Immunosuppressive Treatment Research Articles

Prediction of long-term drug-free outcomes in ACPA-positive and ACPA-negative rheumatoid arthritis by combined clinical and ultrasound assessment of residual disease: a 5-year prospective study

ObjectiveTo delineate, within the framework of current clinical practice and criteria, the sustainability of first-line immuno-suppressive treatment discontinuation in rheumatoid arthritis (RA) and the impact of residual disease in remission...

Should the Start of Immunosuppressive Treatment for COVID-19 Rely upon the Degree of Inflammation or the Time from Onset?

Background and Objectives: A COVID-19 model with a viral first-week phase and an inflammatory second phase has been proposed. It has been suggested that immunosuppressive treatment in the first week is harmful. This study aimed to analyze the potential damage of corticosteroids (CS) administered in the first week of COVID-19. Materials and Methods: This study was performed on a large cohort of consecutive COVID-19 patients admitted to Bellvitge University Hospital (Barcelona, Spain) from March 2020 to April 2021. Patients diagnosed with COVID-19 who were treated with 6 mg of dexamethasone a day for 10 days, and whose initiation of administration occurred within the first 2 weeks from symptom onset were included. We divided the cohort into the following two groups: patients for whom CS were initiated within the first 7 days after symptom onset vs. patients for whom CS were initiated between days 8 and 14. The degree of analytical inflammation (based on lymphocyte count, C-reactive protein, ferritin, lactate dehydrogenase, and D-dimer) upon admission was taken into account. The primary outcome was in-hospital mortality. Results: A total of 581 patients met the inclusion criteria. The results included, as follows: differences in age at baseline between groups (70.8 years old vs. 62.7, p < 0.001); moderate-to-severe dependency (11.9% vs. 4.2%, p = 0.003); the lymphocyte count (840 × 106/L vs. 900, p = 0.033); D-dimer (400 ng/mL vs. 309, p < 0.001); and PaO2/FiO2 (290 vs. 311, p < 0.001). In-hospital mortality in patients who received CS in the first week of symptom onset was higher (29% vs. 12.8%, p < 0.001). The following risk factors were associated with higher in-hospital mortality: age (OR = 1.06, p < 0.001); Charlson index (OR = 1.34, p = 0.001); tachypnea > 20 bpm (OR = 2.58, p < 0.001); ≥3 high-risk criteria of inflammation (OR = 1.94, p = 0.012); and CS onset in the first week (OR = 2.17, p = 0.004). A higher PaO2/FiO2 (OR = 0.99, p < 0.001) and the use of remdesivir (OR = 0.53, p = 0.021) were identified as protective factors. However, when stratified by analytical inflammation criteria, the onset of CS in the first week did not reach statistical significance. Conclusions: The early administration of CS did not demonstrate a significant detrimental effect. These results highlight the need for a nuanced approach to CS therapy in COVID-19 that carefully weighs the risks and benefits based on individual patient characteristics and the severity of the inflammation.

Pan-neurofascin autoimmune nodoparanodopathy: A case report and literature review.

Locked-in syndrome (and its variant, completely locked-in state) generally has a high mortality rate in the acute setting; however, when induced by conditions such as acute inflammatory polyradiculoneuropathy, it may well be curable such that an attempt at cure should be systematically sought by clinicians. A 52-year-old man presented with acute tetraparesia and areflexia, initially diagnosed as Guillain-Barré syndrome. Despite appropriate treatment, his condition deteriorated, evolving into a completely locked-in state. The detection of anti-pan-neurofascin antibodies led to the correct diagnosis, acute pan-neurofascin autoimmune nodoparanodopathy. Immunosuppressive treatment (rituximab) and plasma exchanges were performed. After several months, the patient's neurological symptoms almost completely subsided, without any major sequelae. In patients with locked-in syndrome (or its variant), neurologists and intensive care physicians must be aware of, and look for, the main etiologies (including pan-neurofascin autoimmune nodoparanodopathy), to allow the prompt initiation of treatment and thus a rapid recovery for these ultimately curable conditions. Despite causing major disability, pan-neurofascin autoimmune nodoparanodopathy is curable if the appropriate treatment is given.

Management of Systemic Anti-psoriatic Drugs in PsoriasisPatients with ConcurrentParaplegia or Tetraplegia: Insights From a 6-Year Multicenter, Retrospective Observational Study.

