Pulse Cyclophosphamide Research Articles

Effect of Sequential Intravenous Pulse Cyclophosphamide-Azathioprine in Systemic Sclerosis-Interstitial Lung Disease: An Open-Label Study

Systemic sclerosis (SSc) is a rare connective tissue disorder of unknown aetiology. Pulmonary involvement contributes substantially to its morbidity and mortality. Treatment of pulmonary disease due to SSc remains unsatisfactory. We examined the effect of sequential six-month intravenous pulse therapy with cyclophosphamide (CYC) followed by azathioprine and low-dose corticosteroids on SSc associated interstitial lung disease (SSc-ILD). In a single-centre, prospective, observational, open-labelled study; nine patients (eight females, one male) with SSc-ILD were treated with intravenous pulse CYC (600mg/m(2) body surface area) at monthly interval for six cycles with oral prednisolone 10mg daily. Subsequently, azathioprine (2-3mg/Kg) was administered while continuing with the same dose of prednisolone. Primary end-points were forced vital capacity (FVC) and high resolution computed tomography (HRCT) scan of thorax score. Secondary end-points were quality of life measured by health assessment questionnaire-disability index (HAQ-DI) and six-minute walk distance (6WMD) test. After one year of observation, the FVC showed significant improvement (p=0.003). The 6WMD also improved significantly (p=0.0028). However, change in HRCT scan scoring and HAQ-DI score was not significant. Intravenous, pulse CYC followed by azathioprine along with low-dose corticosteroids produces significant improvement in FVC and 6WMD at 12-month follow-up without significant change in radiological manifestations and health status.

CD19-Targeted CAR-T Cells in Refractory Systemic Lupus Erythematosus: Safety, Efficacy, and Mechanistic Insights from the First Five Patients

Background: Systemic lupus erythematosus (SLE) is an auto-immune disease that is based on dysregulation of the adaptive immune system, autoantibody production and immune complex-mediated tissue damage. While treatment of SLE has substantially improved, a subset of patients experiences severe progressive disease despite T- and B-cell targeted therapy. Aim: For patients with refractory SLE, we aimed to achieve deep depletion of B cells using autologous CD19-CAR T cells with the goal of achieving an immunological reset and drug free remission. Methods: Five patients (4 women, 1 men) with SLE refractory to several immune-suppressive drugs including pulsed steroids, hydroxychloroquine, mycophenolate, cyclophosphamide, intravenous immunoglobulins, rituximab, and belimumab were treated with CD19 CAR T cells in a compassionate use program. Mean patient age was 21.8 ± 2.3 years, mean disease duration was 4.6 ± 3.0 years and mean SLE disease activity index (SLEDAI) was 11.8±3.8. Autologous T cells were transduced with a lentiviral anti-CD19 CAR vector composed of the FMC63 scFv, a CD8-derived hinge region, TNFRSF19-derived transmembrane domain, CD3ζ intracellular domain, and 4-1BB co-stimulatory domain and expanded within the local GMP facility utilizing the closed automated CliniMACS Prodigy® system (Miltenyi Biotec, Bergisch Gladbach, Germany). CAR T cells were re-infused at a dose of 1x106 CAR T cells/kg body weight after lymphodepletion with fludarabine/ cyclophosphamide. All SLE treatments with the exception of low dose prednisolone was stopped before CAR-T cell administration. After CAR-T cell treatment, no other immune-modulatory or immune-suppressive treatment was given. Tolerability was assessed following international guidelines. Results: Despite long-lasting high dose steroid treatment, sufficient numbers of CD19 CAR-T cells could be generated from 5/5 SLE patients. Lymphodepletion led to expected reduction of white blood cells. Following lymphodepletion, CAR T cells expanded in vivo with a peak on day 9 and a deep depletion of B cells was achieved in all patients. Bone marrow toxicity towards non-B cells was short and all patients recovered neutrophils (>500/nL) before day 14 post CAR T cells. Only mild CRS of °I occurred in all five patients. One patient received a single dose of tocilizumab due to persisting fever >24 hours. There were no ICANS, no CRS of any organ, and no infections. Remission of SLE according to DORIS criteria was achieved in all 5 patients after 3 months and the mean (±SD) SLEDAI score after 3 months was 0.4±0.9. Laboratory parameters normalized in all SLE patients after CAR-T transfer including seroconversion of anti-dsDNA antibodies and all patients were free of immune-suppressive drugs by month 3. One patient presented with proteinuria at month 4. Kidney biopsy as well as serum diagnostics showed no signs of SLE. After a steroid pulse, proteinuria went back to normal. Despite reconstitution of B cells no relapse of SLE was observed in the follow up of any of the patients which are now 17, 12, 8, 7, and 5 months after CAR T cell therapy. Reappearing B cells were naïve and showed non-class switched B cell receptors. While pre-existing vaccine-specific antibodies towards measles or VZV persisted, several auto-reactive antibodies were abrogated. Quality of life was poor at decision to treatment and improved substantially at month three. Improvement was mostly driven by abrogation of joint pain and of fatigue. Conclusions: Taken together, the preliminary data from this pilot study show that CD19 CAR T-cell therapy is very well tolerated in patients with a non-malignant B cell derived autoimmune disease and induce rapid remission of severe refractory SLE. Longer follow-up and higher patient numbers from controlled clinical trials are needed to confirm these promising results.

