Autoimmune Lupus Enteritis with Pan Gastrointestinal Involvement in an Adult Patient with Systemic Lupus Erythematosus: Complete Response to Belimumab.

Autoimmune lupus enteritis in systemic lupus erythematosus (SLE) is a rare manifestation that comprises of gastrointestinal tract inflammation with supportive images and/or biopsy findings. We report a unique case of widespread lupus enteritis occurring late in the disease process and in isolation without additional features of active SLE but in the presence of SLE serological activity. There was no clear evidence of active mesenteric vasculitis, intestinal pseudo-obstruction, protein-losing enteropathy, or coagulopathy by imaging or histopathology. This is the first reported case of an SLE patient with pan-gastrointestinal involvement of lupus enteritis responding to Belimumab, with complete resolution of the gastrointestinal syndrome and no further recurrence of gastrointestinal events. Rapid diagnosis and prompt immunomodulatory treatment of lupus-related enteritis are critical to avoid potentially life-threatening complications.

Late-Onset Hemorrhagic Pericardial Effusion and Cardiac Tamponade Associated With Immune Checkpoint Inhibitors: Case Report and Literature Review.

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that target T lymphocytes and stimulate the immune system. However, the use of ICIs is associated with immune-related adverse events (irAEs). Pericardial disease is a cardiovascular irAEs that can present as cardiac tamponade. The precise mechanisms underlying pericardial complications are not fully understood. Late-onset hemorrhagic pericardial effusion associated with ICIs is quite rare; the mechanism and predisposing factors are yet to be determined. This case report describes a patient with diffuse large B-cell lymphoma (DLBCL) who received pembrolizumab for 390 days and subsequently developed cardiac tamponade caused by hemorrhagic pericardial effusion. The purpose of this report is to raise awareness about the occurrence of late-onset cardiac tamponade and provide a summary of available data on patients who experienced hemorrhagic pericardial effusion during ICI treatment.

A Framework to Overcome Challenges in the Management of Infections in Patients with Systemic Lupus Erythematosus.

Infections remain one of the leading causes of death in systemic lupus erythematosus (SLE), despite awareness of factors contributing to increased susceptibility to infectious diseases in SLE. Clinicians report challenges and barriers when encountering infection in SLE as certain infections may mimic a lupus flare. There are no evidence-based practice guidelines in the management of fever in SLE, with suboptimal implementations of evidence-based benefits related to infectious disease control and/or prevention strategies in SLE. Vigilance in identifying an opportunistic infection must be stressed when confronted by a diagnostic challenge during a presentation with a febrile illness in SLE. A balanced approach must focus on management of infections in SLE, and reduction in the glucocorticoids dose, given the need to control lupus disease activity to avoid lupus related organ damage and mortality. Clinical judgement and application of biomarkers of lupus flares could reduce false positives and overdiagnosis and improve differentiation of infections from lupus flares. Further precision-based risk and screening measures must identify individuals who would benefit most from low dose immunosuppressive therapy, targeted immune therapy, and vaccination programs.

Long-term outcome of status epilepticus-related to systemic lupus erythematosus: An observational study and a systematic review.