Patients with psoriasis (PsO) and permanent spinal cord injuries (SCI) resulting in paraplegia and tetraplegia may experience a higher rate of infections compared to patients with PsO without SCI. It can result in further challenges for therapeutic management with immunosuppressants (biological and non-biological treatments). Thus, weaimed to evaluate the rate of infections in patients with PsO and SCI treated with systemic immunosuppressants. This multicenter, retrospective observational study enrolled patients with PsO and traumatic SCI undergoing systemic immunosuppressive treatments for at least 5years. All patients were evaluated by experienced, board-certified dermatologists and neurologists. Demographic and clinical data were collected. We enrolled 23 patients with SCI (16 with paraplegia and 7 with tetraplegia) treated with methotrexate (MTX) and different biologics (tumor necrosis factor (TNF) inhibitors (i) and interleukin (IL)-17i/IL-23i). Globally, patients with SCI treated with MTX displayed higher rates of infection compared to those treated with biologics. Patients with paraplegia had lower rates of infection compared to patients with tetraplegia during anti-psoriatic therapies (p < 0.05). Those treated with TNFi had greater rates of infection than those treated with IL-17i/IL-23i (p < 0.001). Patients with psoriatic arthritis (PsA) experienced a significant diagnostic delay and clinical monitoring of PsA severity was challenging. In patients with moderate-to-severe PsO and concurrent traumatic SCI, dermatologists should consider using IL-17i/IL-23i as first-line therapy.

P0540 Assessment of Metabolic-Associated Liver Disease in Patients with Crohn’s Disease in Long-Term Remission

Abstract Background Previous studies have shown that patients with Crohn’s disease(CD) have an increased risk of metabolic liver disease(MASLD) even in the absence of cardiovascular risk factors. This increased prevalence is attributed to the inflammatory bowel activity itself. However, there is less evidence on whether CD could be an independent risk factor for MASLD in patients in long-term remission Methods A cross-sectional study was conducted, including two cohorts: one of patients with CD in deep remission and another of healthy controls. All participants underwent blood tests, abdominal ultrasound with shear wave elastography(SWE) and FibroScan®. Additionally, CD patients were evaluated to determine clinical, biochemical, and radiological remission(using intestinal ultrasound). Only patients with CD in clinical remission for at least one year, and not receiving immunosuppressive or biological treatments, were included. Patients with clear predisposing risk factors to metabolic liver disease(such as corticosteroid treatment or diabetes) were excluded Results 47 patients were included: 29 controls(61.7%) and 18 with CD in remission(38.3%). The baseline characteristics are summarized in Table1. Regarding the CD remission: Harvey index median was 0(IQR 0-1). Faecal calprotectin mean was 38.8 µg/g(IQR 20.7-57.4), C-reactive protein mean was 0.6mg/dL(IQR 0.5-2.1), and intestinal ultrasound showed normal bowel wall thickness in all patients. The lipid and liver profile is presented in Table2. Considering all included patients, regardless of the presence of steatosis, Fibroscan values were significantly higher in the control group compared to CD patients, although there were no advanced fibrosis in either group(4.9kPa vs 4.1kPa,p=0.04). This was consistent with SWE data(4.3 kPa vs 4.15 kPa), although this difference did not reach statistical significance(p=0.58). ATI values were 0.54 in controls vs 0.58 in CD patients(p=0.38). Considering only patients with steatosis, there was no greater prevalence of steatosis among patients with CD(23.5%) compared to controls(20.8%),p=0.84. By ultrasound, all cases were classified as mild steatosis, except for one patient who was reported as severe, belonging to the CD group. In our sample, among patients with steatosis, those with CD were more frequently diagnosed with dyslipidaemia(75%) compared to controls(0%),p=0.018. Fibroscan values were lower in patients with CD and steatosis(3.9kPa) compared to controls(5.3kPa),p=0.26. Similar to SWE (4.02kPa vs 4.56kPa, p=0.43) and ATI(0.73 vs 0.69,p=0.74) values Conclusion In our experience, there is no increased prevalence of MASLD in CD in the absence of activity, and when present, it may be secondary to underlying cardiovascular risk factors, as in our case was dyslipidaemia

OP38 Comparative efficacy of infliximab and vedolizumab after failure of a first anti-TNF in patients with ulcerative colitis: a double-blind randomized controlled trial (EFFICACI)