Intravenous Cyclophosphamide Therapy for Anti-IFN-γ Autoantibody-Associated Talaromyces marneffei Infection.

High titers of anti-interferon-γ autoantibodies (AIGAs) are an important factor leading to persistent, relapsed, and refractory infections in HIV-negative hosts infected with Talaromyces marneffei (TM). We report 5 patients treated with pulses of high-dose intravenous cyclophosphamide (IVCY) who were followed for 2 years. Before IVCY therapy, all patients had multiple relapses, with a median (interquartile range [IQR]) of 2 (1-3) instances of relapse. The median serum AIGA titers (IQR) were 58 753 (41 203-89 605) ng/mL at diagnosis, 48 189.4 (15 537-83 375) ng/mL before IVCY therapy, and 10 721.2 (5637-13 245) ng/mL at the end of IVCY therapy (P < .05). After 3 months of follow-up, the median AIGA titers (IQR) rose gradually to 21 232.6 (9896-45 626) ng/mL, and to 37 464.2 (19 872-58 321) ng/mL at 24 months (P < .05). Five patients discontinued antimicrobial therapy within 3-12 months after completion of IVCY therapy, but only 1 patient had a relapse. In conclusion, pulses of short-term and high-dose IVCY can effectively reduce AIGA titers.

Incidence of acute exacerbation in patients with interstitial lung disease after COVID-19 vaccination

Acute exacerbations due to COVID-19 vaccination in patients with interstitial lung disease (ILD) have been reported, but their incidence is unknown. We investigated the incidence of exacerbations of ILD and respiratory symptoms due to the mRNA COVID-19 vaccines. A questionnaire survey was conducted on adverse reactions to the mRNA COVID-19 vaccination in 545 patients with ILD attending our hospital and retrospectively examined whether the eligible patients actually developed acute exacerbations of ILD induced by the vaccine. Of the 545 patients, 17 (3.1%) patients were aware of the exacerbation of respiratory symptoms, and four (0.7%) patients developed an acute ILD exacerbation after vaccination. Of the four patients who experienced exacerbations, two had collagen vascular disease-associated ILD, one had nonspecific interstitial pneumonia, another had unclassifiable idiopathic pneumonia, and none had idiopathic pulmonary fibrosis. Four patients were treated using steroid pulse therapy with a steroid taper, and two of the four also received intravenous cyclophosphamide pulse therapy. Tacrolimus was started in one patient with myositis-associated interstitial lung disease. Eventually, all patients exhibited improvement with immunosuppressive treatment and were discharged. COVID-19 vaccination for patients with ILD should be noted for developing acute exacerbations of ILD with low incidence, although manageable with early diagnosis and treatment.

Immunosuppressive therapy versus supportive care in IgA nephropathy patients with stage 3 and 4 chronic kidney disease.

The use of immunosuppressive therapy for immunoglobulin A nephropathy (IgAN) patients with stage 3 or 4 chronic kidney disease (CKD) is controversial. We performed a monocentric retrospective study on 83 consecutive IgAN patients with stage 3 or 4 CKD and proteinuria ≥0.75 g/d (age 41 [33-56] years, 72% male, estimated glomerular filtration rate 36.1 [25.4-47.5] mL/min/1.73 m2) who received uncontrolled supportive care (Supp) (n = 36), corticosteroids/corticotherapy (CS) (n = 14), or CS combined with monthly pulses of cyclophosphamide (CS + CFM) (n = 33) between 2010 and 2017. Patients were followed until composite endpoint (doubling of serum creatinine, end-stage kidney disease (dialysis or kidney transplant) or death, whichever came first) or end of study (January 2020). Patients were followed for a median of 29 (95% confidence interval = 25.2-32.7) months, and 12 (15%) patients experienced the composite endpoint. Within the limitation of a retrospective study, our results suggest no benefit from immunosuppressive therapy in patients with IgAN with stage 3 and 4 CKD as compared with supportive care. There were no differences between the 3 studied groups regarding age, estimated glomerular filtration rate, proteinuria, Oxford classification score, arterial hypertension, and therapy with renin-angiotensin system inhibitors. Mean kidney survival time for the entire cohort was 81.0 (95% confidence interval = 73.1-89.0) months, without significant differences between the 3 groups. In univariate and multivariate Cox regression analysis adjusted for IgAN progression factors, immunosuppressive therapy was not associated with better kidney survival when compared with supportive therapy.

