Systemic Immunosuppressive Therapy Research Articles

Experience of using genetic engineering biological therapy in a patient with psoriasis and chronic renal failure under hemodialysis

Psoriasis is a chronic immune-associated disease of a multifactorial nature. The prevalence of the disease, chronic course, impact on the patient’s quality of life, as well as the connection with the risk of progression of various comorbid conditions necessitate a detailed and comprehensive approach to the treatment of this group of patients. There has been a correlation of psoriasis with the risk of many comorbid pathologies, such as psoriatic arthritis, metabolic syndrome, liver and kidney disorders. There is evidence in the literature about the relationship between chronic renal failure and psoriasis, but the data are limited and require further study. According to Russian clinical guidelines, for moderate and severe forms of psoriasis, the prescription of systemic immunosuppressive therapy, targeted and genetically engineered biological drugs is indicated. Of particular interest is the determination of management tactics and selection of therapy if a patient with psoriasis has concomitant pathology due to the lack of a sufficient number of safety studies taking into account this or that comorbidity. We present the data known to us from a literature review on the stated problem. In view of the need to expand the data of real clinical practice on the possible risks of managing patients with psoriasis, we present a description of our own clinical experience of using the inhibitor interleukin 17A in a patient with chronic renal failure and hemodialysis.

Potentially fatal complications of new systemic anticancer therapies: pearls and pitfalls in their initial management.

Various types of immunotherapy (i.e. immune checkpoint inhibitors [ICIs], chimeric antigen receptor [CAR] T-cells and bispecific T-cell engagers [BiTEs]) and antibody drug conjugates (ADCs) have been used increasingly to treat solid cancers, lymphomas and leukaemias. Patients with serious complications of these therapies can be presented to physicians of different specialties. In this narrative review we discuss potentially fatal complications of new systemic anticancer therapies and some practical considerations for their diagnosis and initial treatment. Clinical presentation of toxicities of new anticancer therapies may be unpredictable and nonspecific. They can mimic other more common medical conditions such as infection or stroke. If not recognized and properly treated these toxicities can progress rapidly into life-threatening conditions. ICIs can cause immune-related inflammatory disorders of various organ systems (e.g. pneumonitis or colitis), and a cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) may develop after treatment with CAR T-cells or BiTEs. The cornerstones of management of these hyper-inflammatory disorders are supportive care and systemic immunosuppressive therapy. The latter should start as soon as symptoms are mild-moderate. Similarly, some severe toxicities of ADCs also require immunosuppressive therapy. A multidisciplinary team including an oncologist/haematologist and a corresponding organ-site specialist (e.g. gastroenterologist in the case of colitis) should be involved in the diagnosis and treatment of these toxicities. Health professionals should be aware of potential serious complications of new systemic anticancer therapies. Early diagnosis and treatment with adequate supportive care and immunosuppressive therapy are crucial for the optimal outcome of patients with these complications.

Organ involvement in newly diagnosed sarcoidosis patients in the Netherlands: The first large European multicentre prospective study

BackgroundClinical presentation and prevalence of organ involvement is highly variable in sarcoidosis and depends on ethnic, genetic and geographical factors. These data are not extensively studied in a Dutch population. AimTo determine the prevalence of organ involvement and the indication for systemic immunosuppressive therapy in newly diagnosed sarcoidosis patients in the Netherlands. MethodsTwo large Dutch teaching hospitals participated in this prospective cohort study. All adult patients with newly diagnosed sarcoidosis were prospectively included and a standardized work-up was performed. Organ involvement was defined using the WASOG instrument. ResultsBetween 2015 and 2020, a total of 330 patients were included, 55% were male, mean age was 46 (SD 14) years. Most of them were white (76%). Pulmonary involvement including thoracic lymph node enlargement was present in 316 patients (96%). Pulmonary parenchymal disease was present in 156 patients (47%). Ten patients (3%) had radiological signs of pulmonary fibrosis. Cutaneous sarcoidosis was present in 74 patients (23%). Routine ophthalmological screening revealed uveitis in 29 patients (12%, n = 256)). Cardiac and neurosarcoidosis were diagnosed in respectively five (2%) and six patients (2%). Renal involvement was observed in 11 (3%) patients. Hypercalcaemia and hypercalciuria were observed in 29 (10%) and 48 (26%, n = 182) patients, respectively. Hepatic involvement was found in 6 patients (2%). In 30% of the patients, systemic immunosuppressive treatment was started at diagnosis. ConclusionsHigh–risk organ involvement in sarcoidosis is uncommon at diagnosis. Indication for systemic immunosuppressive therapy was present in a minority of patients.

