EXPERIENCE WITH TIXAGEVIMAB AND CILGAVIMAB (EVUSHELD) IN 86 RHEUMATIC PATIENTS UNDERGOING ANTI-B CELL THERAPY WITH RITUXIMAB.

The problem of prevention of coronavirus disease 2019 (COVID-19) in patients with immune-mediated inflammatory rheumatic diseases (IMRD) remains highly relevant. The presence of IRD is associated with a high risk of disease and severe course of COVID-19 during immunosuppressive treatment, primarily anti-B cell therapy with rituximab (RTX), and a low level of post-vaccination response in such patients. A new strategy for the prevention and treatment of COVID-19 are virus-neutralizing monoclonal antibodies to coronavirus;currently, combined long-acting monoclonal antibodies tixagevimab and cilgavimab (Evusheld) are registered for prevention in the world and the Russian Federation. . Tixagevimab and cilgavimab (TC) show neutralizing activity against SARS-CoV-2, including the Omicron strain, primarily its variants BA.4, BA.5, BA.2.75 ("Centaur"). Objective - to evaluate the efficacy and safety of TC for pre-exposure prophylaxis of COVID-19 in rheumatic patients receiving RTX, based on a prospective observational study. Materials and methods. The main group included 86 patients with various IMRD receiving RTX: 50 of them had ANCA-associated systemic vasculitis (AAV), 15 - rheumatoid arthritis, 9 - Sjogren's syndrome (SS), 4 - IgG4-related disease, 3 - systemic lupus erythematosus (SLE), 3 - dermatomyositis (DM), 2 - systemic scleroderma (SSD). Median age was 59 (19-82) years;male: female ratio - 1:1,8. From March 26 to August 30 2022, patients received a single intramuscular injection of TC in a total dose of 300 mg, mainly after RTX (in 52% of cases, in 28% on the next day after RTX). The control group included 42 patients with AAV (median age - 45 (35-71) years;male: female ratio - 1:1), also treated with RTX, who did not receive pre-exposure prophylaxis of TC. The duration of observation was 7 months, until November 1 2022. At this time, 98% of confirmed cases of coronavirus in the Russian Federation were Omicron. A telephone and/or online survey of patient has been conducted to detect cases of COVID-19 and adverse reactions. Results. In the TC group, confirmed coronavirus infection have been detected in 17 (20%) patients (AAV - 10, SS - 3, SSD - 2, SLE - 1, DM - 1), with fever in 7 (8%), only in one case hospitalization was required (lung damage was not detected in computed tomography), in two cases, according to CT mild lung damage (CT 1-2), there were no deaths. Good TC's tolerability was noted, signs not associated with COVID-19 or progression of IMRD after administration of TC were observed in 8 (9%) patients (GPA - 3 MPA - 1, RA - 2, SLE - 1, IgG4-related disease - 1), adverse reactions definitely associated with the use of TC were not found. The most serious event not associated with coronavirus infection was the progression of polyneuropathy in a patient with RA. In the control group, 3 (7%) patients were diagnosed with COVID-19, one with severe lung injury (CT 3, pulmonary embolism) and death. Conclusions. The data of clinical studies and our own clinical experience evidence the effectiveness of the use of a combination of long-acting monoclonal antibodies TC (Evusheld), registered for indications for pre-exposure prophylaxis and treatment of COVID-19. Patients with IMRD treated with RTX have a favorable safety profile of TC. The introduction of virus-neutralizing monoclonal antibodies, a new drug class for the prevention and treatment of infectious diseases, opens significant prospects for improving the prognosis of patients with IRD.Copyright © 2023 Ima-Press Publishing House. All rights reserved.

CD40.SARS.CoV2 VACCINE, BUT NOT mRNA, INDUCES SPECIFIC CD8+ T MEMORY STEM CELLS

Background: Vaccination plays a major role in controlling SARS-CoV2 infection but faces the issue of short-term protection. Beyond the generation of Abs, induction of memory CD8+T cells with stem cell-like (Tscm) properties is essential for long-term immunity to viruses. We have designed a sub-unit CD40.CoV-2 vaccine which targets Spike (S) and nucleocapsid (N) regions from SARS-CoV-2 to antigen presenting cells with comparable immunogenicity and protective effect than mRNA BNT162b2 (Pfizer-BioNTech) in preclinical models (Coleon S. EBioMed 2022). We hypothesized that CD40.CoV2 vaccine will elicit CD8+ Tscm cells. Method(s): CD40.CoV2 vaccine is a fully humanized mAb fused to RBD (aa 318-541) and N (aa 276-411). Humanized (hu) NSG mice (HIS-mice) (n=6/ group) received: i) CD40.CoV2 (10 mug equal to 1.3 mug of RBD, i.p.) +/- poly-ICLC (TLR3 agonist;50mug) or ii) BNT162b2 (1mug, i.m.);iii) IgG4.CoV2 (10mug, i.p.) as non-CD40-targeting control. Phenotype and function of splenic S and N-specific T cells were assessed at W5. Result(s): The CD40.CoV2 vaccine +/- poly-CLC induced significant S and N-specific Th1 huCD4+, cytokines-secreting huCD8+ T cells and RBD-specific IgG-switched huB cells as compared to mock injections and non-targeted IgG4.CoV2. CD40.CoV-2 vaccine +/- adjuvant induced higher frequencies of huCD8+ Tscm (CD95+ CD45RA+ CD62L+ ;median, (IQR) 22.4% (12.3-27.4) and 23% (20.7-29.1) +/- adjuvant, respectively) and central memory (TCM;CD45RA- CD62L+) CD8+ T cells (2.7% (2.3-6.2) and 5.1% (3.8-7.8) +/- adjuvant, respectively). In contrast, BNT162b2 induced predominantly effector memory (TEM, CD45RA- CD62L- ;median, (IQR) 63.1% (47.3-72.3)) but not Tscm (1.6% (0.9-6.6)) (figure). CD40.CoV-2 induced huCD8+ Tscm cells exhibit ;i) a higher proliferation index than TCM and TEM;ii) a functional profile secreting TNF and IFNgamma after restimulation with RBD or N peptides;cardinal features of Tscm cells. Conclusion(s): The CD40.SARS.CoV2, but not BNT162b2 vaccine, stimulates selective enrichment in S-and N-specific CD8+ Tscm cells that support longlasting anti-viral immunity. CD40.CoV2 sub-unit is under clinical development as a booster vaccine aimed to maintain durable anti-viral T and humoral responses. (Figure Presented).