Fatal neuromyelitis optica after COVID-19 vaccination

We read with interest the report by Motahharynia and coworkers (Motahharynia et al., 2022Motahharynia A. Naghavi S. Shaygannejad V. Adibi I. Fulminant neuromyelitis optica spectrum disorder (NMOSD) following COVID-19 vaccination: a need for reconsideration?.Mult. Scler. Relat. Disord. 2022; 104035https://doi.org/10.1016/j.msard.2022.104035Abstract Full Text Full Text PDF Scopus (2) Google Scholar) that showed a new-onset Neuromyelitis Optica diagnosis with a fatal outcome after COVID-19 vaccination. The authors report a 70-year-old woman who exhibited neurological symptoms (numbness and weakness in her left limbs) seven days after receiving the third dose of a SARS-CoV-2 inactivated vaccine (Sinovac: CoronaVac). She rapidly progressed to paraplegia, while spinal cord magnetic resonance imaging showed an extensive hemorrhagic lesion in the cervical cord (C1-C7). Cerebrospinal fluid analysis was unremarkable (including the absence of oligoclonal bands), but the patient tested positive for anti-Aquaporin-4. Unfortunately, the patient was refractory to all therapeutic interventions (methylprednisolone pulse therapy, plasma exchange and cyclophosphamide) and died two months after hospitalization (Motahharynia et al., 2022Motahharynia A. Naghavi S. Shaygannejad V. Adibi I. Fulminant neuromyelitis optica spectrum disorder (NMOSD) following COVID-19 vaccination: a need for reconsideration?.Mult. Scler. Relat. Disord. 2022; 104035https://doi.org/10.1016/j.msard.2022.104035Abstract Full Text Full Text PDF Scopus (2) Google Scholar). Neuromyelitis Optica Spectrum Disorder (NMOSD) is rare autoimmune neuro-inflammatory disease that affects the central nervous system (CNS) with predilection for causing lesions in the optic nerves/spinal cord. Usually, the median age for onset is 40-years, although the disease can occur at any age as proposed in this report. CNS-damage during NMOSD is mainly attributed to the presence of autoantibodies such as specific NMO-IgG against astrocyte-end-feet Aquaporin-4 (anti-AQP4) in association with complement system, innate cells (e.g., eosinophils/neutrophils) and pro-inflammatory cytokines (Jarius et al., 2020Jarius S. Paul F. Weinshenker B.G. Levy M. Kim H.J. Wildemann B. Neuromyelitis optica, Nature Reviews Disease Primers. Springer US, 2020https://doi.org/10.1038/s41572-020-0214-9Crossref Scopus (120) Google Scholar). Considering the accumulated reports during the pandemic, we speculate that antiviral immune responses against SARS-CoV-2 natural infection/immunization may trigger CNS-damage in some individuals. Here, we hypothesize that repetition of vaccination with the same vaccine type (inactivated SARS-CoV-2) evoked a robust antiviral immune response including, among others: (I) effector or even senescent/exhausted CD8+ T lymphocytes with massive cytotoxic capacity (e.g., granzymes); (II) pro-inflammatory cytokines derived from CD4+ Th1 (IFN-γ, TNF-α) and Th17 (IL-17, IL-22); (III) neutrophil extracellular traps (NETs) and pro-inflammatory cytokines (e.g., IL-1, IL-6, TNF-α) derived from innate immune cells. All of these components are known to promote blood-brain barrier disruption. In parallel to neutralizing antibodies against SARS-CoV-2, autoreactive clones of B cells may differentiate in plasma cells and release anti-AQP4 due to loss of peripheral autotolerance. Furthermore, it is not possible so far to exclude that neutralizing antibodies against SARS-CoV-2 may also exhibit cross-reactivity with self-antigens in the CNS. More broadly, post-COVID syndrome as well as manifestations after COVID-19 vaccination may share common immunological features (summarized in Fig. 1). The increasing number of reports suggest the occurrence of new-onset/exacerbating NMOSD and related disorders, such as Multiple Sclerosis, in the context of SARS-CoV-2 natural infection/immunization (Finsterer, 2022Finsterer J. Neuromyelitis optica complicating COVID vaccinations.Mult. Scler. Relat. Disord. 2022; 62103809https://doi.org/10.1016/j.msard.2022.103809Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar; Fragoso et al., 2022Fragoso Y.D. Gomes S. Gonçalves M.V.M. Mendes Junior E. Oliveira B.E.S. Rocha d. Santos C.F. dos G.A.C. Tauil C.B. Araujo R.V. Peron J.P.S. New relapse of multiple sclerosis and neuromyelitis optica as a potential adverse event of AstraZeneca AZD1222 vaccination for COVID-19.Mult. Scler. Relat. Disord. 2022; 57: 1-5https://doi.org/10.1016/j.msard.2021.103321Abstract Full Text Full Text PDF Scopus (8) Google Scholar; Khayat-Khoei et al., 2022Khayat-Khoei M. Bhattacharyya S. Katz J. Harrison D. Tauhid S. Bruso P. Houtchens M.K. Edwards K.R. Bakshi R. COVID-19 mRNA vaccination leading to CNS inflammation: a case series.J. Neurol. 2022; 269: 1093-1106https://doi.org/10.1007/s00415-021-10780-7Crossref PubMed Scopus (32) Google Scholar). Despite the need for continuous massive vaccination against SARS-CoV-2, which proved to be effective and safe, we should be aware of rare, aggressive and even fatal CNS-manifestations such as NMOSD in a small proportion of individuals. V.O.B. and C.L.Y. wrote the manuscript. Was in accordance with ethical guidelines. Not applicable. Not applicable. Not applicable. The author declares no conflicts of interest.