Clinical analysis of ear symptoms of 40 patients with ANCA-associated vasculitis

Objective:To analyze the clinical feature, diagnosis and treatment of Anca-associated vasculitis with ear symptoms. Methods:In this retrospective study, we summarized the clinical and laboratory examination, pure tone audiometry, aural immittance measurement, CT scan of temporal bone and treatment of 40 patients in the First Medical Center of the PLA General Hospital. Results:A total of 11 cases（27.5%） had the initial symptom in the ear. The most common symptoms were hearing loss, and the other symptoms included a sense of ear fullness, otorrhea and tinnitus. There were 35 cases with hearing loss: 19 cases with conductive hearing loss（47.5%）, 9 cases with sensorineural hearing loss（22.5%）, and 7 cases with mixed hearing loss（17.5%）. 5 cases had a sense of ear fullness or tinnitus, and the results of the hearing test were normal（12.5%）. All of the 40 patients had multi-system involvement, and respiratory system accounted for the most. All patients had a positive result of Anti-neutrophil cytoplasmic antibody（ANCA）. Treatment included systemic hormonal, immunosuppressive, or biologic therapy. There were 3 cases recovered（7.5%）, 22 cases with alleviated ear symptoms（55.0%）, 6 cases with recurrent hearing loss（15%） and 9 cases had no significant improvement（22.5%）. Conclusion:Conductive deafness（secretory otitis media） can be the first manifestation in the early stage of otitis media with AAV（OMAAV）, later it may turn to binaural mixed deafness. Otolaryngologists need to consider OMAAV diagnosis when diagnosing and treating patients with recurrent secretory otitis media. Multi-system symptom consultation and ANCA examination can help identify. Early systemic medication and the application of immunosuppressants or biological agents can help relieve the ear symptoms.

Sterile granulomatous panuveitis in dogs in the United Kingdom: A review of 33 cases.

To describe the clinical and histopathological features of a sterile granulomatous panuveitis syndrome in 33 dogs that underwent enucleation and ocular histopathology. Retrospective review of the medical records and ocular histopathology reports of 33 cases. Inclusion criteria were enucleation in conjunction with characteristic clinical and histopathological features. Thirteen breeds were represented (including crossbreeds). Panuveitis was acute and fulminating, and secondary glaucoma was common (n = 27). Interval from initial presentation to enucleation was 99 days (median 33 days, range 5-605 days). The mean age at enucleation was 6.7 years. Ocular signs were initially unilateral (n = 18) or bilateral (n = 15). The disease became bilateral in 18/25 cases that initially underwent unilateral enucleation, resulting in enucleation or euthanasia in 9/18 (mean interval of 168 days). Seven out of 59 eyes had a good outcome following topical anti-inflammatory and systemic immunosuppressive therapy. None of the dogs had travel history nor relevant systemic signs from presentation to follow-up (mean 619 days, range 16-3012 days). Histopathology revealed histiocytic and lymphoplasmacytic panuveitis with pigment dispersion, and no infectious agents were identified on light microscopy. To the authors' knowledge, this is the first report of a sterile granulomatous panuveitis syndrome in dogs in the UK. The clinical signs are severe, with rapid progression, and can result in bilateral enucleation or euthanasia in affected dogs. There does not appear to be an age or breed predisposition, however further research is necessary in this regard. Early and aggressive intervention, with both topical and systemic immunosuppressive therapy, is recommended to reduce the risk of blindness, enucleation, and euthanasia.

Therapeutic response of oral chronic graft-versus-host disease to topical corticosteroids according to the 2014 National Institutes of Health (USA) consensus criteria.