Abstract Background No clinical trial has previously assessed the best therapeutic strategy between switching to another anti-TNF or swapping to another class of biologic class after the failure of a first anti-TNF in ulcerative colitis (UC). The aim of the EFFICACI trial was to compare the efficacy of vedolizumab with infliximab in patients who had failed a first sub-cutaneous anti-TNF (golimumab and/or adalimumab). Methods EFFICACI was a French double-blind multicenter randomized controlled trial (1:1) comparing intravenous vedolizumab 300 mg at weeks 0-2-6 to intravenous infliximab 5 mg/kg at weeks 0-2-6. Eligible patients had moderate-to-severe UC, defined by a total Mayo score ≥ 6, despite at least 12 weeks (W) of treatment with adalimumab or golimumab as first line of advanced therapy. The primary endpoint was steroid free clinical remission at W14. The number of patients (N=150) was estimated for a 20% difference in favor of vedolizumab with a type 1 risk of 5% and a power of 80%. Patients were subsequently followed in an open-label fashion until week 54. The analysis was performed on an intention-to-treat basis. Only results at W14 will be presented. (CPP: 2018-002673-21; ClinicalTrial: 35RC17_8841_EFFICACI) Results From January 2018 to December 2023, 151 patients were randomized among 19 centers: 78 in the vedolizumab arm and 73 in the infliximab arm. Characteristics and demographics at inclusion were similar between groups, with 102/151 (67.5%) patients failing adalimumab and 49/151 (32.5%) failing golimumab. Concomitant immunosuppressive treatment with thiopurine or methotrexate was associated with infliximab and vedolizumab for 37/72 (51.4%) patients and 43/78 (55.1%) patients, respectively. At W14, proportions of patients in clinical remission (primary endpoint) were 34.6% (27/78) with vedolizumab and 19.2% (14/73) with infliximab (p=0.033). The clinical response rates were 46/78 (59.0%) with vedolizumab and 36/72 (50.0%) with infliximab (p=0.27). Proportions of patients in clinical response at W2, W6 and W14 are shown in Figure 1. At W14, endoscopic improvement (Mayo endoscopic subscore 0 or 1) was observed in 36/77 (46.8%) patients in the vedolizumab arm and 21/72 (29.2%) in the infliximab arm (p=0.027). No factor at inclusion was predictive of remission at week 14, including pharmacokinetic data for the first-line anti-TNF. Adverse event rates were similar in both groups - 46 (63.9%) infliximab arm, 55/78 (70.51%) vedolizumab arm. Eight patients were hospitalized for a severe flare (5 in the infliximab arm and 3 in the vedolizumab arm). Conclusion After failure of a first subcutaneous anti-TNF, induction therapy with vedolizumab was superior to infliximab in achieving steroid free clinical remission at week 14 in patients with UC.

P0128 IL-27 signalling, but not IL-1B, is functionally relevant in the pathophysiology of immune checkpoint inhibitor induced colitis

Abstract Background Immune checkpoint inhibitors (CPI) augment T-cell responses to tumour cells and have transformed treatment paradigms in cancer. However, CPI frequently trigger autoimmune like events, including potentially life-threatening colitis. Current immunosuppressive treatments for CPI- colitis (CPI-c) incur significant side effects and may even reduce CPI efficacy. New treatments are urgently needed. Methods Changes at gene level, pathway level (GSEA) and predicted upstream regulators (Ingenuity Pathway Analysis-IPA), and enrichment scores (Gene Set Variation Analysis-GSVA) were investigated in colonic biopsies (RNA-sequencing) from patients with CPI-c (n=12), CPI (no colitis) (n=6), healthy controls (n=13) and ulcerative colitis (UC) (n=12). Potentially relevant pathways were functionally tested in preclinical disease models. CPI-c was induced in mice transplanted with a pro-inflammatory microbiota and administered anti-PD-1 and anti-CTLA-4 intraperitoneally (i.p). Anti-IL1R (anakinra), MCC950 (inflammasome inhibitor) and anti-IL27 were administered i.p. Colonic leukocytes were extracted to interrogate myeloid and lymphocyte compartments by flow cytometry. Whole colon segments were processed for histology. Results In CPI-c patients, IL-1B was the top differentially expressed cytokine at gene level with interleukin-1 signalling significantly enriched at pathway level. IPA also identified IL-1B and IL-27 as predicted upstream activators. Interestingly, in vivo blockade of IL-1B, or the inflammasome (MCC950), had no impact on colitis. Administration of IL-27-neutralising antibodies at the onset of CPI-colitis in mice, reduced disease susceptibility and improved histological colitis scores. This was associated with decreased infiltration of colonic lamina propria neutrophils, Ly6C+ inflammatory monocytes and the number of CD8+ IFNg+ T-cells. Conversely, administering neutralising anti-IL27 during established CPI-colitis did not ameliorate disease and was linked to an enhanced CD4+ effector response characterised by heightened production of TNFa and IFNg. Further analysis of colonic biopsies of CPI-c patients confirmed enrichment of IL27-responsive genes which we localised to CD8+ resident memory and CD8+ cytotoxic cells in single cell RNA-seq analyses. Additionally, serum IL-27 levels were significantly elevated in CPI-c patients. Conclusion IL-1B signalling was shown to be dispensable to disease in mice. However, IL-27 signalling has a context specific role, serving as a functionally important activator of innate immune responses, while inhibiting later phases of acquired immunity via suppressing cytotoxic lymphocyte responses. Targeting IL-27 presents an attractive therapeutic approach for CPI-c given its potential tumourogenic effects.