Sarcoidosis-Associated Immune Thrombocytopenic Purpura and Focal Segmental Glomerulosclerosis

Purpose of study A 32-years old male with known multi-system sarcoidosis in remission for 5 years off treatment presented to the emergency room with complaints of generalized weakness, hematemesis, epistaxis, and bruises. Physical examination was notable for petechiae, ecchymosis along with papules and plaques suggestive of active sarcoid skin lesions on his extremities. Laboratory workup was significant for thrombocytopenia 3000/uL, acute kidney injury with sub-nephrotic proteinuria. Peripheral blood smear did not show evidence of hemolysis and direct Coombs test was negative. Infectious workup including COVID-19, HIV, and hepatitis serologies were negative. Computed Tomography (CT) of chest, abdomen, and pelvis showed mild splenomegaly and an increased number of sub-centimeter hilar and mediastinal lymph nodes. The patient was treated with dexamethasone 40 mg daily for 4 days and intravenousimmunoglobulins (IVIG-2 gm/kg) for possible Immune Thrombocytopenic Purpura (ITP) with improvement in platelet count to 42000/uL by day 3. His workup for AKI and sub-nephrotic proteinuria was negative apart from a positive ANA (1: 160) with low complements. The anti-phospholipid antibody panel was negative. The ACE level was markedly elevated (>80U/L). The patient could not get a renal biopsy due to severe thrombocytopenia. He was discharged but was re-admitted in 15 days for severe thrombocytopenia of 1000/uL, epistaxis, and bruising. We continued high dose steroids along with IVIG 1 gm/kg for refractory ITP with minimal response and started anti-CD20 agent (Rituximab) 375 mg/m2 weekly with thrombopoietin-receptor agonist (Eltrombopag). His platelets count improved in response to treatment and subsequent renal biopsy showed focal and segmental glomerulosclerosis along with mild interstitial fibrosis, tubular atrophy thought to be from long standing sarcoidosis. There was also evidence of focal arteriosclerosis with no evidence of granulomas, immune complex, complement, or IgG4 deposition. Given skin lesions, thrombocytopenia, extensive lymphadenopathy, and renal involvement with markedly elevated ACE levels the overall picture was consistent with active multi-system sarcoidosis. His platelet count increased to 177,000/uL at the time of discharge. Currently, the patient is on slow steroid taper along with Eltrombopag 25 mg every other day without any recurrence of his symptoms so far. Methods used We described one case of sarcoidosis with hematologic and renal involvement. Summary of results Our patient developed hematologic and renal complications approximately 6 years after being diagnosed with sarcoidosis. Initially, he did not demonstrate sufficient clinical response to IVIG and high dose steroids. However, after a course of anti-CD20 agent (Rituximab) and with the addition of thrombopoietin-receptor agonist (Eltrombopag) he showed improvement of platelet count and stabilization of the renal function. Currently, the patient is receiving maintenance therapy with Prednisone 7.5 mg daily along with Eltrombopag 25 mg twice weekly with no recurrence of ITP and stable renal function. A further decision on whether the patient needs another cycle of Rituximab will be determined by the patient's clinical course. Conclusions Highly variable manifestations of Sarcoidosis can pose a significant diagnostic and therapeutic challenge as can be seen from our case. ITP is a rare hematological manifestation of sarcoidosis and addition of anti-CD20 agents should be considered in refractory cases.

Reduced COVID-19 vaccine response in patient treated with Dupilumab for IgG4 related disease

Case report: Dupilumab is a novel anti-interleukin- 4 (IL-4) receptor-alpha monoclonal antibody that targets the signaling pathways of IL-4 and IL-13, which are key type 2 cytokines. Current evidence suggests that patients on dupilumab are not at significantly increased risk of SARS-CoV- 2 related hospitalization and mortality and clinicians should avoid preventive cessation of therapy in patients with moderate-to- severe disease necessitating systemic treatment with dupilumab. However, there has been limited data about adequate and durable humoral immune response after vaccination to SARS-CoV- 2 in these patients, with some recent evidence by Runnstrom et al. suggesting that patients with severe asthma or atopic dermatitis on biologic therapies have lower antibody levels after SARS-CoV- 2 mRNA vaccination compared to healthy adults. We previously reported the case of a 71-year- old man with IgG4 related-disease (IgG4-RD) that we successfully treated with dupilumab. This patient was followed over the past three-years while his IgG4-RD remained well controlled on dupilumab which he remained on during the pandemic. Based on the vaccination guidelines and availability, he received two SARS-CoV- 2 mRNA vaccinations on March 24, 2021 and June 18, 2021. On July 24, 2021 (36 days after his last vaccination), during his routine follow up assessment, he was found to have no antibodies against SARS-CoV2. In response to this, we facilitated for him to receive his third booster vaccination on November 10, 2021. In preparation for this, his dupilumab was held for 1 month prior to this date and was continued two weeks after the injection. On December 3, 2021 (23 days after), his SARS-CoV2 Spike Total AB was repeated and found to be elevated at 2282 while his SARS-CoV2 NPROT Total AB was negative, implying immune response through vaccination and not natural exposure. To our knowledge, this is the first case report on a patient with IgG4-RD controlled on dupilumab who was found to have adequate vaccine titres after his dupilumab was held for 1 month after failing to mount a response to the first two vaccination doses while on therapy. As there is evidence that lower vaccine-specific titers afford less protection against COVID-19, acknowledging that holding dupilumab may not be feasible in all cases, this report highlights this approach as one possible strategy to protecting these individuals who may unknowingly remain at high risk for severe disease.

A case report of hepatic angiomyolipoma, inflammatory subtype. Clinico-pathological characterization: a diagnostic challenge.