Chronic graft-versus-host-disease (cGVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. The oral cavity is one of the most frequently affected anatomic sites and is affected in 70% of all patients who develop cGVHD. The objective of this study was to determine the therapeutic response to topical corticosteroids and clinical outcome of patients with oral cGVHD using the 2014 NIH consensus criteria. The oral manifestations of cGVHD were collected at the first and the follow-up (FU) visits after the therapeutic treatment of oral GVHD. The FU intervals were: FU0, first visit; FU1, 0-1 month; FU2, 1-3 months; FU3, 3-6 months; FU4, 6-9 months; and FU5, 9-12 months. The oral cGVHD activity was assessed using the NIH modification of the Schubert Oral Mucosa Rating Scale (OMRS) and Thongprasom sign score. The functional impact was assessed by the organ-specific severity score. Fourteen patients (93.3%) at FU0 were being treated with at least one form of systemic immunosuppressive therapy, i.e., prednisolone, cyclosporin, and tacrolimus. The OMRS was reduced between FU0 and FU3 (p < 0.001), FU0 and FU4 (p < 0.001), and FU0 and FU5 (p = 0.004). The organ-specific severity scores were also reduced between FU0 and FU4 (p = 0.016), and FU0 and FU5 (p = 0.001). There was no significant difference in the highest Thongprasom sign score between all follow-up intervals (FU0-FU5) (p = 0.201). One patient (6.7%) at FU4 and three patients (20.0%) at FU5 did not receive topical corticosteroid therapy for oral cGVHD. The oral cGVHD lesions and functional impacts improved within 6 months and 9 months, respectively. However, most of the patients required topical corticosteroid therapy for more than 1 year to control their symptoms and lesions.

Amniotic Membrane Transplantation-A Surgical Alternative in Peripheral Ulcerative Keratitis

Introduction: Peripheral ulcerative keratitis (PUK) is a group of inflammatory corneal ulcers with stromal thinning and peripheral localization. It begins with immune cellular infiltrates in the juxtalimbal cornea, followed by a crescent-shaped ulcer that appears parallel to the limbus. Medical management includes intense lubrication, antibiotics, along with topical and systemic steroids and immunosuppressants. Definitive surgical management is lamellar patch or penetrating corneal graft. Amniotic membrane has wide array of biological properties, including anti-inflammatory, anti-bacterial, anti-angiogenic, antifibrotic, healing properties hence can be used as an alternative to keratoplasty. Material and Methods: This mono institutional observational retrospective study was conducted on 15 eyes of 15 patients having PUK in a tertiary health care centre. Patients underwent single-layered amniotic membrane transplantation (AMT) in case of corneal thinning involving &lt;1/2 corneal stroma, multi-layered or rolled AMT in cases of corneal thinning involving &gt;1/2 corneal stroma or with moderate to large perforations along with systemic steroids and immunosuppression. Results: All 15 Patients (100%) initially had symptomatic relief,2 patients (13.33%) underwent repeat AMT (86%success rate), 2 failures were noted, out of which 1 patient (6.67%) underwent corneal patch graft while 1 patient (6.67%) underwent large penetrating keratoplasty which failed and landed in Phthisis. Conclusion: AMT is a safe and effective alternative for the surgical management of PUK in combination with local and systemic immunosuppressive therapy. A close collaboration between the ophthalmologist and the physician is mandatory to prevent corneal perforation and decrease patient morbidity and risk of mortality

Preemptive Intervention in Airflow Obstruction Status Prevents the Development of Bronchiolitis Obliterans Syndrome after Allogeneic Stem Cell Transplantation: Multicenter, Prospective Phase II Study (Chiba AFO-01)