Profile and Outcome of Children with Opsoclonus Myoclonus Ataxia: A Tertiary Care Hospital Experience from India

AbstractOpsoclonus myoclonus ataxia syndrome (OMAS) is a rare but treatable, often paraneoplastic neuroimmunologic condition. This is a retrospective chart review of 8 patients diagnosed in the past 11 years at a tertiary care hospital. The mean age of children with OMAS was 21.2 ± 8 months. There was a female preponderance (62.5%). Median symptom duration was 24.5 days (interquartile range [IQR] 12.7; 97.5). All patients had ataxia and irritability; 6 had opsoclonus.An underlying neurogenic tumor was identified in 87.5% (⅞) of the patients by computed tomography (CT)/magnetic resonance imaging. Neuroblastoma was detected in ⅘ with normal 24-hour urinary vanillylmandelic acid and 2 had negative metaiodobenzylguanidine scan.All patients received adrenocorticotropic hormone/steroids for a median of 9.5 months (IQR 5.3; 13.5) with clonazepam. Five received intravenous immunoglobulin (IVIG), including repeated cycles in ⅘. Two received rituximab. One child with relapsing-remitting course received pulse dexamethasone and cyclophosphamide, resulting in improvement. Clonazepam restored ambulation in one with delayed diagnosis and failure of response to steroids. Six patients underwent tumor resection and four needed chemotherapies.Median follow-up was 15 months (IQR 10.7; 23.2). Mean OMAS-severity scale reduced from 10 to 1.4 in the IVIG group and 10.6 to 5.3 in those who did not receive IVIG. Cognitive delay and behavioral issues were seen in 100% treated with steroids only; 50 and 25%, respectively, treated with multimodal immunotherapy. Five had relapses, one with tumor recurrence.Thorax and abdomen CT scan was found to be a sensitive tool for tumor detection. Better motor and cognitive behavioral outcome were noted in patients who received adjunctive IVIG.Future studies on optimum investigation and treatment protocol in various resource settings are needed.

Safety and effectiveness of mepolizumab therapy in remission induction therapy for eosinophilic granulomatosis with polyangiitis: a retrospective study

ObjectivesTo investigate the safety and effectiveness of mepolizumab (MPZ), an anti-interleukin-5 antibody, as remission induction therapy for severe eosinophilic granulomatosis with polyangiitis (EGPA).MethodsThe clinical courses of patients with severe EGPA over 6 months were retrospectively investigated and compared between patients treated with high-dose corticosteroid (CS) plus MPZ therapy (MPZ group, n = 7) and those treated with high-dose CS plus intravenous cyclophosphamide (IVCY) pulse therapy (IVCY group, n = 13). The primary endpoints were the MPZ retention rate and the IVCY completion rate. The secondary endpoints were adverse events and changes in the Birmingham Vasculitis Activity Score (BVAS), Vascular Damage Index (VDI), eosinophil counts, and concomitant CS doses, and the extent and rates of these changes were compared between the MPZ and IVCY groups.ResultsRegarding the primary endpoints, the MPZ retention rate was 100%, and the IVCY completion rate was 61.5%. Regarding the secondary endpoints, adverse events were detected in 2/7 patients (28.6%) in the MPZ group and 7/13 patients (53.8%) in the IVCY group. BVAS and eosinophil counts significantly decreased in both groups at and after month 1, but there was no significant difference in the magnitude of changes between the two groups. VDI scores did not significantly increase in either group, and the degree of changes did not significantly differ between the two groups. Although concomitant CS doses significantly decreased at and after month 1 in both groups, the rates of decrease in CS doses at and after month 3 were significantly higher in the MPZ group.ConclusionsThis study suggested that the use of MPZ as remission induction therapy for severe EGPA might be safe and effective for controlling disease activity and reducing CS doses.

Study on short term treatment response of connective tissue disease related interstitial lung disease

Background: Interstitial lung disease is a major cause of morbidity and mortality in patients suffering from connective tissue diseases. Early detection and prompt recognition of symptoms with appropriate treatment is necessary for effective control of the disease and for better prognosis and long-term survival. Aim: To study the short-term treatment response of patients with connective tissue disease-related interstitial lung disease. Objectives: The purpose of this study was to evaluate the treatment response of connective tissue disease-related interstitial lung disease patients treated with intravenous pulses of cyclophosphamide (CYP) based on improvements in lung function: forced vital capacity (FVC)% predicted, forced expiratory volume in the first second (FEV1)% predicted, dyspnea Borg scale and 6-minute walk test. To determine the factors affecting the treatment outcomes like age, sex, duration of the connective tissue disease, type of connective tissue disease, HRCT type, and presence of PAH. Methods: A cohort study was conducted in the Department of General Medicine, Rheumatology, and Pulmonology at the Amala Institute of Medical Sciences, Thrissur, and Kerala from November 2015 to June 2017 that evaluated 74 patients having connective tissue disease-related ILD. A detailed history and a thorough clinical examination were done.

Hypertrophic pachymeningitis with co-occurrence of anti-neutrophil cytoplasmic antibodies and immunoglobulin G4 seropositivity: Case report and literature review

We report an extremely rare case of hypertrophic pachymeningitis in which a 71-year-old man presented with an intractable recurrent headache for >1 year. During this period, he became positive for immunoglobulin G4 and proteinase 3-antineutrophil cytoplasmic antibodies. Contrast-enhanced magnetic resonance imaging showed characteristic diffuse thickening of the dura. Symptoms were improved by intravenous methylprednisolone (500 mg per day for 5 days) and cyclophosphamide pulse therapy during corticosteroid withdrawal; he remained symptom-free during 1-year follow-up. This case suggests that this disease can be treated by corticosteroids combined with immunosuppressive agents.