BACKGROUND: Angiomyolipoma is a benign mesenchymal neoplasm of a wide histological heterogeneity belonging to the PEComa "family." The liver, after the kidney, is their second most frequent location. However, inflammatory hepatic AMLs constitute a rare entity, with only fourteen documented cases until 2020. These neoplasms can overlap morphological features of IgG4-related diseases, being of great diagnostic relevance to demonstrating myomelanocytic-lineage differentiation of the neoplastic cells. CASE PRESENTATION: we present a new case of an inflammatory hepatic AML resembling an IgG4-related disease in a 35-year-old woman with a subcapsular 5 cm mass confined to segment VII of the right hepatic lobe. Although having reduced its size along the tumor's natural evolution, complete tumor resection was decided due to its hypermetabolic behavior (max. SUV = 12,6) assessed by PET-CT scan. Finally, the patient underwent a right hepatectomy due to spontaneous rupture and bleeding of the lesion during the intervention. All the diagnostic and therapeutic procedures occurred in the last months of the COVID-19 pandemic. CONCLUSIONS: This review aims to describe inflammatory hepatic AML histological and immunohistochemical features. We further sought to establish a clinicopathological contextualization of this tumoral subtype.

Bioavailability of iron and its potential to improve the immune system and ward off COVID-19: a review

Iron is a mineral that plays an important role, especially to prevent anaemia through the production of red blood cells. Iron also plays a role in physiological processes, such as the activation of enzymes and hormones, as well as increasing the immune system in warding off various viral infections. Therefore, iron bioavailability needs to be considered to take the greatest benefit of iron. This review discussed the factors that can affect the bioavailability of iron, various technologies to increase the bioavailability, and its potential in enhancing the immune system. Iron bioavailability can be increased by fortification, fermentation, the addition of vitamin C, and iron encapsulation. Under conditions of adequate iron intake, iron plays an important role in enhancing the immune system through controlling lymphocytes and T cell proliferation. However, excess iron consumption can be at risk of weakening the host's immune response to viruses. Therefore, the appropriate level of iron intake must be maintained accurately to be used optimally and has the potential to ward off viral infections, including the Sars-CoV-2 virus as the cause of COVID-19.Copyright © 2023, Rynnye Lyan Resources. All rights reserved.

Network analysis uncovers relationship between immune profiles and severity of COVID-19

Introduction: Despite the growing number of studies on COVID-19, interpreting the data and extracting meaning from these data is challenging. Method(s): We used a multivariate patient similarity network (PSN) approach to analyse ~85 immune (cellular and humoral) and ~70 clinical features in 250 prospectively recruited patients 4-8 weeks after a SARS-CoV-2 diagnostic PCR. Result(s): Our multivariate analysis identified a minimal immune signature (CD69+CD4+ T-lymphocytes, CTLA-4+ Tlymphocytes and immature B-lymphocytes) that was strongly associated with disease severity and manifested even 4-8 weeks after COVID-19. Visualisation of clinical and laboratory parameters in patient clusters detected by PSN showed that a history of severe COVID-19 was associated with less frequent anosmia/ageusia and higher levels of IgM and IgG 4-8 weeks after COVID-19 compared with mild disease. Conclusion(s): Ours study reveals the relationship between immune profiles and severity of COVID-19, showing that more severe COVID-19 is typical lower proportion on immature B cells and cytotoxic T- lymphocytes. Our study demonstrates the benefits of implementing multivariate data-mining approaches for interpreting complex datasets, not only relating to COVID-19.

Novel bispecific human antibody platform specifically targeting a fully open spike conformation potently neutralizes multiple SARS-CoV-2 variants.

Rapid emergence of new variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has prompted an urgent need for the development of broadly applicable and potently neutralizing antibody platform against the SARS-CoV-2, which can be used for combatting the coronavirus disease 2019 (COVID-19). In this study, based on a noncompeting pair of phage display-derived human monoclonal antibodies (mAbs) specific to the receptor-binding domain (RBD) of SARS-CoV-2 isolated from human synthetic antibody library, we generated K202.B, a novel engineered bispecific antibody with an immunoglobulin G4-single-chain variable fragment design, with sub- or low nanomolar antigen-binding avidity. Compared with the parental mAbs or mAb cocktail, the K202.B antibody showed superior neutralizing potential against a variety of SARS-CoV-2 variants in vitro. Furthermore, structural analysis of bispecific antibody-antigen complexes using cryo-electron microscopy revealed the mode of action of K202.B complexed with a fully open three-RBD-up conformation of SARS-CoV-2 trimeric spike proteins by simultaneously interconnecting two independent epitopes of the SARS-CoV-2 RBD via inter-protomer interactions. Intravenous monotherapy using K202.B exhibited potent neutralizing activity in SARS-CoV-2 wild-type- and B.1.617.2 variant-infected mouse models, without significant toxicity in vivo. The results indicate that this novel approach of development of immunoglobulin G4-based bispecific antibody from an established human recombinant antibody library is likely to be an effective strategy for the rapid development of bispecific antibodies, and timely management against fast-evolving SARS-CoV-2 variants.

Case report: Covid-19 and disseminated tuberculosis coinfection unveiling catastrophic antiphospholipid antibody syndrome: An association or de novo phenomenon