OBJECTIVES: Status epilepticus-related to systemic lupus erythematosus (SE-SLE) is in general attributed to fulminate neuropsychiatric lupus disease activity, yet the long-term outcome of SE-SLE is not well recognized. This is an observational study of 40 SE-SLE patients pooled from 8 cases at a single tertiary care hospital, and 32 SE-SLE patients identified on a systematic review, with focus on electro-clinical characteristics, imaging studies and the underlying etiology of SE-SLE in correlation with long-term outcome. RESULTS: Clinical phenotypes of SE-SLE were heterogeneous, ranging from patients with aura continua to patients in coma. Convulsive SE-SLE occurred among patients with heightened global lupus disease activity and increased cortical and subcortical brain lesion burden localized mostly in the frontal and temporal regions. There were no specific neuroimaging or laboratory abnormalities that allowed early SE-SLE diagnosis where a cluster of cases were of unclear etiology (17.5%). Most SE-SLE cases evolved to refractory SE-SLE with resistance to multiple anti-seizure medications and intravenous anesthetics requiring aggressive immune therapy that led to resolution of SE-SLE active phase. Seizure freedom occurred in 60.0% of patients and the median time to cessation of SE-SLE seizure activity after aggressive therapy was 14 days. Poor long-term outcomes were apparent in SE-SLE patients with one-year mortality (12.5%), recurrent SE-SLE (25.0%), subsequent epilepsy (37.5.1%), poor functional outcome (55.0%) and cognitive impairment (47.5%). A prolonged time to cessation of SE-SLE seizure activity was associated with unfavorable long-term outcome. CONCLUSIONS: Diagnostic accuracy of SE-SLE requires better understanding of the etio-pathogenesis and the spectrum of clinical presentations of SE-SLE. Prompt initiation of immune therapy improve SE-SLE outcome, yet optimal therapeutic strategies remain to be determined. Identifying novel biomarkers that distinguish between different forms of SE-SLE and target cellular inflammatory response will help with specific SE-SLE treatment guidelines and prevent poor outcome.

Autoimmune Dysphagia Related to Rheumatologic Disorders: A Focused Review on Diagnosis and Treatment.

Autoimmune dysphagia is defined as dysphagia caused by autoimmune processes affecting various components of the swallowing process such as muscle, neuromuscular junction, nerves, roots, brainstem, or cortex. These autoimmune causes can be classified into gastroenterological, dermatological, rheumatologic, and neurologic. Rheumatological disorders, such as scleroderma, Sjogren's syndrome, systemic lupus erythematosus, rheumatoid arthritis, sarcoidosis, Behcet's disease, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, or granulomatosis with polyangiitis, have been associated with dysphagia. Autoimmune dysphagia in the context of rheumatological disorders is particularly significant because it can occur as a sole manifestation or as part of a symptom complex associated with the underlying disorder and often responds to immunosuppressive therapies. However, diagnosing autoimmune dysphagia can be challenging as it requires the exclusion of structural and primary motility disorders through procedures such as endoscopy and manometry. Early diagnosis is important to improve the quality of life and prevent significant mortality and morbidity. Management focuses on treating the underlying disease activity, and a multidisciplinary approach involving various medical specialties may be necessary to achieve success. This article aims to review the autoimmune rheumatological conditions that can lead to dysphagia and discuss the associated pathophysiological mechanisms. We also outline the clinical clues and laboratory testing methods that facilitate early diagnosis, with the goal of improving patient outcomes through timely intervention and appropriate management.

Cardiorespiratory Insufficiency and Performance Fatigability in Women with Systemic Lupus Erythematosus.

Purpose: Patients with systemic lupus erythematosus (SLE) experience excessive, debilitating fatigue with previously reported evidence of etiologically mediated cardiorespiratory impairments. Performance fatigability provides a precise characterization of fatigue as it can be quantified objectively as a function of time, frequency, and/or duration. Nevertheless, little consideration has been given to understanding performance fatigability and its physiological determinants in those with SLE. The purpose of this study was to characterize performance fatigability in patients with SLE, utilizing measures surrounding the anaerobic threshold, with emphasis on cardiorespiratory impairment as a potential mediating factor. Methods: This was a case-control study design. 44 physically inactive women, 26 with SLE and 18 controls, completed a treadmill cardiopulmonary exercise test to volitional exhaustion. Results: There were no significant differences in age (SLE 34.8(9.0) vs Control 36.9(7.3) yrs; p=0.422) between groups. BMI (SLE 27.1(5.4) vs Control 23.8(5.2) kg/m2; p=0.045) was significantly higher in the SLE vs Control group. Resting heart rate (SLE 68(16) vs Control 78(15) bpm; p=0.040) was significantly lower in the SLE compared to the Control group. The VO2 corresponding to the anaerobic threshold (AT-VO2), used to identify the onset of exercise-induced fatigue, was significantly lower in women with SLE than in controls (SLE 12.4(3.1) vs Control 16.4(2.2) ml/kg/min; p<0.001), as was AT-stage (SLE 2.5(0.90) vs Control 3.4(0.78); p=0.002). Additionally, Fatigue Severity Score (FSS) was highly and inversely correlated with AT-VO2 (rho=-0.615; p<0.001) and FSS was highly correlated with Functional Aerobic Impairment Index (FAI; rho=0.663; p<0.001). Conclusion: This study underscores severe performance fatigability in patients with SLE and its link to cardiorespiratory insufficiency. Physiological presentation of performance fatigability was observed during very low intensities of exercise, emphasizing the negative impact it may have on physical function in this population.

