation was increased in the interfollicular space of iMCD lymph nodes (N = 26) compared with control lymph nodes by immunohistochemistry (IHC) for pS6, p4EBP1, and p70S6K, known effectors and readouts of mTORC1 activation. IHC for pS6 also revealed increased mTOR activation in iMCD compared with Hodgkin lymphoma, systemic lupus erythematosus, and reactive lymph nodes, suggesting that the mTOR activation in iMCD is not just a product of lymphoproliferation/inflammatory lymphadenopathy. Further, the degree of mTOR activation in iMCD was comparable to autoimmune lymphoproliferative syndrome, a disease driven by mTOR hyperactivation that responds to sirolimus treatment. Gene set enrichment analysis of serum proteomic data from iMCD patients (n = 88) and controls (n = 42) showed significantly enriched mTORC1 signaling. Finally, functional studies revealed increased baseline mTOR pathway activation in peripheral monocytes and T cells from iMCD remission samples compared with healthy controls. IL-6 stimulation augmented mTOR activation in iMCD patients, which was abrogated with JAK1/2 inhibition. These findings support mTOR activation as a novel therapeutic target for iMCD, which is being investigated through a trial of sirolimus (NCT03933904).

Effect of Clinical Trial Experience on Transcatheter Aortic Valve Replacement Outcomes.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) was approved by the Food and Drug Administration (FDA) in November 2011 after a collaborative technology development process involving professional medical societies, the medical device industry, and the FDA. After FDA approval, TAVR was adopted by numerous hospitals that had not participated in TAVR clinical trials. It is uncertain if outcomes at these hospitals were comparable with those at clinical trial hospitals. METHODS AND RESULTS: All patients with Medicare physician claims for TAVR between January 1, 2011, and November 30, 2012, were identified, and postoperative mortality was assessed using Medicare enrollment data. Risk-adjusted mortality was calculated via a multivariable model that adjusted for demographics and comorbidities. We identified 5009 patients who underwent TAVR, with 3617 TAVRs performed at 68 hospitals that had participated in clinical trials and 1392 TAVRs performed at 140 nontrial hospitals. The preoperative characteristics of patients at trial versus nontrial hospitals were similar. There were no significant differences in risk-adjusted 30-day mortality (5.9% versus 5.6%, odds ratio, 0.88; 95% confidence interval, 0.66-1.15; P=0.34) or 180-day mortality (16.5% versus 15.8%, odds ratio, 0.99; 95% confidence interval, 0.75-1.3; P=0.94). CONCLUSIONS: Patients undergoing TAVR at nontrial hospitals had comparable clinical outcomes to patients undergoing TAVR at clinical trial hospitals. This finding contrasts with several other cardiovascular devices and procedures for which higher mortality was observed at hospitals that did not participate in clinical trials. The unique policy and regulatory environment governing TAVR adoption by hospitals may have contributed to better outcomes during the technology diffusion process.

Transcatheter and Surgical Aortic Valve Replacement in Dialysis Patients: A Propensity-Matched Comparison.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) clinical trials in North America excluded patients on dialysis and, consequently, the outcomes of TAVR in dialysis-dependent patients remain unknown. METHODS: All Medicare fee-for-service patients undergoing TAVR (n = 5,005) or surgical aortic valve replacement (SAVR) (n = 32,634) between January 1, 2011, and November 30, 2012, were identified using procedural codes collected by the Centers for Medicare & Medicaid Services. Dialysis status and comorbidities were identified using diagnosis codes present on arrival for TAVR hospitalization. Patients supported on dialysis who underwent TAVR (n = 224) were compared with non-dialysis patients who underwent TAVR as well as a propensity-matched group of contemporaneous dialysis patients who underwent SAVR (n = 194 pairs). RESULTS: The TAVR patients on dialysis were younger than non-dialysis TAVR patients (79.2 years vs 84.1 years; p < 0.01) but had higher prevalence of comorbidities. Dialysis TAVR patients had increased mortality at 30 days (13% vs 6%, p < 0.01) and significantly worse survival by Kaplan-Meier analysis. Multivariable regression found dialysis to be independently associated with worse survival (hazard ratio, 1.73; 95% confidence interval, 1.33% to 2.25%, p < 0.01) in TAVR patients. Propensity-matched dialysis SAVR and dialysis TAVR patients had no significant differences in demographic or risk factors. Matched dialysis TAVR patients had shorter length of stay (6 interquartile range, 4 to 10] vs 10 [IQR 7 to 18] days; p < 0.01) and comparable survival. CONCLUSIONS: TAVR in dialysis patients is associated with decreased survival compared with non-dialysis patients; however, it is comparable with SAVR in high risk dialysis patients based on a propensity-matched comparison.