Background: Disseminated infections such as tuberculosis are known to result in a systemic inflammatory response leading to thrombosis, with increasing reported cases of thrombotic event being observed in patients infected with covid-19. This is the first reported case on co-infection with COVID-19 pneumonia and disseminated tuberculosis causing catastrophic antiphospholipid syndrome (CAPS). Method(s): The report highlighted the challenges in the diagnosis and management which include the use of corticosteroid in setting of systemic infections. Another diagnostic dilemma was to explain the cause of myositis by tuberculous or autoimmune. Case Presentation: We report a 26-year- old man with HbE trait thalassemia who reported unintentional weight loss, night sweats for 1 month prior to the diagnosis of covid-19 infection on 10th March 2022. Seven days later, he was hospitalized for suspected perforated appendix. Computed tomography (CT) abdomen revealed hepatosplenomegaly, prostatitis, seminal vesiculitis. Multiple matted abdominal lymph nodes were not amenable for biopsy. Soon, he appeared toxic, dyspneic required non-invasive ventilation with bilateral parotitis. He had raised erythrocyte sedimentation (ESR) 52 mm/hour, C-reactive protein (CRP) 221 mg/dl, lactate dehydrogenase (LDH) 730U/L. Direct Coomb's antibody was positive but did not have any form of haemolysis. Complement 3 (0.45 g/L) and complement 4 (0.1 g/L) levels were low. Serum IgG4, procalcitonin, anti-nuclear antibody, cultures and virology were negative. Sputum for acid fast bacilli (AFB) was positive on Auramine O stain but the Ziehl-Nelson (ZN) stain and tuberculous PCR (GeneXpert) were negative. Diagnosis of disseminated tuberculosis was made but his abdominal pain persisted despite being on anti-tuberculous therapy (ATT), and he had new evidence of splenic infarct. CT angiogram also revealed celiac trunk and superior mesenteric artery thrombosis. Antiphospholipid (aPL) test was positive for lupus anticoagulant, beta 2 glycoprotein 1 and anti-cardiolipin antibodies. Therapeutic anticoagulation and plasma exchange were initiated for probable CAPS followed by intravenous immunoglobulin and corticosteroid. Thereafter, the patient developed severe bilateral pelvic girdle pain with evidence of myositis on the MRI (Figure 2). Serum creatine kinase was never elevated. Anti-PL- 7 and anti Ro-52 were borderline elevated. He recovered well and ambulant before discharged home. Conclusion(s): Our case highlight the complexicity of presentation of CAPS who manifested as multiple arterial thrombosis. The diagnosis of disseminated tuberculosis relied strongly on microbiological, imaging and clinical presentation as histopathological evidence was not feasible. Management challenges were deciding on corticosteroid in disseminated infection and the need for confirmation of persistent positive aPL test and to monitor myositis symptom to help guide decision making. (Figure Presented).

Impact of a Multidisciplinary Tumor Board on the Care of Patients with Histiocytic Disorders: The Histiocytosis Working Group experience.

INTRODUCTION: Histiocytic disorders pose significant diagnostic and management challenges for the clinicians due to diverse clinical manifestations and often non-specific histopathologic findings. Herein, we report the tumor board experience from the first-of-its-kind Histiocytosis Working Group (HWG). MATERIALS AND METHODS: The HWG was established in June 2017 and consists of experts from 10 subspecialties that discuss cases in a multidisciplinary format. We present the outcome of tumor board case discussions during the first 2 years since its inception (June 2017-June 2019). RESULTS: Forty cases with a suspected histiocytic disorder were reviewed at HWG during this time period. Average number of subspecialties involved in HWG case discussion was 5 (range, 2-9). Histiocytosis Working Group tumor board recommendations led to significant changes in the care of 24 (60%) patients. These included change in diagnosis (n = 11, 27%) and change in treatment (n = 13, 33%). CONCLUSION: Our report highlights the feasibility of a multidisciplinary tumor board and its impact on outcomes of patients with histiocytic disorders.

A PROBABLE CASE OF IGG4-RELATED LUNG DISEASE MIMICKING PNEUMOCONIOSIS

SESSION TITLE: Autoimmune Diseases Gone Wild: Rare Cases of Pulmonary Manifestations SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/18/2022 01:35 pm - 02:35 pm INTRODUCTION: Immunoglobulin G4-related disease (IgG4-RD) is a complex entity related to autoimmune dysfunction and inflammation that can cause mass-like lesions and fibrosis of a variety of organs, including pancreas and/or lungs. IgG4-RD in the lung can have diverse clinical and radiographic presentations. We present a case of suspected IgG4-RD that manifested as idiopathic pancreatitis and interstitial lung disease that mimicked coal workers' pneumoconiosis. CASE PRESENTATION: A 72 year-old male with a decades-long coal mining history and a presumptive diagnosis of coal-worker's pneumoconiosis was admitted to the hospital for necrotizing pancreatitis. There was no evidence of gallstones, elevated triglycerides, history of alcohol use or medication known to precipitate pancreatitis. Two years prior, a presumptive diagnosis of coal-worker's pneumoconiosis had been reached largely on the basis of history and chest imaging (Figure 1) showing a progressive massive pulmonary fibrosis pattern. His hospital course was protracted and complicated by nosocomial COVID-19 treated with remdesivir and a 10-day course of dexamethasone. He then had persistent hypoxemia that worsened after dexamethasone was discontinued. Empiric high-dose methylprednisolone was given and the hypoxemia improved dramatically. However, the hypoxemia and pancreatitis repeatedly worsened with significant dose decrease. Inpatient CT chest showed worsening interstitial reticulation and ground-glass opacities superimposed on prior fibrosis (Figure 2). Serum IgG subclass levels were checked;IgG4 and IgG4:IgG ratio were mildly elevated at 93mg/dL and 0.09, respectively. In the setting of idiopathic pancreatitis, pulmonary fibrosis, and steroid-sensitive hypoxemia, he was diagnosed with probable IgG4-RD involving pancreas and lungs. An association between inhaled occupational exposures and development of IgG4-RD has been observed. To confirm the diagnosis of pulmonary IgG4-RD, a tissue biopsy will be necessary. He is now discharged from hospital on a long steroid taper. DISCUSSION: A serum IgG4 level >125mg/dL or an IgG4:total IgG ratio >0.08 support the diagnosis, as does clinical response to steroids. However, these criteria are nonspecific and will be in the normal range in a substantial minority of cases. Lymphocytes and a predominance of IgG4-positive plasma cells infiltrating fibrotic tissue in involved organs are pathologic hallmarks of IgG4-RD. Lung involvement in patients with pancreatitis due to IgG4-RD is common and likely under recognized. CONCLUSIONS: Pulmonary involvement in IgG4-RD can show a wide array of radiographic patterns, but that seen in this case with pseudotumor and fibrosis is among the most commonly reported. Given the overlap in risk factors and radiographic appearance between IgG4-RD and pneumoconiosis, vigilance for IgG4-RD is warranted. Reference #1: Hirano K., Kawabe T., Komatsu Y., et al. High-rate pulmonary involvement in autoimmune pancreatitis. Internal Medicine Journal. 2006;36(1):58–61. doi: 10.1111/j.1445-5994.2006.01009.x Reference #2: Kamisawa T, Zen Y, Pillai S, Stone JH. IgG4-related disease. Lancet. 2015 Apr 11;385(9976):1460-71. doi: 10.1016/S0140-6736(14)60720-0. Epub 2014 Dec 4. PMID: 25481618. Reference #3: de Buy Wenniger, L. J., Culver, E. L., & Beuers, U. (2014). Exposure to occupational antigens might predispose to IgG4-related disease. Hepatology (Baltimore, Md.), 60(4), 1453–1454. https://doi.org/10.1002/hep.26999 DISCLOSURES: No relevant relationships by Jordan Minish, source=Web Response No relevant relationships by Robert Ousley, source=Web Response No relevant relationships by Meagan Reif, source=Web Response No relevant relationships by Derek Russell, source=Web Response