PDL1 inhibitors may be associated with a lower risk of allograft rejection than PD1 and CTLA4 inhibitors: analysis of the WHO pharmacovigilance database

BackgroundTransplant recipients face increased cancer mortality due to immunosuppressive treatments. Immune checkpoint inhibitors (ICI) have improved survival rates, but data on the use of these agents in transplant recipients is scarce. ICI may trigger allograft rejection, but the absolute risk of AR between the different ICI classes remains to be defined.MethodsVigiBase® (WHO’s pharmacovigilance database) was queried for reports of AR involving CTLA4, PD1, or PDL1 inhibitors. Disproportionality analysis compares the proportion of reports with a specific adverse drug reaction (ADR) and a given drug to the proportion of reports with the same ADR and other drugs. A lower 95% confidence interval for the Information Component (IC) &amp;gt;0 suggests a signal. The comparative Reporting Odds Ratios (ROR) for AR, between PD1 and PDL1 inhibitors, was calculated.ResultsWe gathered 159 AR involving an ICI, especially nivolumab (73, 45.9%), mostly affecting kidneys (87, 54.7%). Median time to onset: 28 days. Fatal outcome: 36 reports (22.6%). ICI were significantly associated with AR: IC=1.7 [1.4;1.9]. Specifically, PD1 inhibitors yielded an IC of 2.0 [1.7;2.2] (152 reports observed compared to 38 expected). By contrast, the IC of PDL1 inhibitors was negative: -2.6 [-6.4;-1.0] (1 observed, 9 expected). The comparative ROR of PD1 compared to PDL1 inhibitors was 33.7 [4.7;240.9] (p=0.0005).ConclusionsWe confirm the association between ICI treatment and AR. Notably, PDL1 inhibitors showed surprisingly low AR reports compared to CTLA4 and PD1 inhibitors. Further prospective studies are warranted to confirm whether PDL1 inhibitors indeed reduce AR risk compared to other ICI.

Retrospective observational study shows accelerometers can monitor effects of canine pruritus treatment.

To evaluate the use of collar-mounted accelerometers to objectively monitor treatment outcomes in canine pruritus. Observational data from 1,803 dogs from 2019 through 2023 were retrospectively analyzed to evaluate the efficacy of collar-mounted accelerometers to assess treatment efficacy for pruritic canine skin diseases. Accelerometer measurements were joined to electronic health records to establish symptoms, diagnoses, and interventions. A directed acyclic graph was used to identify relevant variables to control for, and linear regression was used to model the pruritic behaviors before and after intervention. Significant reductions in pruritic behaviors, particularly scratching and licking, were observed following interventions. Antibody and immunosuppressant treatments exhibited the most pronounced effects on scratching behavior, with a reduction in scratching of up to 40.9% and 23.4%, retrospectively, in the 30 days following intervention relative to the 14 days prior. Collar-mounted accelerometers used to measure pruritic behaviors can detect the effects of interventions for canine pruritus. Pruritus is a common symptom of canine skin diseases, such as atopic dermatitis or allergic dermatitis, which can be difficult to diagnose and manage. This study highlights the use of collar-mounted accelerometers to objectively monitor treatment outcomes for canine pruritus, providing valuable insights into treatment effectiveness that could allow veterinarians and pet owners to optimize management strategies to alleviate the burden of this challenging condition.

Systemic disease activity measured with ESSDAI varies largely over 5 years in a prospective, longitudinal cohort of patients with Sjögren’s disease

ObjectivesThe objectives are to evaluate variation in systemic disease activity (European Alliance of Associations For Rheumatology (EULAR) Sjögren’s Syndrome Disease Activity Index (ESSDAI)) over time at group and individual patient...