MO262: Intravenous Cyclophosphamide for High-Risk Primary PLA2R-Positive Membranous Nephropathy

Abstract BACKGROUND AND AIMS The mainstay of treatment for high-risk primary membranous nephropathy (MN) is the cyclic steroid-oral cyclophosphamide (CYC) regimen (modified Ponticelli regimen). However, there has been increasing awareness of serious treatment-related toxicity. Intravenous CYC offers the potential benefit of lower cumulative dose and a lower rate of adverse events. Therefore, we aimed to evaluate the efficacy and safety of intravenous CYC in high-risk primary PLA2R-positive MN. METHOD We retrospectively examined the renal outcome on 1 August 2020 of 40 adult patients [age 57 (interquartile range (IQR) 48–69] years, 70% male, serum creatinine 1.1 (IQR 0.9–1.3) mg/dL) who were diagnosed with MN by kidney biopsy and had positive serum anti-PLA2R ab at diagnosis [median titer 257.3 (IQR 86.4–603.0) RU/mL] during 2016–2019. We included only patients with first episode MN at high risk according to 2021 KDIGO guideline, and who were followed for at least 6 months. All patients received CYC at a dose of 600 mg/m2 every 4 weeks for up to 6 months in conjunction with prednisone at a dose of 0.75 mg/kg daily (up to 60 mg/day) with gradual tapering to 0.5 mg/kg/day by 3 months and 0.1 mg/kg/day by 6 months. The outcomes were as follows: kidney survival defined as kidney replacement therapy (KRT) initiation; partial (proteinuria 0.5–3.5 g/24 h) or complete remission (proteinuria &amp;lt; 0.5 g/24 h and serum albumin ≥ 3.5 g/dL)—whichever came first. RESULTS Patients were followed for a median of 26 (95% CI 19.2–32.7) months, and 27 (67%) patients reached a form of remission with complete remission observed in 15 patients (37%) and partial remission in 12 (30%). Cumulative remission rates were 24% after 6 months, 57% after 12 months and 77% after 24 months. Median time to cumulative remission was 11.0 (95%CI 6.6–15.3) months. Absence of response was observed in 13 patients (33%), three (8%) of whom started KRT after a mean follow-up of 4.2 (95% CI 3.9–4.5) years. Patients who did not respond to immunosuppression had more severe nephrotic syndrome [24 h proteinuria 12.5 (IQR 7.9–15.0) versus 6.1 (IQR 4.0–8.7) g/24 h, P = .002; serum albumin 2.1 (IQR 2.0–2.3) versus 2.4 (IQR 2.0–2.8) g/dL, P = .04] at diagnosis, but similar titer of PLA2R ab [417 (IQR 258–690) versus 185.7 (IQR 85–439) RU/mL, P = .2]. In the Cox proportional hazard model, only lower serum albumin [HR 3.9 (95% CI 1.2–12.3), P = .01] was retained as a risk factor for absence of remission, while 24 h proteinuria [HR 1.0 (95% CI 0.9–1.0), P = .6], baseline PLA2R ab titer [HR 1.0 (95% CI 0.9–1.0), P = .7] and kidney biopsy chronicity index [HR 1.0 (95% CI 0.8–1.2), P = .5] were not. Clinical relapse occurred in 3 of 27 (11%) patients at a mean of 11 months after treatment discontinuation. During the follow-up period five (13%) patients died. Cardiovascular disease (three patients) and infections (two patients) were the main causes of death; apparently not related to CYC treatment. Median cumulative dose of CYC was 7.2g. None of the patients required blood transfusions or granulocyte–colony-stimulating factor for the management of myelosuppression. Two patient developed community-acquired pneumonia after the first CYC dose and required hospital admission. When the infection resolved, immunosuppressive treatment was successfully completed. CONCLUSION Monthly intravenous CYC pulses in patients with high-risk primary PLA2R-positive MN seems to be an effective and safe alternative for treatment. Also, in these patients, lower serum albumin at diagnosis is an early marker for lack of remission.

Anti-NMDAR Encephalitis with Poor Recovery on Steroid Pulse and IVIg: Practical Approach to Intensive Immunotherapy

Anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) is a well-defined autoimmune encephalitis that is responsive to early intensive immunotherapy. Recent international consensus regarding treatment of NMDARE provides a practical treatment algorithm for immunotherapy escalation, while considering a patient's age, disease severity, and other background information. First-line immunotherapy, which includes an intravenous (IV) corticosteroid pulse with the addition of either intravenous immunoglobulins (IVIg) or plasma exchange, should be offered to all NMDARE-diagnosed patients as soon as possible. In cases where insufficient improvement follows a repeat of the first-line combination therapy (assessed on day 14 after the initial treatment), second-line immunotherapy comprising rituximab or an IV cyclophosphamide pulse (IVCPA) is considered. Per the recent expert consensus, rituximab is preferred to IVCPA as the second-line drug of choice, although the use of either drug in the treatment of NMDARE is off-label. Most patients show gradual improvement in the first few weeks following the introduction of second-line therapy, although repeated and alternating use of both drugs is often required. Some patients, whose NMDARE was refractory to the aforementioned therapies, have also been successfully treated with tocilizumab or bortezomib. Moreover, several international clinical trials involving rituximab, inebilizumab, bortezomib, and rozanolixizumab in the treatment of autoimmune encephalitis (AE, which includes NMDARE) are being conducted to establish high-grade evidence for the treatment of AE.

Disease Severity and Response to Induction Therapy in Hispanic Patients With Antineutrophilic Cytoplasmic Autoantibody-Associated Vasculitis-Related Diffuse Alveolar Hemorrhage.