IGG4-RELATED PLEURAL DISEASE: A CAUSE OF RECURRENT PLEURAL EFFUSION AFTER COVID-19 VACCINATION

SESSION TITLE: Challenging Disorders of the Pleura SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/18/2022 01:35 pm - 02:35 pm INTRODUCTION: Great effort went into finding a vaccine to decrease the impact of COVID-19 virus. Pfizer vaccine which is a part of mRNA of the virus wrapped with lipid nanoparticles is one of them. Though its side effects are benign, rarely it can lead to IgG4 related lung disease (IgG4-RLD). Therefore, having a high degree of suspicion is important for early diagnosis and effective treatment. CASE PRESENTATION: The patient is a 71-year-old male with COPD, CAD, and prostate cancer developed dyspnea after receiving 2 doses of Pfizer vaccine. CT chest revealed a new left pleural effusion, 1.4L fluid was removed which was negative for malignant cells with lymphocytic predominance. After 10 days, his symptoms worsened and repeat CT scan revealed large left pleural effusion. Thoracoscopy was done with drainage of 2.5L pleural fluid followed by pleural biopsy and chemical pleurodesis with insertion of an indwelling tunneled catheter. Pleural biopsy revealed chronic organizing pleuritis with lymphoid and mesothelial hyperplasia. The tunneled catheter stopped draining after 3 months but oxygen requirement increased. A repeat CT scan revealed loculated pleural effusions and only 40 ml was drained due to bloody output. Thoracoscopy revealed multiloculated effusions with visceral pleural thickening and partial decortication was done. Pathology revealed pleural thickening and fibrosis with increased IgG4-positive plasma cells in pulmonary parenchyma. Blood IgG4 level was 268 mg/dl. He was diagnosed with IgG4-related disease (IgG4-RD) affecting lungs and pleura. DISCUSSION: Although IgG4 related nephritis after Pfizer vaccine has been reported(1), this is the 1st reported case of IgG4-RLD. Autoimmunity is a trigger for pathogenesis with involvement of Th-2 cell. The vaccine stimulates robust antigen-specific T-cell responses leading to antibody production that trigger autoimmune reactions due to molecular mimicry. Four patterns are observed including mediastinal, parenchymal, pleural, and airway involvement. Mediastinal and hilar lymphadenopathy is the commonest patterns(2). Our patient had loculated pleural effusion complicated by pleural thickening and fibrosis. For diagnosis of IgG4-RD, 3 criteria need to be fullfilled: consistent organ involvement;serum IgG4 level >135 mg/dL;histopathology showing marked lymphoplasmacytic infiltration(2). Our case fulfilled all 3 criteria and involved lungs;thus, diagnosed with IgG4-RLD. Most patients have a favorable response with corticosteroid therapy in 2 weeks. For steroid-refractory cases, immunosuppressants can be used(3). CONCLUSIONS: With increased COVID-19 vaccination, more autoimmune events including IgG4-RLD can happen. As multiple doses are offered, close observation is needed for prompt diagnosis and management of such diseases. Ultimately, theoretical risks must be balanced against known benefits, and discussion between providers and patients is important. Reference #1: Christophe M, Delphine K, Christine K A, Aurélie F, Gilles B, Mohamed H. Relapse of IgG4-related nephritis following mRNA COVID-19 vaccine. Kidney International. Vol 100, Issue 2, P465-466, August, 2021. DOI: https://doi.org/10.1016/j.kint.2021.06.002 Reference #2: Ryu JH, Sekiguchi H, Yi ES. Pulmonary manifestations of immunoglobulin G4-related sclerosing disease. Eur Respir J 2012;39:180–6 Reference #3: Campbell SN, Rubio E, Loschner AL. Clinical review of pulmonary manifestations of IgG4-related disease. Ann Am Thorac Soc 2014;11:1466–75. DISCLOSURES: no disclosure on file for Ola Al-Jobory;No relevant relationships by Ahmad Hallak No relevant relationships by Manish Patel No relevant relationships by Saria Tasnim

An Unusual Clinical Evolution in Anticontactin- 1 Positive CIDP

Specific clinical, electrophysiological and serological features are used to recognise a phenotype fitting the atypical chronic inflammatory demyelinating (CIDP) variant spectrum. We report a 28-year-old male patient, without any significant history apart from a recent asymptomatic COVID-19 infection, presenting at first with bilateral facial nerve palsy, subsequently -three months later- developing an subacute onset symmetric sensory ataxia and arefl exia, and thirdly experiencing diffuse rapidly progressive motor deficits. Additional investigations suggested an autoimmune polyneuropathy: Liquor analysis showed cytoalbuminologic dissociation. Cerebrospinal fluid protein elevation was remarkable: 631 mg/dL. Nerve conduction studies showed prominent distal latencies prolongation and dispersion of the potentials, meeting the electrodiagnostic criteria of the European Federation of Neurological Societies/Peripheral Nerve Society for CIDP (2021). Full spine magnetic resonance imaging depicted pathological thickening and enhancement of the roots of the cauda equina as seen in radiculitis. There was no or poor response to conventional treatment, i.e. immunoglobulins (IVIG), corticosteroids and even plasmapheresis. Muscle weakness deteriorated. Presence of serum IgG4 anti- contactin-1 (CNTN1) antibodies was found by ELISA identifi- cation and titration, and the patient improved substantially after rituximab treatment. While contributing to the expanding confidence in nodal and paranodal antibodies as valuable biomarkers in clinical practice, our case entails several peculiarities: 1/ SARS-CoV2 positivity as a possible trigger of this auto-immune polyneuropathy 2/ A considerably younger age of onset than in the patients already described (range 33-76 years). 3/ The clinical course progressed in an atypical manner even for atypical CIDP: Initial presentation with bilateral asymmetric facial palsy, followed by sensory ataxia, which prompted the initial diagnosis of Miller-Fisher syndrome, and later development of severe motor impairment. 4/ Proteinorachy was so pronounced that we considered neuroborreliosis as a potential associated disorder. Borrelia seroconversion occurred after the first IVIG-treatment, and could be false positive. However, the patient was treated with intravenous ceftriaxone, which had no effect on the clinic. 5/ Antibodies against CNTN1 were undetectable after 2 months of rituximab. Emphasising the both diagnostic and therapeutic importance of recognising a phenotype compatible with atypical CIDP, an underrecognized and consequently undertreated disease where early diagnosis and prevention of axonal damage is crucial in.

