OMERACT 2023 Systemic Lupus Erythematosus Special Interest Group: Winnowing and Binning Preliminary Candidate Domains for the Core Outcome Set.

BACKGROUND: The Outcome Measures in Rheumatology (OMERACT) Systemic Lupus Erythematosus (SLE) Working Group held a Special Interest Group (SIG) at the OMERACT 2023 conference in Colorado Springs where SLE collaborators reviewed domain sub-themes generated through qualitative research and literature review. OBJECTIVE: The objective of the SIG and the subsequent meetings of the SLE Working Group was to begin the winnowing and binning of candidate domain sub-themes into a preliminary list of candidate domains that will proceed to the consensus Delphi exercise for the SLE COS. METHODS: Four breakout groups at the SLE SIG in Colorado Springs winnowed and binned 132 domain sub-themes into candidate domains, which was continued with a series of virtual meetings by an advisory group of SLE patient research partners (PRPs), members of the OMERACT SLE Working Group Steering Committee, and other collaborators. RESULTS: The 132 domain sub-themes were reduced to a preliminary list of 20 candidate domains based on their clinical and research relevance for clinical trials and research studies. CONCLUSION: A meaningful and substantial winnowing and binning of candidate domains for the SLE COS was achieved resulting in a preliminary list of 20 candidate domains.

Assessing the Utility of the Montreal Cognitive Assessment in Screening for Cognitive Impairment in Patients With Systemic Lupus Erythematosus.

OBJECTIVE: Screening for cognitive impairment (CI) in systemic lupus erythematosus (SLE) relies on the American College of Rheumatology (ACR) neuropsychological battery (NB). By studying the concurrent criterion validity, our goal was to assess the Montreal Cognitive Assessment (MoCA) as a screening tool for CI compared to the ACR-NB and to evaluate the added value of the MoCA to the Automated Neuropsychological Assessment Metrics (ANAM). METHODS: A total of 285 adult SLE patients were administered the ACR-NB, MoCA, and ANAM. For the ACR-NB, patients were classified as having CI if there was a Z score of ≤-1.5 in ≥2 domains. The area under the curve (AUC) and sensitivities/specificities were determined. A discriminant function analysis was applied to assess the ability of the MoCA to differentiate between CI, undetermined CI, and non-CI patients. RESULTS: CI was not accurately identified by the MoCA compared to the ACR-NB (AUC of 0.66). Sensitivity and specificity were poor at 50% and 69%, respectively, for the cutoff of 26, and 80% and 45%, respectively, for the cutoff of 28. The MoCA had a low ability to identify CI status. The addition of the MoCA to the ANAM led to improvement on the AUC by only 2.5%. CONCLUSION: The MoCA does not have adequate concurrent criterion validity to accurately identify CI in patients with SLE. The low specificity of the MoCA may lead to overdiagnosis and concern among patients. Adding the MoCA to the ANAM does not substantially improve the accuracy of the ANAM. These results do not support using the MoCA as a screening tool for CI in patients with SLE.

Steroid treatment suppresses the CD4+ T-cell response to the third dose of mRNA COVID-19 vaccine in systemic autoimmune rheumatic disease patients.

Prolonged steroid treatment has a suppressive effect on the immune system, however, its effect on the cellular response to mRNA vaccine is unknown. Here we assessed the impact of prolonged steroid treatment on the T-cell and humoral response to the SARS-CoV-2 spike (S) peptide following the third dose of the BNT162b2 vaccine in systemic autoimmune rheumatic disease patients. We found that CD4 T-cell response to the S peptide in patients on high-dose long-term steroid treatment showed significantly less S-peptide specific response, compare to low-dose or untreated patients. Remarkably, these results were not reflected in their humoral response, since almost all patients in the cohort had sufficient antibody levels. Moreover, S-peptide activation failed to induce significant mRNA levels of IFNγ and TNFα in patients receiving high-dose steroids. RNA-sequencing datasets analysis implies that steroid treatments' inhibitory effect of nuclear factor kappa-B signaling may interfere with the activation of S-specific CD4 T-cells. This reveals that high-dose steroid treatment inhibits T-cell response to the mRNA vaccine, despite having sufficient antibody levels. Since T-cell immunity is a crucial factor in the immune response to viruses, our findings highlight the need for enhancing the efficiency of vaccines in immune-suppressive patients, by modulation of the T-cell response.

Immunogenicity and safety of the mRNA-based BNT162b2 vaccine in systemic autoimmune rheumatic diseases patients.