Lamotrigine-Induced Lupus With Aseptic Meningitis and Hemophagocytic Lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome characterized by disordered immune activation resulting in cytokine storm and inflammation. We present a 27-year-old woman who had a fever and diffuse rash after recently starting lamotrigine. She developed meningismus and polyarthralgia. Laboratory results revealed cytopenia, elevated serum aminotransferases, hypofibrinogenemia and elevated ferritin. Cerebrospinal fluid analysis suggested aseptic meningitis. Antinuclear antibody and rheumatoid factor serologies were positive, complement levels of C3 were decreased, and antihistone antibody was negative. A bone marrow biopsy demonstrated hemophagocytic macrophages and the diagnosis of HLH was made. The patient was empirically started on high-dose intravenous dexamethasone following which both her mental status and laboratory indices markedly improved. Lamotrigine has been shown to induce lupus-like syndrome, aseptic meningitis, and HLH, but not concomitantly. Our patient was recently started on lamotrigine, likely inducing her underlying undiagnosed lupus, in addition to, resulting in aseptic meningitis and a cytokine storm leading to HLH.

The Meaningful Role of Patients, and Other Stakeholders in Clinical Practice Guideline Development.

Patient participation is an integral component in the development of clinical practice guidelines. However, patient engagement remains suboptimal, which signifies a predicament in guideline's legitimacy and transparency. Limited budgets, logistic constraints, and discordance in patients' and researchers' perception of a meaningful involvement are some barriers that hinder patient engagement. Advancing skill development across various roles within the guideline's process will enrich patient's contribution and allow them to voice their experience, knowledge, perspective, and concerns. Continuing patient education and evaluation of their engagement on both outcome and process will facilitate team cohesion, trustworthiness, and value to achieve optimal quality of care.

The association of breathing pattern with exercise tolerance and perceived fatigue in women with systemic lupus erythematosus: an exploratory case-control study.

The aims of the study were to (1) to characterize the breathing pattern and work of breathing during peak exercise in patients with SLE; (2) to examine the extent to which the breathing pattern and work of breathing impact the exercise capacity and fatigue. Forty-one women participated in the study (SLE: n = 23, median = 35, range = 21-57 years, control: n = 18, median = 38, range = 22-45 years). Each subject performed a treadmill cardiopulmonary exercise test (a modified Bruce treadmill protocol) ending with volitional exhaustion. Breathing mechanic was characterized by measures of expired minute volume (VE), tidal volume (Vt), respiratory rate (f), work of breathing, and cardiorespiratory fitness was quantified by measures of peak oxygen consumption (VO2) and time to exhaustion. Data presented as median and interquartile range (IQR). Women with SLE had lower Vt {1221 [488.8] mL/min vs. 1716 [453.1] mL; p = .006}, VE {58.9 [18.9] L/min vs 70 [28.1] L/min, p = 0.04} and increased breathing frequency {51.5 [10.8] vs 43.6 [37.8] bpm, p = 0.01} compared to the control group. The time to exhaustion and peak VO2 during the CPET were significantly reduced in those with SLE compared to controls {13.3 [10.2] vs 16.1 [2.2] min; p = 0.004}, {20 [6.1] mL/kg/min vs 26.6 [7] mL/kg/min p < 0.001}, respectively. Differences remained when the analyses were controlled for the observed differences in peak VO2. When the regression model adjusted for the peak VO2, it had been shown that Vt, WOB and f were explained variances in the fatigue severity by 64% [p < 0.001]. The decline in VE and Vt coupled with a decreased peak VO2, and work of breathing may have contributed to low cardiorespiratory fitness and fatigue in patients with systemic lupus erythematosus.