THE COURSE of NOVEL CORONAVIRUS DISEASE 2019 (COVID-19) in PATIENTS with IGG4-RELATED DISEASE TREATED with RITUXIMAB

Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease 2019 (COVID-19) raised many questions and concerns about the safety of different immunosuppressive agents in patients (pts) with rheumatic diseases during the pandemic. There is some data that anti-B-cell depletion strategies could lead to more severe disease course. Rituximab (RTM) is one of the most effective, safe and well tolerated agents in IgG4-related disease (IgG4-RD) treatment. Information about the course of COVID-19 in pts with IgG4-RD is lacking. Objectives: To examine clinical course of COVID-19 in pts with IgG4-RD treated with anti-CD20 monoclonal antibody (RTM). Methods: Single center observational study. We searched in our clinical base from 2019 to 2021 years for pts with IgG4-RD, treated with RTM within this period. Diagnosis of IgG4-RD was based on comprehensive diagnostic criteria (H. Umehara, 2011). COVID-19 infection was registered when PCR test results were positive. RTM was administered in two 1000 mg infusions 14 days apart for the 1st course, then 500 mg every 6 months. We used mean ± standard deviation and median values with interquartile range of 25-75 percentile to characterize quantitative data. Results: Fifteen pts, 6 women and 9 men, mean age 53.2 ± 12 years, receiving RTM monotherapy were included. The majority of patients (80%) had multiple organ involvement, mean number 2,3 (from 1 to 5): dacryadenitis-11 pts, sialadenitis-10 pts, AIP 1-4 pts, lung disease-3 pts, sclerosing cholangiris-2 pts, kidney disease-2 pts, retroperitoneal fbrosis-1 pt, aortitis-1 pt, prostatitis-1 pt. Median duration of IgG4-RD before COVID-19 onset was 48 [27;72] months, median duration of RTM treatment was 22 [11,5;30,5] months and median time from the last dose of RTM was 2 [1;4,5] months. Three pts had arterial hypertension or coronary heart disease anamnesis, 4 pts had asthma, 2 pts were overweight and 1 had class 3 obesity. No pts were vaccinated against SARS-CoV-2. Six patients (40%) required hospitalization and 4 of them received IL-6 inhibitors, only 1 required mechanical lung ventilation, 6 patients (40%) had only minor symptoms and didn't require any specifc treatment, glucocorticoids were administered to 8 patients. All patients, except one, were older than 50, but they didn't have severe comorbidities. One patient, a 46 year-old man with a long anamnesis of IgG4-related dacryo-and sialad-enitis, bronchial asthma, arterial hypertension class 3 and class 3 obesity, died. Due to small number of studied pts no statistical correlations could be established. Conclusion: The proportion of hospitalized pts with IgG4-RD and RTM treatment was surprisingly high. The worst course was in patient with severe comorbidity. It appears that RTM can have negative impact on susceptibility to COVID-19 and its disease course.

LUNG INVOLVEMENT in VEXAS SYNDROME

Background: Vacuoles, E1 enzyme, X-linked, autoinfammatory, somatic (VEXAS) syndrome is a recently identifed disorder caused by somatic mutations in the UBA1 gene of myeloid cells. Various manifestations of pulmonary involvement have been reported, but a detailed description of lung involvement and radiologic fndings is lacking. Objectives: To describe lung involvement in VEXAS syndrome. Methods: A retrospective cohort study was conducted of all patients iden-tifed at the Mayo Clinic with VEXAS syndrome since October 2020. Clinical records and chest high resolution computed tomography (HRCT) scans were reviewed. Results: Our cohort comprised 22 white men with a median age of 69 years (IQR 62-74, range 57-84). Hematologic disorders including multiple myeloma, myelodysplastic syndrome and pancytopenia were present in 10 patients (45%), rheumatologic diseases including granulomatosis with poly-angiitis, IgG4-related disease, polyarteritis nodosa, relapsing polychondritis, and rheumatoid arthritis were found in 10 patients (45%), and 4 patients had dermatologic presentations including Sweet syndrome, Schnitzer-like syndrome or drug rash with eosinophilia skin syndrome (DRESS). VEXAS syndrome-related features included fever (18, 82%), skin lesions (20, 91%), lung infiltrates (12, 55%), chondritis (10, 45%), venous thromboembolism (12, 55%), macrocytic anemia (21, 96%), and bone marrow vacuoles (21, 96%). Other manifestations observed were arthritis, scleritis, hoarseness and hearing loss. Median erythrocyte sedimentation rate (ESR) was 69 mm/1st hour (IQR 34.3-118.8) and median C-reactive protein (CRP) of 55.5 mg/dL (IQR 11.4-98.8). The somatic mutations affecting methionine-41 (p.Met41) in UBA1 gene were: 11 (50%) p.Met41Thr, 7 (32%) p.Met41Val, 2 (9%) p.Met41Leu, and 2 (9%) in the splice site. All patients received glu-cocorticoids (GC) (median duration of treatment was 2.6 years);21 (96%) received conventional immunosuppressive agents (methotrexate, aza-thioprine, mycophenolate, leflunomide, cyclosporin, hydroxychloroquine, tofacitinib, ruxolitinib) and 9 (41%) received biologic agents (rituximab, tocilizumab, infliximab, etanercept, adalimumab, golimumab, abatacept). Respiratory symptoms included dyspnea and cough present in 21 (95%) and 12 (55%), respectively, and were documented prior to VEXAS diagnosis. Most of the patients were non-smokers (14, 64%) and obstructive sleep apnea (OSA) was present in 11 patients (50%). Seven patients (32%) used non-invasive ventilation, 6 used C-PAP, and 1 used Bi-PAP. Bronchoalveolar lavage (BAL) was available in 4 patients, and the findings were compatible with neutrophilic alveolitis in 3. Two patients had lung biopsies (2 transbronchial and 1 surgical) that showed ATTR amyloidosis and organizing pneumonia with lymphoid interstitial pneumonia, respectively. Pulmonary function tests were available in 9 (41%) patients and showed normal results in 5;3 patients had isolated reduction in DLCO and 1 with mild restriction. On chest HRCT, 16 patients (73%) had parenchymal changes including ground-glass opacities in 9, septal thickening in 4, and nodules in 3;pleural effusions were present in 3 patients, air-trapping in 3 patients and tracheomalacia in 1 patient. Follow-up chest HRCT was available for 8 patients (36%), the ground-glass opacities resolved in 5 patients, 3 patients manifested new or increased ground-glass opacities, and 1 patient had increased interlobular septal thickening. After 1 year of follow-up, 4 patients (17%) had died;3 due to pneumonia (2 COVID-19,1 bacterial) and 1 due to heart failure. VEXAS flares occurred in 18 patients (82%), the maximum number of relapses was 7, and they were mainly managed with GC and with changes in the immuno-suppressive regimen. Conclusion: Pulmonary involvement was documented by chest HRCT in most patients with VEXAS syndrome. Respiratory symptoms occurred in over one half of patients and about 20% had PFT abnormalities. The pulmonary manifestations of VEXAS are nonspecifc and characterized predominantly by infamma-tory parenchymal involvement.