Background: Bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic stem cell transplantation (allo-HCT) is recognized as pulmonary chronic graft-versus-host disease (GVHD), a progressive, irreversible, and sometimes fatal complication. Periodic pulmonary function testing (PFT) for early diagnosis and timely therapeutic intervention is essential. However, effective monitoring and adequate treatment strategy for BOS have not been established. The airflow obstruction (AFO) criteria (predicted FEV1 second decreased by 5% a year or more, and FEV1-second rate &amp;lt;80%) had proposed to detect of a precursor of BOS, and even at AFO status, it was confirmed that increasing the risk in mortality of 2.3-fold (95% CI, 1.6- 3.3; P &amp;lt; 0.001) (JW Chien et al. Am J Respir Crit Care Med. 2003). In our single-center retrospective analysis, 67.2% of AFO patients progressed to BOS, and similarly, the AFO was associated with poor survival (Nakao et al., in submission). Although immunosuppressive agents, especially steroids, are usually administered or augmented for new-onset BOS, sufficient response has not necessarily been obtained. The feasibility study with inhaled fluticasone, azithromycin, and montelukast (FAM) with a brief steroid pulse had been reported, which was well tolerated; however, about one-third were a failure at 6 months, showed efficacy was extremely limited in advanced BOS. From these findings, we hypothesized that close monitoring and early intervention from the diagnosis of AFO using inhaled steroid long-acting β2-agonist budesonide/formoterol fumarate hydrate, clarithromycin, and montelukast (BCM) triplet therapy, could avert the progression to BOS. We conducted a multicenter, single-arm, open-label, prospective phase II study (Chiba AFO-01). This study was approved by the certified clinical research review board at Chiba University Hospital. (jRCTs031180338) Patients and Method: PFT was performed before and every 3 months after allo-HCT for 2 years, and from the time when the AFO criteria were met, BCM therapy was started and continued for 1 year. BOS and GVHD diagnoses were made according to the 2014 NIH Consensus Development Project on Criteria for Clinical Trials (BBMT 2015). The primary endpoint was the inhibition rate of BOS progression, and the secondary endpoints were AFO incidence rate, recurrence rate, survival rate, GVHD, intervention rate of systemic immunosuppressive therapy, and safety of BCM therapy. The statistical analysis plan considered it effective if the incidence of BOS with triple treatment was less than 65% with a two-sided P-value &amp;lt;0.10. Results: Between June 2016 and June 2018, 85 patients were enrolled, and 84 were included in the analysis. One was excluded from the analysis due to deviation. Fifteen of eighty-four (17.9%) met AFO criteria at the median of 178 days (63-728) after allo-HCT, and the 2-year cumulative incidence of AFO was 26.1%. Fourteen with AFO received the BCM treatment. Three patients developed BOS (0, 182, 420 days after onset of AFO). The BOS progression rate was 21.4% (95% CI: 4.7-50.8%), which was significantly below the threshold (65%) set by historical control, had demonstrated the inhibitory effect on BOS progression significantly ( P&amp;lt;0.001). No significant difference was observed in the relationship between AFO and primary disease, stem cell source, pretreatment, and chronic GVHD incidence compared to the non-AFO group. At the AFO diagnosis, 80% had not developed or concurrently diagnosed with chronic GVHD. During the study period, 80% had developed an active chronic GVHD in the AFO group and 54.2% in the non-AFO group. The BCM therapy was feasible, and 9 completed the treatment. Five were discontinued due to the development of IPS in 2, disease progression in 1, bacterial pneumonia in 1, and patient's preference in 1. No difference was observed between the two groups in 2-year OS (AFO 86.7% vs non-AFO 94.2%, Log-rank P=0.55) Conclusion: We revealed the target timeframe for PFT monitoring for early identifying patients at risk for subsequent BOS after allo-SCT. PFT monitoring and therapeutic intervention with BCM therapy for patients with AFO could improve outcomes. The therapeutic intervention from the BOS diagnosis is too late to improve prognosis, and early therapeutic intervention is essential when respiratory function decline is observed, regardless of the presence or absence of chronic GVHD.

A Novel JAK1 Inhibitor SHR0302 for Treatment of Chronic Graft-Verse-Host Disease: A Phase I Clinical Trial

Background: Chronic graft-versus-host disease (cGVHD) is a frequent and potentially life-threatening complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Standard steroid first-line treatment could not satisfy therapeutic need due to its limited efficacy. SHR0302 is a highly selective Janus kinase (JAK) 1 inhibitor, which could alleviate symptoms and improve the survival of cGVHD mice in our preclinical study. Herein, we reported updated safety and efficacy results of SHR0302 plus prednisone as first-line treatment for patients with naïve-treatment moderate or severe cGVHD. Methods: This was a Phase I open-label study. Patients who were aged 18-70, and confirmedly diagnosed with first-episode moderate/severe cGVHD requiring systemic immunosuppressive therapy after allo-HSCT were included in the study. cGVHD was defined according to national institutes of health (NIH) criteria. A 3+3 design including five dose levels (1mg/2mg/4mg/6mg/8mg once a day) was implemented to define the optimal dose of SHR0302. Meanwhile, prednisone was concurrently administrated with a dose of 1mg/kg/d and then gradually tapered after two weeks. The primary endpoint was safety, and the secondary endpoints were overall response rate (ORR) at day 28 and week 24. Dose-limiting toxicities (DLTs) were defined as grade 4 hematologic toxicity or grade 3 non-hematologic toxicity associated with SHR0302 which occurred in the first 28 days of study treatment. Results: From April 2020 to July 2022, 18 patients were enrolled in the trial. Till May 2023, the median follow-up was 17.3 months (range, 1.8-31.7). The median age of the patients was 47 years (range, 31-64). 13 (72.2%) patients had severe cGVHD, and the other 5 had moderate cGVHD. Almost all patients had more than one organ involved, and the most commonly involved organs were skin (66.7%), and mouth (50.0%). In contrast, lung (5.6%) and genital tract (5.6%) involvements were uncommon. Median duration of SHR0302 treatment was 6.3 months (range, 1.5-23.2). Overall, all (100%) patients experienced adverse events (AEs) related to SHR0302 and/or prednisone, and grade 3 or 4 AEs were observed in 7 (38.89%) patients. The most common SHR0302 treatment-related adverse events (TRAEs) included hypercholesterolemia (61.11%, n=11), hypertriglyceridemia (44.44%, n=8), platelet count decreased (38.89%, n=7), and anemia (16.67%, n=3). There were no serious AEs (SAEs) related with SHR0302, and no patient experienced SHR0302 dose reduction / discontinuation or death due to AEs. Only one patient developed DLT (grade≥3 hypercholesterolemia) in the highest dose-level group who had preexisting hypercholesterolemia. The maximum tolerated dose (MTD) was not reached. The ORR and complete remission (CR) rates were 94.44% and 27.77% at week 4, and were 82.35% and 64.71% at week 24, respectively. Among 18 evaluable patients, only 1 patient treated at dose level 1 showed no response at week 4. The event-free survival (EFS) at 24 months was 72.20% (95% CI, 51.40%-93.00%). Prednisone was discontinued in 8 (44.4%) patients at 24 weeks and all immunosuppressants, including SHR0302, were stopped in 4 (22.2%) patients with CR before the 24-week assessment. Conclusions: In summary, SHR0302 in combination with prednisone had a good safety and could achieve a high response for naïve-treatment cGVHD, which suggests that SHR0302 combination might become an optimal choice for naïve-treatment cGVHD.