ObjectivesWe examined the response to induction therapy of Hispanic patients with antibody-associated vasculitis (AAV)-related diffuse alveolar hemorrhage (DAH). This study aimed to determine the severity of disease at presentation and the response to induction therapy in our patient population.MethodsWe retrospectively reviewed the clinical data of Hispanic patients hospitalized with antineutrophil cytoplasmic antibody (ANCA) vasculitis between October 1, 2010, and December 31, 2021. We identified 98 Hispanic patients hospitalized with AAV and 19 admitted with AAV-related DAH. The Birmingham Vasculitis Activity Score (BVAS) was obtained from all patients on presentation.ResultsBased on the 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides, 12 patients met the diagnostic criteria for microscopic polyangiitis (MPA) and seven met the criteria for diagnosing granulomatosis with polyangiitis (GPA). All patients received methylprednisolone therapy. Induction therapy consisted of cyclophosphamide pulse therapy (n=3), cyclophosphamide plus plasmapheresis (PLEX) (n=1), rituximab induction therapy (n=8), and rituximab induction plus plasmapheresis (n=6), and one patient received one dose of cyclophosphamide followed by rituximab plus plasmapheresis. The average BVAS was 25.53 at presentation. Survival at six months included 67% (n=2) treated with cyclophosphamide alone, 75% (n=6) treated with rituximab alone, and 50% (n=3) treated with rituximab plus PLEX. The patient who received an initial loading dose of cyclophosphamide followed by rituximab plus PLEX did survive for six months; however, the patient treated with cyclophosphamide plus PLEX did not have early survival.ConclusionsHispanic patients with ANCA-associated vasculitis present with a more severe disease burden at presentation based on BVAS. Approximately 37% of our patient population had early death (death at <6 months) despite adhering to the standard of care for induction therapy. Due to the more significant disease burden at presentation, it is vital to include ethnic minorities in large clinical trials to help improve outcomes in these patient populations.

P046 A rare case of peripheral T cell lymphoma presenting as peripheral neuropathy &amp; myositis

Abstract Background/Aims Peripheral T cell Lymphomas are a heterogeneous group of very aggressive and rare lymphomas in the western world accounting for 5% to 15% of non-Hodgkin lymphomas. Inflammatory myositis and nephropathy associated with hematological malignancies are extremely rare. Methods A 64-year-old gentleman presented with progressive neuropathy with pain and numbness in feet, clawing in both hands, muscle weakness and wasting. He also noticed a rash in his groin and scrotum (erythematous) and new erectile dysfunction along with Raynaud’s, dry eyes, and unintentional weight loss over a year. His paternal uncle suffered from peripheral neuropathy. He had splinter hemorrhage and telangiectasia on general examination. Neurological examination revealed clawing of hands, muscle wasting in his hands and legs in distribution of right median, ulnar, left radial, bilateral sural and bilateral peroneal nerve. Results He had normal routine blood tests (FBC, U&amp;Es and LFTS and CRP). Rheumatology work up revealed CK of 204, LDH 317, ANA 1: 640 titre, negative ENA, dsDNA, ANCA, RF, anti CCP antibodies, myositis blot, normal C3, C4, protein electrophoresis, IgG sub classes and negative para neoplastic screen including anti Ri, anti Yo and anti Hu and a negative urine dip for blood or proteins. Echocardiogram revealed small pericardial effusion. PET scan showed markedly avid lesion in ascending colon proven to be low-grade tubulovillous adenoma on biopsy. MRI of thighs showed inflammatory change consistent with myositis and nerve conduction studies has revealed mono neuritis multiplex. Peroneal nerve biopsy showed small vessel lymphocytic vasculitis followed by skin biopsy of thigh and shin consistent with features of lymphocytic vasculitis and angiocentric NK cell lymphomatous changes. On the bases of his presenting symptoms and investigations, he was treated with 60mg of oral prednisolone and pulsed cyclophosphamide at dose of 15mg /kg for 6 cycles for multisystemic inflammatory condition causing mono neuritis multiplex and myositis. His cyclophosphamide was stopped after 4 cycles as there was no response to treatment and MDT review confirmed that skin and nerve biopsies features were consistent with peripheral T cell lymphoma. Further treatment was with CH(O)P (minus vincristine) under the care of oncologists. Conclusion Peripheral T cell lymphoma (PTCL) is a rare and aggressive heterogeneous group of lymphomas. Risk factors include family history of hematological malignancies and smoking. Rashes may be the antecedent finding in about 20% to 50% of angioimmunoblastic T cell lymphoma patients, with skin manifestations ranging from urticarial lesions to nodular tumor. Patients with cutaneous T cell lymphomas often present with “chronic dermatitis” which is resistant to therapy, early-stage having a predilection for folds and non-exposed sun areas. Cancer associated inflammatory myopathies are rare syndromes occurring in 10%-30% of all malignancies and inflammatory myopathies associated with hematological malignancies are even rarer entities. Disclosure M. Ashraf: None. J. David: None.