Increasing Frequency of Left Ventricular Assist Device Exchanges in the United States.

BACKGROUND: Recent reports indicate an increased prevalence and earlier onset of pump thrombosis and associated pump exchanges after left ventricular assist device (LVAD) implantation. Questions remain regarding the current rate and clinical effect of pump exchanges. METHODS: All United States Medicare fee-for-service patients undergoing LVAD implantations (n = 3,166) between January 2009 and December 2012 were identified by procedural codes present on carrier claims collected by the Centers for Medicare & Medicaid Services. Pump exchange, pump removal, heart transplantation, and death were collected from subsequent carrier claim and denominator files. Comorbidities present before implantation were generated using the Elixhauser comorbidity index. RESULTS: Compared with patients who received LVADs before March 1, 2011, LVAD recipients after March 1, 2011, were older on average (63.9 vs 62.2 years, p < 0.01), more likely to be male (82.3% vs. 79.4%, p = 0.04), and had a higher incidence of common comorbidities. The later cohort had higher occurrence of pump exchange by Kaplan-Meier time-to-event estimates and Fisher exact tests at 3 months (1.8 vs 0.8, p = 0.02), 6 months (3.3 vs 1.0, p < 0.01), and 12 months (4.9 vs 2.2, p < 0.01). Cox regression analysis found time-dependent pump exchange was associated with worse survival (hazard ratio, 2.5; 95% confidence interval, 1.8 to 3.62; p < 0.01) after adjusting for age, gender, and comorbidities. CONCLUSIONS: Although LVAD exchanges remain relatively uncommon, a significant increase in the incidence of the procedure has occurred since March 1, 2011. Pump exchanges are highly associated with death, and further research is required to understand the cause of this disturbing trend and surveillance to determine its trajectory.

Outcomes of aortic root replacement after previous aortic root replacement: the "true" redo root.

BACKGROUND: Aortic reoperations are technically challenging. This study evaluated outcomes after "true" redo root replacement (previous full root replacement) stratified by cause of prosthesis failure. METHODS: Data were compared for 793 patients who underwent a first-time sternotomy (de novo group) and 120 patients who had previously undergone full aortic root replacement (redo group), of which 76 underwent reoperation due to structural valve deterioration (degenerative group), and 44 due to endocarditis (infection group). RESULTS: Overall mortality was 4% (n = 28) in the de novo group and 5% (n = 6) in the redo group (p = 0.43) (degenerative group, 3%, infection group, 9%; p = 0.19). The infection group had an increased incidence of renal failure, sternal infection, prolonged ventilation, reoperation for bleeding, multisystem failure, and sepsis, and an increased hospital length of stay. The degenerative group and the de novo group had a similar risk of perioperative death and major complications. The 5-year survival was 86.3% ± 1.3% for the de novo group and 77.3% ± 4.6% for the redo group (p ≤ 0.01; degenerative, 86.3% ± 5%; infection, 65.3% ± 7.7%; p < 0.01; p = 0.98 for de novo vs degenerative). Multivariate analysis demonstrated that reoperation for degenerative failure did not increase the risk of perioperative or late death. CONCLUSIONS: Redo aortic root replacement can be performed with low perioperative morbidity and death. The presence of infection increases the risk of complications and worsens survival. However, redo root replacement for degenerative failure can be performed with similar short-term complication risk and midterm survival as de novo root replacement.

Aortic and mitral valve replacement versus transcatheter aortic valve replacement in propensity-matched patients.