2701. Mycobacterial Immune Reconstitution Inflammatory Syndrome Following Hematopoietic Cell Transplantation for GATA2 Deficiency

Abstract Background Immune reconstitution inflammatory syndrome (IRIS) was first described in patients with HIV and opportunistic infections starting antiretroviral therapy, but may be seen following hematopoietic cell transplantation (HCT) in patients with pre-existing infections. GATA2 deficiency is a genetic disorder with a marked susceptibility to mycobacterial infections, and is treated definitively with HCT. The clinical factors and pathogenesis of IRIS in HCT require further investigation. Methods We conducted a retrospective review of 32 patients with GATA2 deficiency and mycobacterial infections who completed &amp;gt; 6 months of follow-up after HCT. Uniform criteria were used to define cases of IRIS (Image 1). IRIS cases were classified as either early (post-HCT day &amp;lt; 60), intermediate (days 61-120), or late (day &amp;gt; 120). Image 1. Post-Hematopoietic Cell Transplant IRIS Criteria Criteria were adapted to hematopoietic cell transplantation from the AIDS Clinical Trial Group IRIS criteria. Results Clinical characteristics are shown in Image 2. IRIS was identified in 12 (35%) patients (Images 2-3). These patients were more likely to have disseminated infection (P=0.03), an elevated pre-HCT ferritin (P=0.03), and a lower day 30 post-HCT CD4 count (P=0.04). Median time to IRIS was 100 days (Image 4). Pre-transplant duration of mycobacterial therapy correlated with time to IRIS (Pearson’s r=0.58, P=0.05). Conditioning regimens using total body irradiation with or without cyclophosphamide were associated with longer time to IRIS (hazard ratio=0.04, P=0.02). A rise in CD3 chimerism was seen during early cases of IRIS, but not intermediate to late (P=0.002). IRIS emerged during tapering of systemic immunosuppressive therapy in 33% of cases. IRIS was managed conservatively (50%), by intensification of anti-mycobacterial treatment (8%) or by intensification of immunosuppression (42%). Conclusion Development of mycobacterial IRIS after HCT for GATA2 deficiency was associated with disseminated infection, a high pre-transplant ferritin, and low day 30 CD4 count. These findings suggest that antigen burden, a hyperinflammatory state leading into transplantation, and CD4 nadir after HCT have a role in its pathogenesis. Early cases of IRIS may emerge during lymphoid engraftment and CD4 recovery, whereas late cases may emerge with decreases in immunosuppressive therapy and more intensive conditioning regimens. Clinical outcomes were similar to non-IRIS patients. Disclosures All Authors: No reported disclosures

Infectious Disease Screening prior to Systemic Immunomodulatory Therapy in Hidradenitis Suppurativa: Consensus Guidelines from the Asia-Pacific Hidradenitis Suppurativa Foundation