DOP067 Selective JAK1 blockade with Upadacitinib is effective in immune checkpoint inhibitor-induced colitis

Abstract Background Immune checkpoint inhibitors (CPI) have transformed cancer outcomes, but frequently trigger autoimmune- like events, including life-threatening colitis. Current immunosuppressive treatments for CPI- colitis (CPI-c) incur significant side effects and may compromise CPI efficacy, highlighting the need for new therapies. Methods RNA sequencing was performed on colonic biopsies from patients with CPI-c (n=12), CPI (no colitis, n=6), healthy controls (n=13), and UC (n=12). Gene expression, pathway level (GSEA) and cellular composition were analysed. Cell-cell communication were analysed using a single-cell RNA sequencing reposited dataset. Colonic organoids from CPI-c and controls were cultured and treated with IFNg ± JAK1-STAT inhibition with Upadacitinib . The impact of JAK1 blockade was evaluated in vivo using pre-clinical models of CPI-c1. Colonic leukocytes were analysed by flow cytometry. Clinical and endoscopic outcomes were defined in five patients with treatment-refractory CPI-c, following treatment with Upadacitinib 45mg for 8 weeks. Results Gene expression profiling of colonic biopsies highlighted overactivity of the JAK1-dependent cytokine IFNg in CPI-c. IFNg responsive transcripts, including CXCL9, CXCL10, IDO1, GZMB and STAT1, were among the most upregulated transcripts, with IFNg signalling identified as the top enriched pathway. Cellular deconvolution revealed enrichment of TH1 and CD8+ memory cells. Cell-cell communication analysis indicated distinct dialogue mediated by IFNg between T-cell subsets in CPI-c, including TH17+PD1+ and epithelial cells, and inflammatory enterocytes. Colonic organoids from CPI-c patients retained high baseline expression of IFNg-responsive transcripts, and significantly over-expressed these following ex vivo stimulation with IFNg, which was corroborated at protein level. Upadacitinib treatment of stimulated organoids reversed these changes. In vivo administration of Upadacitinib significantly reduced pathological features and severity of CPI-c in preclinical models of disease. Encouraged by these findings, we treated 5 patients with severe, treatment refractory CPI-c with Upadacitinib. All achieved rapidly resolution of disease with complete mucosal healing, no adverse events, and favourable 9-month cancer outcomes were sustained. Conclusion IFNg signalling was highly upregulated in CPI-colitis patients, which was recapitulated in a novel CPI-c derived colonic organoid model and in vivo models of disease. Upadacitinib improved organoid morphology, reduced IFNg targets, and ameliorated CPI-c in mice. Moreover, Upadacitinib rapidly rescued treatment refractory patients highlighting its potential as a promising therapeutic approach in patients with severe disease.

P1226 Inflammatory Bowel Diseases and Prior Malignant Diagnoses - A Danish Nationwide Cohort Study 1996-2022

Abstract Background Due to the increasing prevalence of inflammatory bowel diseases (IBD), an ageing population and the increased risk of cancer associated with IBD, the number of patients diagnosed before or while having their IBD is increasing. We aimed to describe the treatment of IBD patients with a prior malignant diagnosis relative to IBD patients without. Methods Danish national registers were used to identify all incident Crohn’s disease (CD) and Ulcerative Colitis (UC) patients in Denmark, their exposure to drugs and surgeries, and cancer status, between 1996-2022. Cox regressions compared the risk of exposure to medications and the risk of surgery for patients with malignant comorbidity. Results 58,402 incident IBD patients (18,383 CD (31.5%), 40,019 UC (68.5%)) were included and followed for a median of 10 years (IQR: 5, 17 yrs). 2,370 (4.1%) had cancer prior to IBD. Of the remaining 56,032 IBD patients, 4,445 (7.9%) had their first cancer diagnosis after their IBD diagnosis. Anti-TNF therapy was used in 16% (n = 92) of CD patients with cancer prior to IBD and in 41% (n = 6,857) of CD patients without cancer. Anti-TNF was used in 9.0% (n = 161) of UC patients with cancer prior to IBD and in 20% (n = 7,159) of UC patients without cancer. Immunomodulators were used in 27% (n = 159) of CD patients with cancer prior to IBD and in 52% (n = 8,594) of CD patients without cancer. Immunomodulators were used in 12% (n = 220) of UC patients with cancer prior to IBD and in 27% (n = 9,555) UC patients without cancer. Exposure to medical therapy was visualised in Figure 1 Being diagnosed with cancer prior to CD diagnosis was negatively associated with exposure to immunomodulators (p = 0.005), while it increased the risk of receiving no medical treatment compared to CD patients without prior cancer (p &amp;lt; 0.001). The need for surgery was not associated with having cancer prior to CD diagnosis (p = 0.705). In UC patients, a negative association was found for both immunomodulators (p = 0.001) and for receiving no treatment (p &amp;lt; 0.001), while a positive association was found for both anti-TNF (p = 0.027) and anti-integrin therapy (p &amp;lt; 0.001) for UC patients with prior cancer. Prior cancer increased the risk of requiring surgery for UC patients (p &amp;lt; 0.001) Conclusion Patients with cancer prior to IBD were treated differently than patients without prior cancer as they received less immunomodulator therapy and more often received no medical therapy at all. UC patients more often required surgery, while this was not the case for CD patients. This supports the need for an individualised approach to immunosuppressive treatment for IBD patients with cancer.