BACKGROUND: The COVID-19 outbreak has led to the rapid development and administration of the COVID-19 vaccines worldwide. Data about the immunogenicity and adverse effects of the vaccine on patients with systemic autoimmune rheumatic diseases (SARDs) is emerging. AIM: To evaluate Pfizer/BioNTech (BNT162b2) mRNA-based vaccine second-dose immunogenicity and safety, and the relation between them, in patients with SARDs. METHODS: A total of one hundred forty tow adults who received two doses of the BNT162b2 vaccine were included in the study. The SARDs group included Ninety-nine patients and the control group (forty-three participants) comprised a mixture of healthy participants and patients who were seen at the rheumatology clinic for non-SARDs. Anti-SARS-CoV-2 IgG antibodies against the Spike protein were evaluated using a SARS-CoV-2 IgG immunoassay. A level of > 150 AU/mL was considered positive. An adverse effects questionnaire was given to the participants upon their first visit to the clinic after their BNT162b2 vaccination. RESULTS: Of the 142 participants, 116 were seropositive (81.7%) and 26 (18.3%) were seronegative. Of the seronegative participants, 96.2% were SARDs patients. The proportion of seropositivity in the SARDs patients treated with any immunosuppressant was significantly lower (69.9%) compared to the control group and SARDs patients not receiving immunosuppressants (96.8%). A significant negative correlation between seronegativity and treatment with rituximab, mycophenolate mofetil (MMF), and prednisone was found in the SARDs group (p = 0.004, 0.044, 0.007 respectively). No fever was observed following the BNT162b2 vaccine in seronegative patients, and the frequency of musculoskeletal adverse effects upon the second dose of the BNT162b2 vaccine was significantly higher in seropositive compared to seronegative patients and in the control group compared to the SARDs patients (p = 0.045, p = 0.02 respectively). CONCLUSION: A decline in the immunogenicity to the second dose of BNT162b2 mRNA is seen in patients with SARDs, especially in patients treated with rituximab, MMF, and prednisone. Adverse effects of the vaccine including fever and musculoskeletal symptoms might be a signal for the acquisition of immunity in those patients. KEY POINTS: • BNT162b2 mRNA vaccine is less immunogenic in SARDs patients compared to the control group. • Rituximab, prednisone, and mycophenolate mofetil significantly reduced immunogenicity to the vaccine. • There is a correlation between immunogenicity and adverse effects of the vaccine.

Neuropsychiatric Systemic Lupus Erythematosus in Older Adults: Diagnosis and Management.

Systemic lupus erythematosus (SLE) is a multisystem chronic autoimmune disease with variable clinical manifestations. Neuropsychiatric systemic lupus erythematosus (NPSLE) includes the neurologic syndromes of the central, peripheral and autonomic nervous system and the psychiatric syndromes observed in patients with SLE. Neuropsychiatric systemic lupus erythematosus events may present as an initial manifestation of SLE or may be diagnosed later in the course of the disease. Older adults with NPLSE include those who are ageing with known SLE and those with late-onset SLE. The diagnosis of NPSLE across the lifespan continues to be hampered by the lack of sensitive and specific laboratory and imaging biomarkers. In this review, we discuss the particular complexity of NPSLE diagnosis and management in older adults. We first discuss the epidemiology of late-onset NPSLE, then review principles of diagnosis of NPSLE, highlighting issues that are pertinent to older adults and that make diagnosis and attribution more challenging, such as atypical disease presentation, higher medical comorbidity, and differences in neuroimaging and autoantibody investigations. We also discuss clinical issues that are of particular relevance to older adults that have a high degree of overlap with SLE, including drug-induced lupus, cerebrovascular disease and neurocognitive disorders. Finally, we review the management of NPSLE, mainly moderate to high- dose glucocorticoids and immunosuppressants, again highlighting considerations for older adults, such as increased medication (especially glucocorticoids) adverse effects, ageing-related pharmacokinetic changes that can affect SLE medication management, medication dosing and attention to medical comorbidities affecting brain health.

Validity and reliability of patient reported outcomes measurement information system computerized adaptive tests in systemic lupus erythematous.