Background: Current infectious disease screening recommendations for hidradenitis suppurativa (HS) are adopted from recommendations in chronic plaque psoriasis. No HS-specific guidelines for infectious disease screening prior to immunomodulatory therapy have been developed. Objectives: The aim of the study was to establish an expert Delphi consensus of recommendations regarding infectious disease screening prior to systemic immunomodulatory therapy in HS. Methods: Participants were identified via recent publications in the field and were sent a questionnaire regarding infectious diseases encountered in the setting of HS, and opinions regarding infectious disease screening prior to various systemic immunomodulatory therapies. All questions were informed by a systematic literature review regarding infections exacerbated or precipitated by immunomodulatory therapy. Questionnaire responses were followed by round-table discussion with a core group of 8 experts followed by a final round of questionnaires resulting in achievement of consensus. Results: 44 expert HS physicians from 12 countries on 5 continents participated in the development of the expert consensus recommendations. Consensus recommendations include screening for hepatitis B, hepatitis C and tuberculosis in all individuals with HS prior to therapy. All immunomodulatory therapies (biologic and systemic immunosuppressant therapy) should be preceded by infectious disease screening including patient and location-specific considerations for endemic local diseases and high-risk activities and occupations. Clinical assessment has a significant role in determining the need for laboratory screening in the setting of many uncommon or tropical diseases such as leprosy, leishmaniasis and strongyloidiasis. Conclusions: The presented consensus recommendations are the first specifically developed for pre-treatment infectious disease screening in HS.

Histocompatibility Leukocyte Antigen-A29-Associated Retinal Vasculitis without Choroidal Lesions: A Report of 4 Cases.

This study describes a cohort of patients presenting with histocompatibility leukocyte antigen (HLA)-A29-associated retinal vasculitis without choroidal lesions that may share clinical features with birdshot retinochoroiditis. The methods include a retrospective chart review of patients presenting with HLA-A29-associated retinal vasculitis without choroidal lesions. The data on the patients were entered retrospectively into a new database and analyzed. Four patients who had HLA-A29-associated retinal vasculitis without choroidal lesions were identified. The median age at presentation was 40 years (range: 14-71); 75% were female. At presentation, all four patients had a visual acuity of 20/50 or better in both eyes. All the eyes had mild vitritis, three eyes (37.5%) had cystoid macular edema, and two eyes (25%) had optic disc edema. All the patients required treatment with systemic steroids and immunosuppressive therapy. HLA-A29-associated retinal vasculitis without choroidal lesions appears to share many clinical features with birdshot chorioretinitis, including the need for systemic immunosuppressive therapy. Whether this entity represents an early form of birdshot retinochoroiditis or a more localized variant of the disease is a topic for additional studies.

Prognostic impact of venous thromboembolism on the course of sarcoidosis: A multicenter retrospective case-control study

Sarcoidosis is an independent risk factor for venous thromboembolism (VTE). However, the characteristics and clinical evolution of sarcoidosis patients presenting a VTE (sarcoidosis/VTE group) in the course of their disease are not known. Consequently, if VTE occurrence is associated with a more severe disease is still pending.We conducted a retrospective case-control study of sarcoidosis/VTE patients compared to matched sarcoidosis controls without VTE in two French tertiary centers, analysed and compared the clinical, biological, functional, imaging and evolutive profiles of the two groups.Sixty-one patients were included with at least one episode of VTE during course of sarcoidosis. At sarcoidosis onset (before/at the time of VTE occurrence) the number of affected organs, radiological stages and pulmonary functional tests were not significantly different between the two groups. In contrast, we found that sarcoidosis/VTE patients required more frequently a systemic immunosuppressive therapy (corticosteroids and/or immunosuppressors, 79% versus 58%; p = 0.008). The functional course was also poorer in sarcoidosis/VTE patients with a more frequent decrease in functional vital capacity (33% versus 18% in sarcoidosis/VTE patients and controls, respectively, p = 0.008). Finally, sarcoidosis/VTE patients presented more frequently with pulmonary hypertension (10% versus 1% in patients and controls, respectively, p = 0.006), and their survival was significantly worse (log-rank p <0.001).The occurrence of VTE during sarcoidosis is associated with a more severe disease and a poorer prognosis. The occurrence of VTE during sarcoidosis might signal a more inflammatory and/or evolutive disease in sarcoidosis/VTE patients and should be taken in consideration when designing therapeutic strategies for them.