P050 Rapidly worsening subcutaneous oedema in a young boy: a case of juvenile dermatomyositis

Abstract Background/Aims Juvenile onset dermatomyositis (JDM) is a rare disease with an incidence of 2-4 per million. The presentation includes skin manifestations of heliotrope rash, Gottron's papules, nail fold changes, bilateral peri-orbital or upper eyelid edema and focal mild facial swelling with muscle weakness. Widespread and generalized subcutaneous oedema is a rare presentation in JDM. Methods A 4-year-old previously healthy boy presented to a tertiary care hospital in Sri Lanka with generalized rash involving the face, limbs and trunk for seven days associated with facial puffiness and hair loss. He also complained of generalized myalgia and irritability and refused to walk. He did not have dysphagia, dysphonia or shortness of breath. He had a prodromal febrile illness two weeks back that had been treated as a viral fever. He had evidence of palatal ulcers, chelitis, malar rash, erythema of eyelids, eyelid swelling and necrotic vasculitic lesions in peripheries. He had tenderness over his thighs with muscle power being MRC grade 3/5 in the proximal muscles of his lower limbs. Arm and neck flexors’ power was normal. Results His ESR was raised at 35 mm/hour and CRP was normal. His CPK was 2726 U/l, AST was raised at 931 U/l, ALT was 511 U/l and albumin was 33 g/l. His ANA, dsDNA and ENA panel was negative. A myositis immunoblot could not be done due to financial constraints. An EMG showed evidence of myositis in his proximal muscles. He fulfilled the criteria for juvenile dermatomyositis based on Bohan and Peter’s criteria. He was treated with high dose steroids, dexamethasone 2 mg 6 hourly. While receiving steroids he deteriorated with worsening subcutaneous oedema of face and neck with high fever spikes. The oedema progressed to involve his whole body. His muscle power deteriorated with involvement of his arms. A venogram ruled out any obstructive venous disease. A CT CAP ruled out any underlying malignancy. His 2D echo revealed normal heart function. He was converted to IV Methylprednisolone 30 mg/kg and was started on plasmapharesis. He improved after the 3rd cycle and was started on cyclophosphamide infusions. He received six cyclophosphamide pulses with a tapering course of steroids. He remains controlled in his disease with no new muscle weakness or skin manifestations. However, he remains steroid dependent and is awaiting treatment with Rituximab. Conclusion Subcutaneous oedema in JDM is attributed to a vasculopathy. This is associated with severe rapidly progresssive disease with high mortality and requires aggressive immunosuppression. As seen in our patient disease is resistant to conventional treatment. Early recognition leads to better outcomes in these patients. Disclosure S. Janagan: None. W.A.E. Udeshika: None. P.M. Samarasinghe: None. J.D. Jagoda: None.

P055 Granulomatosis with polyangiitis presenting as compressive cervico-thoracic myelopathy

Abstract Background/Aims Granulomatosis with polyangiitis (GPA), a subgroup of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), is a small vessel vasculitis, characteristically associated with granulomatous inflammation. It demonstrates an increased propensity for pulmonary and renal involvement, in addition to ear, nose and throat disease. Central nervous system involvement is rare. Methods We present the case of a 64-year-old male who presented with a 6-week history of upper back pain and gradual deterioration in his gait, with associated lower limb paraesthesia and leg weakness. Results His background medical history is significant for a right sided mastoidectomy, in addition to recurrent episodes of sinusitis, with nasal crusting. He also had a history of frequent epistaxis requiring cauterisation. Neurological examination was significant for a spastic paraparesis, with MRC grade 3/5 weakness in lower limb flexors bilaterally, bilateral lower limb hypertonia, sustained clonus, hyperreflexia, and extensor plantar responses. Sensory examination revealed a mid-thoracic sensory level. Other systems examination were normal. Routine blood tests revealed normal full blood count, renal and liver indices. Inflammatory markers were elevated: C-reactive protein 43 mg/L (0-5 mg/L) and erythrocyte sedimentation rate 80 mm/hr (0-15 mm/hr). Gadolinium enhanced MRI spine and brain revealed a circumferential enhancing mass-like lesion extending from C5 to T9 with compression of the spinal cord at T2 and T3 levels, with normal brain parenchyma. There was evidence of mild sinusitis in the maxillary sinuses. CT of the thorax, abdomen and pelvis was normal. Urinalysis was normal, as was his urinary protein creatinine ratio, and there was no evidence of red cell casts. ANCA revealed a strongly positive perinuclear pattern (p-ANCA) with a markedly elevated myeloperoxidase (MPO) autoantibody, 117 (0-10 units/mL). Proteinase-3 (PR3) was negative. On identification of spinal cord compromise, the patient underwent urgent neurosurgical evaluation, and surgical exploration. During surgery, direct visualisation revealed the lesion to be solid and mass-like and samples of the tissue excised were sent for pathological analysis. Histopathological studies revealed a dense lymphocytic infiltrate, with fibrinoid necrosis of blood vessel wall consistent with vasculitis. There was no evidence of granuloma formation. A diagnosis of MPO positive GPA causing compressive myelopathy was made. He was commenced on high dose glucocorticoids which were tapered as per PEXIVAS reduced dose regimen. In tandem, he was commenced on pulsed intravenous cyclophosphamide. Within days of treatment initiation his neurological status improved, and he is currently engaging in rehabilitation. At his most recent review he was walking independently with crutches. Conclusion Our case highlights a rare cause of myelopathy but one that should enter the differential diagnosis when assessing a patient presenting with myelopathy, particularly with a mass-like lesion on neuroimaging. It should be treated aggressively and as part of the life-threatening organ involvement algorithm. Disclosure P. Harkins: None. R. Field: None. S. Hutchinson: None. R. Conway: None.