A SURVEY on ACCEPTANCE of COVID-19 VACCINATION among PATIENTS with RHEUMATIC DISEASES-A SINGLE CENTER EXPERIENCE in MALAYSIA

Background: According to Statista, 78.5% of the population in Malaysia have completed their vaccination as of 6th january 2022 [1].The acceptance of patients with rheumatic diseases on Covid-19 vaccination is crucial in the long term protection against Covid-19 infection. We conducted a survey to determine the acceptance of Covid-19 vaccination amongst patients with underlying rheumatic disease. Objectives: To fnd out the reasons of vaccination refusal amongst rheumatology patients. Methods: This was an interview survey. All rheumatology patients who were follow up in rheumatology clinic Hospital Sultan Ismail, Malaysia from 26th April 2021 to 25th July 2021 (total 3 months) were interviewed. Demographic and diagnosis of the patients were collected. Results: A total of 952 patients were identified. 83.7% of them were female patients (797/952) and majority of them were Malay (46.4%). This was followed by Chinese (36.1%), Indian (16.3%) and others (1.2%). The mean age group was 48 (range from 13-85). 97.6% of the respondents were categorized as having inactive disease during the interview sessions. 36.6% of the patients were diagnosed to have rheumatoid arthritis and 29.1% of them were having systemic lupus erythematosus. These were followed by psoriatic arthritis (10.9%), mixed connective tissue disease (5.5%), systemic sclerosis (2.9%), gout (2.6%), Sjogren syndrome (1.9%), ankylosing spondylitis (1.6%), myositis (1.5%), vascu-litis (1.3%), osteoarthritis (1.2%), antiphospholipid syndrome (0.9%), non-specific arthralgia (0.8%), juvenile idiopathic arthritis (0.8%), seronegative spondyloarthropathy (0.8%), undifferentiated connective tissue disease (0.7%), adult onset still's disease 0.5%) and others (< 0.5% each for Ig G 4 related disease, soft tissue rheumatism and fibro-myalgia). 87.3% of them were keen or have already received Covid-19 vaccination. 12.7% of them were not keen for the vaccination with various reasons. 48.8% of them were worrying about worsening clinical condition, 12.4% of them were not keen as they concerned about side effects (3 worry about fever, 1 worry about hepatitis, 1 for nausea, 1 for dizziness, 1 for breathlessness, and 7 for non-specific reasons). 10.7% of them were not keen due to pregnancy, 5.79% of them were not keen as worried about allergic reactions, 4.9% of them were worrying about sudden cardiac death, 4% were not keen as on chemotherapy treatment, 3 % of them doubted the efficacy of vaccination, 2.5% were not keen as they worried about heart disease, 2.5% worried about increase risks of infection and others (2 for old age, 2 for thrombotic event, 2 for drug interaction and 1 patient due to hemodialysis). Conclusion: The overall acceptance rate of Covid-19 vaccination amongst patients with rheumatic diseases is very encouraging with the percentage of >85% despite of lacking knowledge about vaccine Covid-19. This result can assist our Ministry of Health to plan for future battle to improve vaccine uptake that hopefully can lead to herd immunity against COVID-19 infection. More counseling sessions are required to clear up the doubts of vaccination and increase the vaccination rate amongst rheumatic patients.

COMPARISON OF THE HUMORAL AND CELLULAR IMMUNITY IN COVID-19 CONVALESCENTS

The SARS-CoV-2 virus caused the COVID-19 pandemic is related to the SARS-CoV-1 and MERS coronaviruses, which were resulted in 2003 and 2012 epidemics. Antibodies in patients with COVID-19 emerge 7–14 days after the onset of symptoms and gradually increase. Because the COVID-19 pandemic is still in progress, it is hard to say how long the immunological memory to the SARS-CoV-2 virus may be retained. The aim of this study was to study a ratio between humoral and cellular immunity against the SARS-CoV-2 S protein in COVID-19 convalescents. There were enrolled 60 adults with mild to moderate COVID-19 2 to 12 months prior to the examination. The control group consisted of 15 adults without COVID-19 or unvaccinated. Specific antibodies to the SARS-CoV-2 virus were determined by ELISA with the SARS-CoV-2-IgG-ELISA-BEST kit. To determine the specific IgG and IgA subclasses, the anti-IgG conjugate from the kit was replaced with a conjugate against the IgG subclasses and IgA. Additional incubation with or without denaturing urea solution was used to determine the avidity of antibodies. Peripheral blood mononuclear cells were isolated by gradient centrifugation, incubated with or without coronavirus S antigen for 20 hours, stained by fluorescently labeled antibodies, and the percentage of CD8highCD107a cells was assessed on flow cytometer BD FACSCanto II. In the control group, neither humoral nor cellular immunity against the SARS-CoV-2 S protein was found. In the group of convalescents, the level of IgG antibodies against the SARS-CoV-2 S protein varies greatly not being strictly associated with the disease duration, with 57% and 43% of COVID-19 patients having high vs. low level of humoral response, respectively. A correlation between level of specific IgG and IgA was r = 0.43. The avidity of antibodies increased over time in convalescents comprising 49.9% at 6–12 months afterwards. No virus-specific IgG2 and IgG4 subclasses were detected, and the percentage of IgG1 increased over time comprising 100% 6–12 months after recovery. 50% of the subjects examined had high cellular immunity, no correlations with the level of humoral immunity were found. We identified 4 combinations of humoral and cellular immunity against the SARS-CoV-2 S protein: high humoral and cellular, low humoral and cellular, high humoral and low cellular, and vice versa, low humoral and high cellular immunity.