Isolated Antineutrophil Cytoplasmic Antibody-Associated Coronary Vasculitis and Valvulitis.

A 30-year-old woman presented with angina pectoris. Coronary angiography revealed severe stenosis in the left main and right coronary arteries that did not improve with intracoronary nitroglycerin. Coronary computed tomography angiography and positron emission tomography revealed coronary ostia inflammation and aortic root fat stranding. She was diagnosed with vasculitis and valvulitis and received immunotherapy and coronary bypass. (Level of Difficulty: Advanced.).

Hepatitis B virus infection associated with polyarteritis nodosa and microscopic polyangiitis.

We reported a unique case with the coexistence of classic and cutaneous polyarteritis nodosa (PAN), and microscopic polyangiitis (MPA) in hepatitis virus-associated vasculitis. A 77-year-old Asian man presented with extremity weakness and weight loss found to have bilateral foot drop and rash on his hands and legs. Labs reveal positive for hepatitis B core antibody and perinuclear-antineutrophil cytoplasmic antibody (p-ANCA), decreased C3 and C4 levels. Skin biopsy of rash shows medium vessel vasculitis suggesting PAN. Interestingly, renal biopsy showed features of necrotising medium-sized arteritis consistent with PAN and focal crescentic glomerulonephritis consistent with MPA. The patient was treated with 1 g of solumedrol daily for 3 days, followed by oral steroids and cyclophosphamide treatment for vasculitis, and entecavir for chronic hepatitis B infection, resulting in resolution of symptoms. The patient has not had a relapse at 6 months.

Anti-synthetase syndrome in a patient with recurrent episodes of pulmonary embolism: a case report.

Anti-synthetase syndrome (ASS) is characterized by myositis that is associated with progressive interstitial lung disease (ILD). The prognosis of the disease is affected by the type and degree of pulmonary involvement. We report a rare case of ASS with positive Anti-EJ antibody presenting with a combination of recurrent deep vein thrombosis/pulmonary embolism (DVT/PE) and progressive ILD. This case demonstrates the delayed diagnosis of ASS and the association of thromboembolic disease and ASS. Physicians should have a high index of suspicion for ASS, as early diagnosis and management alters the morbidity and prognosis of patients with ASS. ABBREVIATIONS: ASS: Anti-synthetase syndrome; Ab: Antibody; Ag: Antigen; ANA: Anti-nuclear antibodies; CK: Creatine kinase; CRP: C-reactive protein; DVT: Deep Vein Thrombosis; ESR: Erythrocyte Sedimentation Rate; ILD: Interstitial lung disease; PE: Pulmonary Embolism; CTA: CT Angiography.

Measuring and monitoring health-related quality of life responsiveness in systemic lupus erythematosus patients: current perspectives.

OBJECTIVE: Little is known about health-related quality of life (HRQoL) responsiveness in systemic lupus erythematosus (SLE) patients, compared to other chronic diseases. This review summarizes the available data in HRQoL responsiveness and sensitivity to change in SLE, and recommends directions for research and clinical application. METHODS: A review of the literature was conducted reporting on HRQoL responsiveness in adult SLE patients between 1984 and 2018. HRQoL studies were assessed for responsiveness, sensitivity of change, minimal important differences, minimal clinical important differences, or change in improvement or deterioration. RESULTS: Responsiveness or sensitivity to change in health-related status was observed in Medical Outcome Survey Short Form-36, SLE Symptom Checklist, EuroQoL, and Medical Outcomes Study Short Form 6D. SLE-specific quality of life questionnaire demonstrated greater responsiveness than the individual domains of SF-36. Lupus quality of life showed large responsiveness when there was improvement. LupusPRO and its derivative Lupus Impact Tracker were found to be responsive to change in disease activity, reflecting both improvement and worsening. Lupus Impact Tracker and physical health and pain domains of Lupus quality of life were responsive to SLE composite responder index. CONCLUSION: This review highlights the need for further studies that capture responsiveness and change in HRQoL that are clinically meaningful and sustained. Most importantly, the choice of one measure over another is influenced by the purpose of the HRQoL measure, the particular HRQoL domain, and the SLE disease state that are relevant to the research question.