BACKGROUND: The evaluation of Patient Reported Outcomes Measurement Information System (PROMIS) computerized adaptive test (CAT) in adults with systemic lupus erythematous (SLE) is an emerging field of research. We aimed to examine the test-retest reliability and construct validity of the PROMIS CAT in a Canadian cohort of patients with SLE. METHODS: Two hundred twenty-seven patients completed 14 domains of PROMIS CAT and seven legacy instruments during their clinical visits. Test-retest reliability of PROMIS was evaluated 7-10 days from baseline using intraclass correlation coefficient (ICC (2; 1)). The construct validity of the PROMIS CAT domains was evaluated against the commonly used legacy instruments, and also in comparison to disease activity and disease damage using Spearman correlations. A multitrait-multimethod matrix (MMM) approach was used to further assess construct validity comparing selected 10 domains of PROMIS and SF-36 domains. RESULTS: Moderate to excellent reliability was found for all domains (ICC [2;1] ranging from lowest, 0.66 for Sleep Disturbance and highest, 0.93 for the Mobility domain). Comparing seven legacy instruments with 14 domains of PROMIS CAT, moderate to strong correlations (0.51-0.91) were identified. The average time to complete all PROMIS CAT domains was 11.7 min. The MMM further established construct validity by showing moderate to strong correlations (0.55-0.87) between select PROMIS and SF-36 domains; the average correlations from similar traits (convergent validity) were significantly greater than the average correlations from different traits. CONCLUSIONS: These results provide evidence on the reliability and validity of PROMIS CAT in SLE in a Canadian cohort.

Clinical experience with biologic treatment in resistant eosinophilic fasciitis: Case reports and review of the literature.

RATIONALE: Eosinophilic fasciitis (EF) is an uncommon connective tissue disorder characterized by limb and trunk erythema, with symmetrical thickening of the skin. Its pathogenesis is poorly understood. Treatment consists mainly of glucocorticoids. Yet, no randomized trials have evaluated therapies for this rare disease and the optimal treatment modality remains unclear. Although most patients show partial or complete response to glucocorticoids, many relapse upon drug tapering, while others either do not respond at all or fail to sustain prolonged remission. Second-line therapy for this rare disorder includes mainly methotrexate (MTX), azathioprine, cyclosporine and hydroxychloroquine. Recently, several attempts using rituximab and intravenous immunoglobulins (IVIG) have shown good clinical results. PATIENT CONCERNS: The three patients had good clinical response to glucocorticoid treatment, followed by disease flare when the drug dose was tapered. Adding methotrexate in all patients and azathioprine to patient 3 did not lead to remission. DIAGNOSES: EF was diagnosed in all patients based on clinical presentation accompanied by fascia biopsy that demonstrated eosinophilic fasciitis. INTERVENTIONS: The patients were successfully treated with rituximab or IVIG, achieving sustained remission. OUTCOMES: The three cases had good clinical response to glucocorticoid treatment, followed by disease flare when the drug dose was tapered. The patients were then successfully treated with rituximab or IVIG, achieving sustained remission. LESSONS: This review of three cases of EF supports the results of previous reports, suggesting addition of rituximab and IVIG is an effective treatment for patients with refractory disease.

Association between depression and anxiety with skin and musculoskeletal clinical phenotypes in systemic lupus erythematosus.

OBJECTIVES: To study the clinical phenotypes, determined based on cumulative disease activity manifestations, and sociodemographic factors associated with depression and anxiety in SLE. METHODS: Patients attending a single centre were assessed for depression and anxiety. SLE clinical phenotypes were based on the organ systems of cumulative 10-year SLE Disease Activity Index 2000 (SLEDAI-2K), prior to visit. Multivariable logistic regression analyses for depression, anxiety, and coexisting anxiety and depression were performed to study associated SLE clinical phenotypes and other factors. RESULTS: Among 341 patients, the prevalence of anxiety and depression was 34% and 27%, respectively, while 21% had coexisting anxiety and depression. Patients with skin involvement had significantly higher likelihood of anxiety compared with patients with no skin involvement [adjusted odds ratio (aOR) = 1.8; 95% CI: 1.1, 3.0]. Patients with skin involvement also had higher likelihood of having coexisting anxiety and depression (aOR = 2.0, 95% CI: 1.2, 3.9). Patients with musculoskeletal (MSK) (aOR = 1.9; 95% CI: 1.1, 3.5) and skin system (aOR = 1.8; 95% CI: 1.04, 3.2) involvement had higher likelihood of depression compared with patients without skin or musculoskeletal involvement. Employment status and fibromyalgia at the time of the visit, and inception status were significantly associated with anxiety, depression, and coexisting anxiety and depression, respectively. CONCLUSION: SLE clinical phenotypes, specifically skin or MSK systems, along with fibromyalgia, employment and shorter disease duration were associated with anxiety or depression. Routine patient screening, especially among patients with shorter disease duration, for these associations may facilitate the diagnosis of these mental health disorders, and allow for more timely diagnosis.

Validity Evidence for the Use of Automated Neuropsychologic Assessment Metrics As a Screening Tool for Cognitive Impairment in Systemic Lupus Erythematosus.