Clinicopathological characteristics and key therapeutic options for liver involvement with vasculitis

Vasculitis, involving any levels of vessels throughout the body, has variable nonspecific clinical presentation and complicated classification, hence, the diagnose is difficult. The liver is not the major organ involved, so it is prone to overlook vasculitis-associated liver injuries. The main manifestations of vasculitis involving the liver include abnormal liver biochemistry test (mainly increase of cholestatic liver enzymes), portal hypertension, and hepatic occupying lesions. Treatment principles are primarily directed at systemic immunosuppressive therapy for vasculitis. This review summarized the classification of vasculitis, major presentations of liver involvement in vasculitis, and the principles of treatment, to improve the awareness of the rare vascular diseases.

Mode of action, indications and recommendations on extracorporeal photopheresis (ECP).

Extracorporeal photopheresis (ECP) has gained importance in the treatment of several diseases. Initially introduced as a new therapeutic modality for the treatment of patients with cutaneous T-cell lymphoma, the indications for the use of ECP have expanded to include hematology and transplantation immunology. Extracorporeal photopheresis has found its place in the treatment plan of cutaneous T-cell lymphoma, systemic sclerosis, graft-versus-host disease, organ transplantation such as heart and lung, sometimes as first-line therapy and very often in combination with various systemic immunosuppressive therapies. The procedure basically consists of three steps: leukapheresis, photoactivation and reinfusion. The following article presents possible theories about the mechanism of action, which is not yet fully understood, and discusses the five most common indications for ECP treatment with corresponding therapy recommendations.

Systemic immunosuppression does not affect revascularization outcomes in patients with chronic limb-threatening ischemia

ObjectiveMany patients with chronic limb-threatening ischemia (CLTI) have additional comorbidities requiring systemic immunosuppression. Few studies have analyzed whether these medications may inhibit graft integration and effectiveness, or conversely, whether they may prevent inflammation and/or restenosis. Therefore, our study aim was to examine the effect of systemic immunosuppression vs no immunosuppression on outcomes after any first-time lower extremity revascularization for CLTI. MethodsWe identified all patients undergoing first-time infrainguinal bypass graft (BPG) or percutaneous transluminal angioplasty with or without stenting (PTA/S) for CLTI at our institution between 2005 and 2014. Patients were stratified by procedure type and immunosuppression status, defined as ≥6 weeks of any systemic immunosuppression therapy ongoing at the time of intervention. Immunosuppression vs nonimmunosuppression were the primary comparison groups in our analyses. Primary outcomes included perioperative complications, reintervention, primary patency, and limb salvage, with Kaplan-Meier and Cox proportional hazard models used for univariate and multivariate analyses, respectively. ResultsAmong 1312 patients, 667 (51%) underwent BPG and 651 (49%) underwent PTA/S, of whom 65 (10%) and 95 (15%) were on systemic immunosuppression therapy, respectively. Whether assessing BPG or PTA/S patients, there were no differences noted in perioperative outcomes, including perioperative mortality, myocardial infarction, stroke, hematoma, or surgical site infection (P > .05). For BPG patients, Kaplan-Meier analysis and log-rank testing demonstrated no significant difference in three-year reintervention (37% vs 33% [control]; P = .75), major amputation (27% vs 15%; P = .64), or primary patency (72% vs 66%; P = .35) rates. Multivariate analysis via Cox regression confirmed these findings (immunosuppression hazard ratio [HR] for reintervention, 0.95; 95% CI, 0.56-1.60; P = .85; for major amputation, HR, 1.44; 95% CI, 0.70-2.96; P = .32; and for primary patency. HR, 0.97; 95% CI, 0.69-1.38; P = .88). For PTA/S patients, univariate analysis revealed similar rates of reintervention (37% vs 39% [control]; P = .57) and primary patency (59% vs 63%; P = .21); however, immunosuppressed patients had higher rates of major amputation (23% vs 12%; P = .01). After using Cox regression to adjust for baseline demographics, as well as operative and anatomic characteristics, immunosuppression was not associated with any differences in reintervention (HR, 0.75; 95% CI, 0.49-1.16; P = .20), major amputation (HR, 1.46; 95% CI, 0.81-2.62; P = .20), or primary patency (HR, 0.84; 95% CI, 0.59-1.19; P = .32). Sensitivity analyses for the differences in makeup of immunosuppression regimens (steroids vs other classes) did not alter the interpretation of any findings in either BPG or PTA/S cohorts. ConclusionsOur findings demonstrate that patients with chronic systemic immunosuppression, as compared with those who are not immunosuppressed, does not have a significant effect on late outcomes after lower extremity revascularization, as measured by primary patency, reintervention, or major amputation.