BACKGROUND: Recent studies have suggested that transcatheter aortic valve replacement (TAVR) may have superior outcomes compared with aortic valve replacement (AVR) for high-risk patients with significant mitral regurgitation (MR). Considering significant MR is frequently addressed with a mitral valve repair or replacement (MVR) at the time of open aortic valve replacement, this study compares TAVR and AVR/MVR in propensity-matched pairs of patients with significant MR. METHODS: We evaluated all patients presenting with moderate or greater MR undergoing either TAVR or AVR/MVR at a single institution from 2002 to 2012. Patients who underwent other cardiac operations or had preoperative endocarditis were excluded. Of 306 patients in the AVR/MVR group and 147 patients in the TAVR group, propensity analysis matched 40 pairs of patients. Standard univariate, logistic regression, and propensity matching techniques were used. RESULTS: There was no significant difference between TAVR patients and AVR/MVR patients, respectively, in preoperative average age (76 ± 7.4 versus 78 ± 6.9 years, p = 0.68), ejection fraction (53 ± 15 versus 51 ± 17, p = 0.68), The Society of Thoracic Surgeons score (9.9 ± 3.1 versus 9.3 ± 3.4, p = 0.61), or 30-day mortality (7.5% versus 2.5%, p = 0.6). Postoperative MR was significantly improved for both TAVR and AVR/MVR, but AVR/MVR showed significantly greater improvement (-2.33 ± 1.23 versus -0.88 ± 0.79, p < 0.001). Among 30-day survivors, midterm survival was significantly better in the AVR/MVR group compared with the TAVR group (log rank p = 0.04). CONCLUSIONS: In a propensity-matched analysis of patients with significant MR, AVR/MVR and TAVR had equivalent perioperative outcomes, but AVR/MVR had more reduction in MR and may have superior midterm survival when compared with TAVR among 30-day survivors.

Factors associated with vascular complications in patients undergoing balloon-expandable transfemoral transcatheter aortic valve replacement via open versus percutaneous approaches.

BACKGROUND: Vascular complications after transfemoral transcatheter aortic valve replacement are common and associated with significant morbidity and mortality. Little is known about the effect of access approach on vascular complications. METHODS AND RESULTS: Between 2007 and 2013, 331 patients underwent transfemoral transcatheter aortic valve replacement via open surgical (OS) or fully percutaneous (PC) approaches. Patient data and clinical outcomes were collected. Valve Academic Research Consortium-defined vascular complications were noted. Multivariable analysis with propensity matching was performed, and vascular complications, mortality, and length of stay were assessed. One hundred twenty patients were treated with the OS approach and 211 patients via the PC approach. There were fewer major vascular complications (11% versus 20%; P=0.03) and shorter length of stay (7.5 versus 9.9 days; P=0.003) in the PC group when compared with those in the OS group. In multivariable analysis, vascular complications were more likely in women (odds ratio, 2.2; P=0.02) and with increasing differences between sheath outer diameter and minimal artery diameter (overall vascular complications: odds ratio, 1.4; P=0.02 and major vascular complications: odds ratio, 2.0; P<0.001). Propensity-matched analysis demonstrated no difference in vascular complications between the OS and the PC groups (22% versus 19%; P=0.73) but significantly reduced length of stay in the PC group (7.9 versus 10.0 days; P=0.04). CONCLUSIONS: Transfemoral transcatheter aortic valve replacement performed via the PC route is associated with similar risk of vascular complications and significantly lower postprocedural length of stay than the OS route. The degree of sheath oversizing with respect to iliofemoral minimal artery diameter and female sex are associated with vascular complications regardless of access approach.

Ventricular assist device implant in the elderly is associated with increased, but respectable risk: a multi-institutional study.

BACKGROUND: There are an increasing number of elderly patients with end-stage heart failure. Destination mechanical circulatory support is often the only therapy available for these patients who are not transplant candidates. The outcomes after continuous flow left ventricular assist device (CF LVAD) implant in older patients remains unclear. We undertook this multi-institutional study to quantify short-term and midterm outcomes after CF LVAD implant in the elderly. METHODS: We retrospectively analyzed all patients in the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) national registry that underwent implant of a CF LVAD (June 2006 to April 2012). Patients were divided into 2 cohorts based upon age (<70 years [n = 4,439] and ≥ 70 years (n = 590]). Preoperative, intraoperative, and postoperative variables were analyzed. The primary endpoint, survival, was compared between cohorts. RESULTS: Patients age 70 and older were more hemodynamically stable pre-VAD implant as evidenced by INTERMACS profile and inotrope dependence. Perioperative outcomes, including median bypass time (89 vs 89 minutes) and length of stay (0.657 vs 0.657 months) were similar between cohorts (p = not significant). Kaplan-Meier analysis revealed a significant difference in 2-year survival between patients aged 70 years or greater (63%) and less than 70 (71%, p < 0.001). Multivariable Cox proportional hazard analysis revealed age as an independent predictor of mortality during follow-up (p < 0.001). Nonetheless, midterm cumulative survival in the older cohort was still reasonable (63% at 2 years). CONCLUSIONS: Multi-institutional analysis revealed advanced age as a predictor of increased mortality after CF LVAD implantation. Careful patient selection is critical in the elderly to optimize long-term outcomes after CF LVAD implantation.