Aneurysmal rupture in microscopic polyangiitis: a case-based review.

Microscopic polyangiitis (MPA) affects small and medium vessel, which sometimes leads to arterial aneurysms. In English database, only 15 reports refer to ruptured aneurysms in MPA. We experienced a fatal case with MPA who developed multiple visceral aneurysms, resulting in rupture of the hepatic aneurysm. For the better knowledge of aneurysmal rupture in MPA, we reviewed the feature of 16 cases, including our case. Organ involvement observed was glomerulonephritis 100%, pulmonary involvement 25%, peripheral neuropathy 25%, and purpura 12.5%. Locations of ruptured aneurysms were left gastric artery 31.25%, renal and hepatic artery 18.75% each, intracranial and splenic artery 12.5% each, and gastroepiploic and mesenteric artery 6.25% each. Median time to rupture was 45days after systemic symptom onset, and 15days after immunosuppressive treatment induction. Symptoms at rupture were visceral pain 68.75% and hemodynamic instability 62.5%. Pathological findings of ruptured aneurysms were acute vasculitis in 5, no evidence of active inflammation in 3. Causes of death were aneurysmal rupture in 5, treatment complications in 3, and total mortality rate was 50%. In conclusion, the initial presentation of MPA resulting in ruptured aneurysms tends to be renal-limited vasculitis. Aneurysms of abdominal medium-sized arteries tend to rupture, from 4weeks after systemic symptom onset to 2weeks after immunosuppressive treatment induction. Most aneurysms are less than 10mm in diameter, develop asymptomatically in a few days, and are recognized when they rupture. Early induction of immunosuppressive treatment has the potential to shrink aneurysms and prevent rupture.

Secondary cryofibrinogenemia is related to more severe microangiopathic involvement in systemic sclerosis: results from a retrospective observational study.

The aims of this study were to investigate the prevalence of cryofibrinogenemia in a cohort of patients with systemic sclerosis (SSc) regardless of clinical manifestations, who were admitted to our hospital and determine the associations among CF positivity, disease features and ongoing therapies. This was a monocentric and retrospective study. The inclusion criteria were a diagnosis of SSc (according to the ACR/EULAR 2013 classification criteria), regular administration of i.v. prostanoids, and CF testing between February 2020 and February 2022. Data on demographic, clinical, and immunological features and ongoing treatments were retrospectively collected. Categorical data were compared with the chi-square test or Fisher's exact test, while quantitative variables comparisons were carried out with Student's t test or Mann‒Whitney test. In total, 101 SSc patients were ultimately enrolled. The majority of patients were female (92.1%) and had the limited cutaneous form of SSc (81.2%). CF positivity was observed in 69.3% of the patients, whereas only 9% presented cryoglobulins and CF. CF positivity was negatively associated to RNAP3 antibodies (p = 0.027). No direct associations with specific clinical phenotypes were observed. No associations with immunosuppressive treatments were identified, however a positive association with nifedipine administration (p = 0.040), and a negative association with endothelin receptor antagonists (ERAs) plus phosphodiesterase-5 (PDE5) inhibitors regimen (p = 0.031) were observed. Macitentan administration was also associated to CF cryocrit ≥ 1% (p = 0.045). Among patients who were not treated with ERAs, an estimated pulmonary artery systolic pressure ≥ 30mmHg was significantly associated with CF positivity (p = 0.025). Moreover, a cryocrit ≥3% was associated with a relative risk of 3.44 (95% CI 1.26-9.39, p = 0.016) for digital amputation and 5.17 (95% CI 1.18-22.6, p = 0.029) for death. Isolated CF is a frequent phenomenon observed in SSc patients and is associated with a higher administration of vasoactive drugs, probably identifying a SSc clinical phenotype with a more severe microvascular involvement. Moreover, a higher cryocrit is associated with an increased risk of death and digital amputations. Screening SSc patients for CF would represent an opportunity to provide better therapeutic approaches by anticipating ERA administration in an earlier phase, thereby preventing the manifestation of severe microvascular involvement. Key Points • Cryofibrinogen is a cryoprotein that can cause microangiopathic damage. • Isolated cryofibrinogenemia is common in patients with systemic sclerosis. • SSc patients should be tested for cryofibrinogen because a high cryocrit (≥ 3%) is associated with death and/or digital amputation due to necrosis. • Cryofibrinogen is associated with indirect markers of pulmonary arterial hypertension in patients not treated with endothelin receptor agonists (ERAs). • ERAs could play a role in preventing cryofibrinogen damage.