43852 JAK inhibitor safety compared to traditional systemic immunosuppressive therapies

43852 JAK inhibitor safety compared to traditional systemic immunosuppressive therapies

Feasibility of an implantable bioreactor for renal cell therapy using silicon nanopore membranes

The definitive treatment for end-stage renal disease is kidney transplantation, which remains limited by organ availability and post-transplant complications. Alternatively, an implantable bioartificial kidney could address both problems while enhancing the quality and length of patient life. An implantable bioartificial kidney requires a bioreactor containing renal cells to replicate key native cell functions, such as water and solute reabsorption, and metabolic and endocrinologic functions. Here, we report a proof-of-concept implantable bioreactor containing silicon nanopore membranes to offer a level of immunoprotection to human renal epithelial cells. After implantation into pigs without systemic anticoagulation or immunosuppression therapy for 7 days, we show that cells maintain >90% viability and functionality, with normal or elevated transporter gene expression and vitamin D activation. Despite implantation into a xenograft model, we find that cells exhibit minimal damage, and recipient cytokine levels are not suggestive of hyperacute rejection. These initial data confirm the potential feasibility of an implantable bioreactor for renal cell therapy utilizing silicon nanopore membranes.

Ultra-High Frequency UltraSound (UHFUS) Assessment of Barrier Function in Moderate-to-Severe Atopic Dermatitis during Dupilumab Treatment.

Atopic dermatitis (AD) is a chronic multifactorial inflammatory disease characterized by intense itching and inflammatory eczematous lesions. Biological disease-modifying drugs, such as dupilumab are recommended for patients with moderate-to-severe AD, refractory to systemic immunosuppressive therapies. Disease monitoring is performed by clinical scores. Since 1970, however, the use of ultrasound and particularly high-frequency ultrasound (HFUS), has identified alterations in dermal echogenicity, called the subepidermal low-echogenic band (SLEB), that correlates with disease severity and response to treatment. We enrolled 18 patients with moderate-to-severe AD, divided into two groups: twelve patients in the dupilumab treatment (Group A) and six patients in standard treatment, from February 2019 to November 2019. We performed ultra-high frequency ultrasound (UHFUS) evaluation of lesional and non-lesional skin, focusing on SLEB average thicknesses measurement, epidermal thickness, and vascular signal in correlation with objective disease scores (EASI, IGA), patient's reported scores (Sleep Quality NRS and Itch NRS), and TEWL and corneometry at baseline (T0), after 1 month (T1) and 2 months (T2). The SLEB average thickness measurement, vascular signal, and epidermal thickness showed a statistically significant reduction in lesional skin of the biological treatment group and no significant reduction in non-lesional skin in both groups. In the lesional skin of the standard treatment group, only epidermal thickness showed a statistically significant reduction. Our study demonstrates that SLEB measurement, vascular signals, and epidermal thickness could be used as objective parameters in monitoring the AD treatment response, while the presence of SLEB in non-lesional skin could be used as a marker of subclinical inflammation and could predict development of clinical lesions, suggesting a pro-active therapy. Further follow-up and research are needed to clarify the association of SLEB decrease/disappearance with a reduction of flares/prolongment of the disease remission time.

Cytomegalovirus colitis unmasking human immunodeficiency virus infection as a cause of IgA vasculitis

BackgroundHuman immunodeficiency virus (HIV) has a protean clinical picture, in rare instances manifesting as systemic autoimmune disorders such as vasculitides. HIV-induced autoimmune diseases often do not respond well to systemic immunosuppressive therapy. Opportunistic infections may occur in patients with either acquired immunodeficiency syndrome (AIDS) or heavy immunosuppressive treatment, and can further complicate the clinical presentation.Case presentationA patient presenting with immunoglobulin A (IgA) vasculitis (IgAV) with treatment-refractory purpuric skin rash and suspect intestinal vasculitis was discovered to have AIDS. HIV was the trigger of IgAV, and cytomegalovirus (CMV) colitis mimicked intestinal vasculitis. Antiretroviral treatment improved both CMV colitis and the control of the autoimmune disease.ConclusionsAn autoimmune disease relapsing despite adequate immunosuppressive treatment and/or the presence of recurrent severe opportunistic infections may be clues to an underlying HIV infection.