Minimally invasive approach provides at least equivalent results for surgical correction of mitral regurgitation: a propensity-matched comparison.

OBJECTIVE: Minimally invasive approaches to mitral valve surgery are increasingly used, but the surgical approach must not compromise the clinical outcome for improved cosmesis. We examined the outcomes of mitral repair performed through right minithoracotomy or median sternotomy. METHODS: Between January 2002 and October 2011, 1011 isolated mitral valve repairs were performed in the University of Pennsylvania health system (455 sternotomies, 556 right minithoracotomies). To account for key differences in preoperative risk profiles, propensity scores identified 201 well-matched patient pairs with mitral regurgitation of any cause and 153 pairs with myxomatous disease. RESULTS: In-hospital mortality was similar between propensity-matched groups (0% vs 0% for the degenerative cohort; 0% vs 0.5%, P = .5 for the overall cohort; in minimally invasive and sternotomy groups, respectively). Incidence of stroke, infection, myocardial infarction, exploration for postoperative hemorrhage, renal failure, and atrial fibrillation also were comparable. Transfusion was less frequent in the minimally invasive groups (11.8% vs 20.3%, P = .04 for the degenerative cohort; 14.0% vs 22.9%, P = .03 for the overall cohort), but time to extubation and discharge was similar. A 99% repair rate was achieved in patients with myxomatous disease, and a minimally invasive approach did not significantly increase the likelihood of a failed repair resulting in mitral valve replacement. Patients undergoing minimally invasive mitral repair were more likely to have no residual post-repair mitral regurgitation (97.4% vs 92.1%, P = .04 for the degenerative cohort; 95.5% vs 89.6%, P = .02 for the overall cohort). In the overall matched cohort, early readmission rates were higher in patients undergoing sternotomies (12.6% vs 4.4%, P = .01). Over 9 years of follow-up, there was no significant difference in long-term survival between groups (P = .8). CONCLUSIONS: In appropriate patients with isolated mitral valve disease of any cause, a right minithoracotomy approach may be used without compromising clinical outcome.

Quantitative evaluation of change in coexistent mitral regurgitation after aortic valve replacement.

OBJECTIVES: Management of intermediate degrees of mitral regurgitation during aortic valve replacement for aortic stenosis remains controversial. We sought to evaluate the degree of reduction of mitral regurgitation in patients undergoing aortic valve replacement, as well as a mathematical relationship between aortic valve gradient reduction and the degree of mitral regurgitation decrement. METHODS: We retrospectively analyzed demographic, intraoperative, and echocardiographic data on 802 patients who underwent aortic valve replacement or aortic root replacement between January 2010 and March 2011. A total of 578 patients underwent aortic valve replacement or aortic root replacement without intervention on the mitral valve. We excluded 88 patients with severe aortic insufficiency, 3 patients who underwent ventricular assist device placement, 4 patients who underwent prior mitral valve replacement, and 21 patients with incomplete data, yielding 462 patients for analysis. For each patient, the degree of pre- and postoperative mitral regurgitation was graded on a standard 0 to 4+ scale. RESULTS: Of the 462 patients, 289 patients had at least mild mitral regurgitation. On average, mitral regurgitation decreased 0.24 degrees per patient for this cohort of 289 patients. Of the 56 patients with at least moderate mitral regurgitation, mitral regurgitation decreased 0.54 degrees per patient. Of 62 patients who underwent isolated aortic valve replacements, who had at least mild mitral regurgitation, and who had no evidence of structural mitral valve disease, mitral regurgitation decreased 0.24 degrees per patient. Linear regression analysis revealed no relationship between reduction in mitral regurgitation and gradient reduction across the aortic valve. CONCLUSIONS: Reduction in mitral regurgitation after relief of aortic outflow tract obstruction is modest at best. Further, the magnitude of gradient change across the aortic valve has little influence on the degree of reduction in mitral regurgitation. These observations argue at minimum for performing a prospective evaluation of the clinical benefits of addressing moderate mitral regurgitation at the time of aortic valve intervention and may support a more aggressive approach to concomitant mitral surgery.