Altered functional neuronal activity in neuropsychiatric lupus: A systematic review of the fMRI investigations.

OBJECTIVE: Recent years have seen a rapid increase in the investigation of neuropsychiatric lupus (NPSLE) through the use of functional magnetic resonance imaging (fMRI). Measuring specific neuronal activity in regional brain structures during a cognitive task may identify possible biomarker for NPSLE. METHODS: A systematic review of fMRI studies of systemic lupus erythematosus (SLE) is carried out to address common findings that characterize NPSLE. RESULTS: A disturbance to the working memory and executive function brain regions is among the most well-replicated finding. Differences in brain activation may relate to an early primary dysfunction of these regions. Increased functional connectivity strength in the fronto-parietal cortex in the resting state is correlated with SLE disease activity in one study. Decrease functional connectivity is observed in lupus patients with long-term disease. However, there is strong evidence that points toward a lack of effective integration of distributed functional brain regions and disruptions in the subtle modulation of brain function in relation to task demands in SLE. Limitations of the literature to date include the use of small sample size and the lack of addressing the effect of confounding variables, including immunosuppressive treatment. CONCLUSION: Careful definitions of the fMRI technique used both in the design, analyses, and interpretation of high dimensional data is needed, when dealing with a limited number of SLE subjects with heterogeneous manifestations and unknown pathophysiology.

Measuring disease activity in adults with systemic lupus erythematosus: the challenges of administrative burden and responsiveness to patient concerns in clinical research.

Measuring lupus disease activity accurately remains a challenging and demanding task given the complex multi-system nature of lupus, an illness known for its variability between patients and within the same patient over time. Many have attempted to define what disease activity means and how it should be measured, and several instruments were devised for a standardized assessment of disease activity and outcome domains in clinical research. Several of these measuring tools have been able to detect clinical improvement and have demonstrated adequate reliability, validity, and sensitivity to change in observational studies, and some were found to be useful in randomized controlled trials. However, several failed clinical trials have confronted these metrics, as they were not intended for clinical trials. The Outcome Measures Rheumatology group and the US Food and Drug Administration have recommended using measures of disease activity, cumulative organ damage, health-related quality of life, and adverse events as outcomes of interest. Composite responder indices that determine disease global improvement, ensure no significant worsening in unaffected organ systems, and include a physician's global assessment have been used in randomized clinical trials. Yet unmet therapeutic needs were further challenged by the complex content and psychometric information of the updated instruments, including increased administrative burden associated with demanding training and cost of instruments, and small effect size associated with responsiveness to patient concerns. Nevertheless, with the progress of novel targeted therapy, refining the disease activity metrics is essential. Selection of the disease activity endpoints which is a defining aspect of clinical trial design must be tailored to the outcome of interest and measured by a reliably rated scale characterized by minimal administrative burden. An optimal scale should be simple and practical and incorporate elements of patient concerns.

Recurrent pneumatosis intestinalis in a patient with dermatomyositis.

A 51-year-old woman with dermatomyositis (DM) on chronic immunosuppressive therapy was hospitalised for evaluation of haematuria. Surprisingly, abdominal imaging demonstrated pneumoperitoneum and pneumatosis intestinalis (PI). Her abdominal examination and white cell count were normal, but she subsequently developed nausea and fever. Owing to concern for perforation, a hemicolectomy was performed. Pathology revealed PI without inflammatory, ischaemic or neoplastic features, and she recovered uneventfully. Her immunosuppressive therapy was discontinued. Six months later, a follow-up CT of the abdomen revealed recurrence of PI. As she was asymptomatic, she was managed conservatively with resolution of PI on subsequent imaging. PI is characterised by the presence of gas within the wall of the intestine. Its aetiology is often unclear but this case highlights the association between PI and both immunosuppressive therapy and DM. A review of PI in patients with DM suggests that clinically stable patients may be observed, while avoiding surgical intervention.