IMPACT OF COVID-19 ON THE CLINICAL OUTCOMES AND MANAGEMENT OF IGG4 RELATED DISEASE PATIENTS WITH PANCREATOBILIARY INVOLVEMENT: A MULTICENTER RETROSPECTIVE STUDY

Background: Coronavirus disease 2019 (COVID-19) has affected more than 249 million people worldwide as of November 2021. Patients with chronic immune-mediated inflammatory diseases are at risk of viral infections either related to their underlying immune dysfunction or the immunosuppressive therapy, but little is known about the impact of COVID19 on outcomes and management of pancreatobiliary IgG4 related disease (IgG4 RD) patients. Methods: This was a multicenter retrospective cohort study aiming to investigate the impact of COVID-19 on the clinical outcomes and management of pancreatobiliary IgG4 RD patients in different geographic areas with COVID-19 outbreak. Pancreatobiliary IgG4 RD patients aged 18 years or older from 7 referral centers in Hong Kong, Japan, Thailand, Singapore, the United States and Italy were included. Case definition of IgG4 RD: elevated serum IgG4 serology with typical features of pancreatobiliary involvement on imaging, EUS, ERCP and/ or typical histopathologic features of IgG4 RD. Medical records were reviewed for IgG4 RD status (organ involvement, disease activity, treatment status), COVID-19 infection and outcome. Outcome measures were incidence and severity of COVID-19 in pancreatobiliary IgG4 RD patients, medical treatment for the IgG4 disease during COVID-19 and incidence of postponement or discontinuation of indicated medical treatment for IgG4 RD during COVID-19. Results: 101 pancreatobiliary IgG4 RD patients (mean age 66.4 +/- 12.1 years, male 74.3%) from 7 referral centers were included from January 2020 to November 2020. Major comorbidities of patients: none in 21.8%, diabetes in 45.5%, hypertension in 49.5%, ischemic heart disease in 8.9%, chronic liver disease in 8.9%, chronic kidney disease in 9.9% and cancer in 5.0% of patients. IgG4 RD organ involvement: pancreas only in 36.6%, pancreas and bile duct in 16.8%, bile duct only in 14.9%, pancreatobiliary and other organs in 26.7% of patients. The mean serum IgG4 serology level was 4.72+/-7.31 g/L. In 2020, 27.7% of patients had active IgG4 disease while 72.3% of patients were in remission. In 2020, 65.3% of patients received treatment (steroid in 48.5%, thiopurines in 22.7%, steroid and thiopurines in 25.8%, rituximab in 1.5%), while 30.7% of patients were not on treatment. 2 patients (2.0%) had COVID-19 infection, with 1 patient requiring ICU admission. All infected patients recovered from COVID-19 without flare up of IgG4 RD. In 2020, 6.9% of patients had postponement or discontinuation of indicated medical treatment for IgG4 RD during COVID-19 outbreak due to concern of COVID-19 infection while on immunosuppressive therapy. Conclusion: In this study, low incidence of COVID-19 infection and low rates of postponement or discontinuation of indicated medical treatment were observed in pancreatobiliary IgG4 RD patients during COVID-19 outbreak in 2020. (Table Presented)

An Unusual Case of CLIPPERS

Objective: To present an unusual presentation of CLIPPERS that was responsive to rituximab Background: CLIPPERS (chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids) is a neuroinflammatory disorder typically affecting the brainstem and cerebellum with clinical and radiographic improvement with steroids. One reported case showed improvement with rituximab. We present a case of CLIPPERS with supra- and infratentorial involvement that improved with rituximab. Design/Methods: A 30-year-old male presented with several months of headaches, dizziness, and face and arm numbness, then developed diplopia and gait ataxia. Serial MRI's showed worsening punctate enhancing and T2-hyperintense lesions in the brainstem and supratentorial white matter over months. Workup showed normal CSF cell count, and negative CSF cytology, ACE, VDRL, oligoclonal bands, serologic IgG4, Coccidioidomycosis, Lupus, rheumatoid arthritis, and COVID. Vascular imaging showed no evidence of vasculitis. Biopsy showed a dense perivascular lymphocytic infiltrate including B and T cells, without evidence of vasculitis or lymphoma. He received IVIG and IV solumedrol, with symptom resolution and some improvement on imaging. Rituximab was started with subsequent resolution of the lesions on MRI. Results: NA Conclusions: CLIPPERS has a variable clinical presentation but typically includes gait ataxia and diplopia. MRI shows multiple punctate/curvilinear enhancing lesions in the brainstem and cerebellum, rarely in the spinal cord or supratentorially. Differential diagnoses include neurosarcoidosis, Behcet's disease, vasculitis, lymphoma, chronic infections, glioma, and demyelinating disease. It is characterized by responsiveness to steroids, and patients require long-term steroid or steroid-sparing agent treatment, at least until resolution of enhancement. Methotrexate, hydroxychloroquine, and cyclophosphamide are most commonly used. There was one report of treatment with rituximab with 4 years stability. Our case was unusual as he had supra and infratentorial lesions, and he had good response to rituximab. Rituximab should be considered in the treatment of CLIPPERS.