A case of mucormycosis caused by Rhizopus microsporus in a renal transplant patient.

A 54-year-old man who had been on the kidney donor register for 32years received a kidney from a 9-year-old boy who had died of fulminant myocarditis. The post-operative course was poor, and hemodialysis was still needed after surgery. A kidney biopsy one hour after surgery showed a neutrophil-predominant inflammatory cell infiltrate localized to the peritubular capillaries (PTC) and acute tubular necrosis of the proximal tubule. Rhizopus species was detected in a perirenal white exudate taken 29days postoperatively, and the transplanted kidney was removed on postoperative day 45. The removed kidney showed fungal collection formation localized in the arteries and endotheliitis and embolization of the arteries. Renal damage caused by mucormycosis due to Rhizopus microspores was diagnosed. Mucormycosis is a fungal infection with a strong vascular affinity that develops along the vascular wall but does not extend beyond it. The infection leads to arterial infarction and organ failure. This report presents a rare case in which mucormycosis, which had been nested within the peritubular capillaries of the donor kidney, proliferated under immunosuppressive treatment but did so only in the artery, leading to infarction of the kidney. Neutrophilic collections within the PTC on one hour biopsy may be helpful in the early diagnosis of fungal infections.

The fate of the rectum in ulcerative colitis at index surgery and beyond—a contemporary cohort

PurposeProctectomy is frequently deferred at index colectomy for ulcerative colitis due to acuity or immunosuppressive treatments. The retained rectum remains symptomatic in over 50% with associated cancer risk. Management options include index or delayed proctectomy with or without restoration of continuity or surveillance. Comparative studies of perioperative outcomes and reasons for retaining the rectum are lacking.MethodsThis 13-year retrospective cohort assesses the fate of the rectum in 168 ulcerative colitis patients by analysing index proctectomy, staged proctectomy and retained rectal remnant determinants and outcomes. The primary outcome was the fate of the rectum. Secondary analysis included perioperative morbidity, length of stay and decision-making determinants.ResultsProctectomy was performed in 69% of patients, with 16.1% at index surgery. Restorative surgery rate was 44%. Index proctectomy patients were older (54 vs 37 years, p < 0.01), more co-morbid (59.3% vs 38.2%, p = 0.04) and likely to have elective surgery (81.5% vs 21.3%, p < 0.01) or neoplasia (33.3% vs 1.1%, p < 0.01). Outcomes after staged proctectomy were comparable, with age influencing restoration of continuity (33.5 vs 46 years, p < 0.01). Younger patients were indecisive on proctectomy, while those opting for endoscopic surveillance were older (median 65 years, p < 0.01), had more complications (64.3%, p = 0.23) and prolonged hospitalisation (median 15 days, p = 0.02) at colectomy.ConclusionsIndex proctocolectomy for ulcerative colitis is infrequently performed. Perioperative outcomes of restorative and non-restorative staged proctectomy are comparable. Perioperative experience at colectomy may influence patient decisions regarding future management of their rectum.

Serum bactericidal activity against meningococcus in patients with systemic lupus erythematosus.