Exploratory study on oxygen consumption on-kinetics during treadmill walking in women with systemic lupus erythematosus.

OBJECTIVE: To determine whether oxygen consumption (V o(2)) on-kinetics differed between groups of women with systemic lupus erythematosus (SLE) and sedentary but otherwise healthy controls. DESIGN: Exploratory case-control study. SETTING: Medical school exercise physiology laboratory. PARTICIPANTS: Convenience samples of women with SLE (n=12) and sedentary but otherwise healthy controls (n=10). INTERVENTION: None. MAIN OUTCOME MEASURES: V o(2) on-kinetics indices including time to steady state, rate constant, mean response time (MRT), transition constant, and oxygen deficit measured during bouts of treadmill walking at intensities of 3 and 5 metabolic equivalents (METs). RESULTS: Time to steady state and oxygen deficit were increased and rate constant was decreased in the women with SLE compared with controls. At the 5-MET energy demand, the transition constant was lower and MRT was longer in the women with SLE than in controls. For a similar relative energy expenditure that was slightly lower than the anaerobic threshold, the transition constant was higher in controls than in women with SLE. CONCLUSION: V o(2) on-kinetics was prolonged in women with SLE. The prolongation was concomitant with an increase in oxygen deficit and may underlie performance fatigability in women with SLE.

Immediate type I hypersensitivity response implicated in worsening injection site reactions to adalimumab.

BACKGROUND: Tumor necrosis factor (TNF) inhibitors such as adalimumab, etanercept, and infliximab play an increasingly important role in the management of a variety of chronic inflammatory disorders. With their increasing use, a wide spectrum of dermatological adverse effects, including injection site reactions and the development of dermatitis, have been recognized. Previous studies have implicated the role of the delayed-type hypersensitivity reaction in mediation of injection site reactions to etanercept. To our knowledge, there have been no published studies on immunologic mechanism of injection site reactions to adalimumab to date. OBSERVATIONS: We describe 2 patients with a history of worsening injection site reactions to adalimumab. Findings from skin testing in both patients were suggestive of an immediate type I hypersensitivity reaction to adalimumab. A histamine release assay performed on peripheral blood leukocytes from both patients demonstrated significant histamine release on exposure to adalimumab. Furthermore, passive transfer of serum from one of the allergic patients to basophils from a nonatopic, healthy donor sensitized those cells to release significant amounts of histamine with exposure to adalimumab. Conclusion This study demonstrates that an IgE-mediated immediate type I hypersensitivity reaction plays a role in the mediation of worsening injection site reactions in some patients receiving adalimumab.

Recurrent benign lymphocytic (mollaret) meningitis in systemic lupus erythematosus.

BACKGROUND: Aseptic meningitis is one of the most infrequent neuropsychiatric manifestations of systemic lupus erythematosus (SLE) with multifactorial etiologies including medications such as nonsteroidal anti-inflammatory drugs, azathioprine, and trimethoprim-sulfamethoxasole, as well as viruses and malignancy. Recurrent aseptic meningitis in SLE is rare, and remains a diagnostic challenge. METHODS: We report a unique SLE patient with recurrent (10 episodes), benign (self-limited) lymphocytic aseptic meningitis, which suggests the diagnosis of Mollaret meningitis. There was no prior use of medications known to provoke meningitis. No infectious etiology was identified and chronic meningitis was not observed. The patient had spontaneous resolution of symptoms with no neurologic sequelae. CONCLUSION: Recurrent benign lymphocytic aseptic meningitis is recognized in this SLE patient. We propose that noninfectious Mollaret meningitis be classified as a feature of neuropsychiatric SLE syndromes.