Diffuse blistering rash with ocular involvement

Diffuse blistering rash with ocular involvement

Treating Patients With ANCA-Associated Vasculitis and Very Severe Renal Injury With an Intensified B Cell Depletion Therapy: Comparison With a Control Cohort Receiving a Conventional Therapy.

Rituximab (RTX), an anti-CD20 monoclonal antibody, has shown to be an effective induction treatment for small-vessel vasculitides associated with antineutrophil cytoplasm antibodies (AAV) in both newly diagnosed and relapsing patients. However, the role of RTX in the management of the most severe cases of AAV remains to be fully elucidated. The aim of this study was to assess both safety and efficacy of an intensified B-cell depletion therapy (IBCDT) protocol, including RTX, cyclophosphamide (CYC), and methylprednisolone pulses without additional maintenance immunosuppressive therapy in a cohort of 15 AAV patients with the most severe features of AVV renal involvement (as <15 ml/min GFR and histological findings of paucimmune necrotizing glomerulonephritis with more than 50% crescents of non-sclerotic glomeruli at the renal biopsy). Results of the IBCDT regimen have been compared to those obtained in a control cohort of 10 patients with AAV treated with a conventional therapy regimen based on oral CYC and steroids followed by a prolonged maintenance therapy with azathioprine (AZA). Plasma exchange was equally employed in the study and the control group. Complete clinical remission (BVAS 0) was observed at 6 months in 14 of 15 patients treated with IBCDT (93%). All cases who achieved a complete clinical remission experienced a depletion of peripheral blood B cells at the end of therapy. Of the 10 dialysis dependent patients at onset, 6 subjects (60%) experienced a functional recovery allowing the suspension of dialysis treatment. When compared to the control group, no statistically significant difference was observed in patients treated with IBCDT in terms of overall survival, 6-month therapeutic response rate, and 6-, and 12-month functional renal recovery. The cumulative total dose of CYC in the case group was on average 1 g/patient while in the control group on average 8.5 g/patient (p = 0.00008). Despite the retrospective design and relative limited sample size, IBCDT appeared to be safe and had the same efficacy profile when compared to the conventional therapy with CYC plus AZA in the management of the most severe patients with AAV. Additionally, this avoided the need of prolonged maintenance therapy for long, and limited the exposure to CYC with consequent reduced toxicity and drug-related side effect rates.

Benefits and risks of haematopoietic stem cell transplantation for systemic sclerosis: A systematic review and meta-analysis.

We aimed to evaluate the efficacy and safety of haematopoietic stem cell transplantation (HSCT) in patients with systemic sclerosis. A systematic literature review and meta-analysis were carried out. We compared survival outcomes using the Kaplan-Meier method with patient-level data between HSCT and intravenous pulse cyclophosphamide. Additionally, the incidence rate of treatment-related deaths with HSCT was pooled using a random-effect model. Of the 2091 articles screened, 22 were included: 3 randomized controlled trials and 19 observational studies. HSCT studies showed significant improvement in the skin thickness score and lung function. Despite treatment-related deaths being higher in HSCT than in intravenous pulse cyclophosphamide, the Kaplan-Meier analysis showed a high survival rate of 2 years post-transplant (log-rank, P = 0.004). The pooled frequency of transplant-related death from 700 systemic sclerosis patients was 6.30% (95% confidence interval 4.21-8.38). However, the estimated frequency of treatment-related deaths has been reducing over the last decade. HSCT is an effective treatment for systemic sclerosis, but the optimal indications must be carefully determined by balancing the risks.

Clinicohistological Profile and Outcomes of Rapidly Progressive Glomerulonephritis: A Prospective Study from North India.

The prevalence of this rare and fatal entity varies in different regions and ethnicities. The objective of this study was to determine clinicopathological characteristics and predictors of outcome in rapidly progressive glomerulonephritis (RPGN). We aimed to prospectively study the clinicopathological profile and determine the predictors of renal outcome in patients with RPGN. This study included 40 patients of biopsy-proven RPGN. The diagnosis of RPGN was based on renal histology showing crescents in >50% of glomeruli. All patients were given induction with intravenous (IV) methylprednisolone (0.5 g) for three days followed by maintenance with oral prednisolone (1 mg/kg/day) and six IV pulses of cyclophosphamide (0.5 g) given fortnightly followed by maintenance therapy with azathioprine (2 mg/kg/day). The outcomes were recorded. Three-fourth of the patients (77.4%) required renal replacement therapy (RRT) at diagnosis. More than half of patients (57.5%) were antineutrophil cytoplasmic antibodies mediated. Immune complex and anti-glomerular basement membrane (GBM) disease constituted 25% and 17.5%, respectively. Clinical features, biochemical parameters, histological features, and type of RPGN were analyzed for association with primary outcomes. Entry serum creatinine, entry estimated glomerular filtration rate (eGFR), RRT on admission, interstitial fibrosis, tubular atrophy, and interstitial infiltrates were the parameters which showed association with primary outcomes of the study (P <0.05). In secondary outcomes, infections were the most common (55%), followed by neutropenia (40%). One-fourth of the patients (25%) died during the course of the study. Cause of mortality was infections (50%), cardiovascular system (30%), stroke (10%), and unknown (10%). Our prospective study from north India shows that RPGN is not an uncommon cause of renal failure and there is preponderance in the elderly patients (>60 years). Pauci-immune RPGN is the most common cause of RPGN followed by immune-complex and anti-GBM disease. Entry serum creatinine, eGFR, and RRT on admission predicted the outcome.