Patients with systemic lupus erythematosus (SLE) are susceptible to infectious diseases owing to various immunosuppressive treatments and disease characteristics. Meningococcal infections progress rapidly with a high incidence of severe complications and mortality; therefore, meningococcal vaccination is needed. However, there is limited evidence regarding the immunity and immunogenicity of patients with SLE. This study aimed to analyze the serum bactericidal activity against meningococci in patients with SLE in two domestic institutions in Korea. Serum samples were collected from patients diagnosed with SLE (age < 19 years) at Seoul National University Children's Hospital and Ewha Womans University Mokdong Hospital in 2016-2018. Serum bactericidal activity against the four meningococcal serogroups was analyzed using a serum bactericidal assay with rabbit serum. The patients' demographic information, diagnostic history, and disease activity status were obtained from electronic medical records. The mean age of the 41 included patients was 20.3±5.4 (range, 10-35) years. All but one patient received steroids. The sera of most of the patients (34/41 [82.9%]) lacked bactericidal activity against serogroup A. Some patients showed bactericidal activity against serogroups C, W-135, and Y (63.4%, 56.1%, and 61.0%, respectively). There were no significant differences in the geometric mean indices based on complement consumption state or anti-double-stranded DNA antibody positivity. Although the sera of some patients exhibited serum bactericidal activity against meningococci, most remained seronegative. It is important that patients with SLE at risk of meningococcal infection receive appropriate vaccinations. Our findings serve as baseline serological data for meningococcal vaccination policies for patients with SLE.

NORSE secondary to anti-GAD65 antibody-positive encephalitis treated with novel adjunctive rapid titrationVNS protocol.

New Onset Refractory Status Epilepticus (NORSE) is a rare and severe condition characterized by refractory seizures in individuals without a prior history of epilepsy. This case report describes a 37-year-old woman diagnosed with anti-glutamic acid decarboxylase 65 (anti-GAD65) antibody-positive encephalitis-related NORSE. Her seizures were refractory to multiple interventions, including anti-seizure medications, anesthetics, immunotherapies, a ketogenic diet, and electroconvulsive therapy. Seizures recurred twice during the tapering of anesthetic medications. However, after 32 days of treatment, the seizures were successfully controlled. To maintain seizure control and facilitate the weaning of anesthetics, a Vagus Nerve Stimulator (VNS) was implanted using a novel rapid titration protocol. This allowed for the successful tapering of anesthetics by day 50, with no recurrence of seizures. At her 9-month follow-up, the patient remained seizure-free and had an improved quality of life. This case highlights that early initiation of immunosuppressive treatment may lead to a favorable prognosis. The novel application of VNS therapy assisted seizure control in NORSE, thus encouraging further research investigating the potential role of VNS in this condition. PLAIN LANGUAGE SUMMARY: New Onset Refractory Status Epilepticus (NORSE) is a rare and severe condition characterized by relentless seizures in individuals without a prior epilepsy history. This report shares the case of a 37-year-old woman with NORSE, associated with a high anti-glutamic acid decarboxylase 65 antibody titer. Her seizures were super-refractory, requiring multiple anti-seizure medications, anesthetics, immunotherapies, a ketogenic diet, and electroconvulsive therapy. Seizures recurred twice during the tapering of anesthetic medications. However, by hospital day 32, the seizures were successfully controlled with these interventions. To further stabilize seizure control and enable the successful discontinuation of anesthetics, a Vagus Nerve Stimulator (VNS) was implanted. The patient had no further seizures and gradually recovered back to her pre-disease baseline. This case suggests that a novel rapid VNS titration protocol could be a promising treatment option for NORSE, warranting further investigation.

Pathogenetic Mechanisms Linking Sarcoidosis to Lymphoma.

Sarcoidosis and lymphoma share immunopathological characteristics that suggest a complex, interconnected relationship. This article examines the multi-faceted mechanisms linking sarcoidosis to lymphoma, a phenomenon called sarcoidosis-lymphoma syndrome (SLS). SLS is hard to diagnose, requiring distinct criteria and imaging to differentiate overlapping features and histological differences. The co-occurrence of these diseases may be explained by genetic predispositions, immune dysregulation, and environmental factors that enhance malignancy risk. In active sarcoidosis, chronic inflammation and granuloma formation induce the production of cytokines that can contribute to lymphoma development. The role of macrophage polarization is also discussed. Immunosuppressive treatment prescribed in sarcoidosis patients, particularly corticosteroids and biological agents, may increase the susceptibility to lymphoproliferative malignancies. These common mechanisms emphasize the need for vigilant monitoring of lymphoma in patients with sarcoidosis, as this granulomatous disease can mimic and promote the development of lymphoma.

Efgartigimod efficacy and safety in refractory myasthenia gravis: UK’s first real-world experience

BackgroundWe report our experience of patients with generalised myasthenia gravis (gMG) treated with efgartigimod, an neonatal Fc receptor antagonist, under the Early Access to Medicine Scheme (EAMS) in the UK.MethodsData...