OBJECTIVE: Screening for cognitive impairment in systemic lupus erythematosus (SLE) conventionally relies on the American College of Rheumatology (ACR) neuropsychologic battery (NB), which is not universally available. To develop a more accessible screening approach, we assessed validity of the Automated Neuropsychological Assessment Metrics (ANAM). Using the ACR NB as the gold standard for cognitive impairment classification, the objectives were 1) to measure overall discriminative validity of the ANAM for cognitive impairment versus no cognitive impairment, 2) to identify ANAM subtests and scores that best differentiate patients with cognitive impairment from those with no cognitive impairment, and 3) to derive ANAM composite indices and cutoffs. METHODS: A total of 211 consecutive adult patients, female and male, with SLE were administered the ANAM and ACR NB. 1) For overall discriminative validity of the ANAM, we compared patients with cognitive impairment versus those with no cognitive impairment on 4 scores. 2) Six ANAM models using different scores were developed, and the most discriminatory subtests were selected using logistic regression analyses. The area under the receiver operating characteristic curve (AUC) was calculated to establish ANAM validity against the ACR NB. 3) ANAM composite indices and cutoffs were derived for the best models, and sensitivities and specificities were calculated. RESULTS: Patients with no cognitive impairment performed better on most ANAM subtests, supporting ANAM's discriminative validity. Cognitive impairment could be accurately identified by selected ANAM subtests with top models, demonstrating excellent AUCs of 81% and 84%. Derived composite indices and cutoffs demonstrated sensitivity of 78-80% and specificity of 70%. CONCLUSION: This study provides support for ANAM's discriminative validity for cognitive impairment and utility for cognitive screening in adult SLE. Derived composite indices and cutoffs enhance clinical applicability.

Novel biological therapeutic approaches to cutaneous lupus erythematosus.

INTRODUCTION: Cutaneous lupus erythematosus (CLE) encompasses a spectrum of dermatologic manifestations which can occur with or without systemic lupus erythematosus (SLE). Treatment of CLE is challenging as the traditional treatments are off label and often fail and there is no drug specifically approved for CLE. The knowledge gained from the emerging trials on biologic therapy in SLE has provided insight into the utility of biologic therapy for CLE. AREAS COVERED: An overview is provided on the biological agents studied for CLE discussing their immunological target, their efficacy in treating the various CLE manifestations and the outcome measures used. EXPERT OPINION: There is a paucity of trials dedicated to the biologic treatment of CLE. Several of the described biological treatments' efficacy suggests that different clinical phenotypes of CLE may require different immunological targeted therapies. Recently published and ongoing trials of SLE focusing on novel agents for CLE using the Cutaneous Lupus Area and Severity Index (CLASI) as the outcome measure have shown promising results. Further trials designed specifically to study the efficacy of biologic treatment in CLE subgroups with or without systemic involvement using specific metrics for assessing cutaneous involvement are needed and will aid in illuminating the role of biologic therapy in CLE.

A practical approach to infarction of the spleen as a rare manifestation of multiple common diseases.

INTRODUCTION: There are insufficient data on the aetiologic factors underlying splenic infarction (SI). Therefore, there is no consensus regarding the appropriate diagnostic approach. METHODS: We conducted a retrospective analysis of all patients admitted with SI from January 2004 to December 2014. Medical records were screened for the clinical presentation, underlying causes, associated medical conditions and methods of patient evaluation. RESULTS: We found 89 subjects with 90 episodes of SI. Presentation of SI was characterized by abdominal, flank and chest pain (82.2%, 18.9%, 7.8%, respectively); leukocytosis (in 67% of tested subjects); elevated LDH (72%), CRP (97.5%) and D-Dimer (100%). The main underlying mechanisms were cardioembolic (54.4%), vascular (20%), haematologic disorders (15.6%) and multiple causes (21.1%). Atrial fibrillation and atherosclerosis were common in older patients (age > 70 years) while antiphospholipid syndrome occurred exclusively in younger individuals. SI was the presentation of previously unknown medical conditions in 38% of patients. Abdominal CT, ECG, echocardiography and blood cultures demonstrated the highest diagnostic yield. CONCLUSIONS: Contributing factors are identified in the majority of SI patients. We recommend CT, ECG, echocardiography and blood cultures in all cases. Atrial fibrillation should be sought in older patients, while APLS and haematologic disorders should be suspected in younger ones. KEY MESSAGES There is no consensus regarding the diagnostic approach and management of splenic infarction. Cardiovascular disease and atrial fibrillation are the main causes for SI in elderly subjects while hematological, infectious and other causes are more prevalent in younger ones. Our data strongly suggests a high diagnostic yield for CT scan, ECG, blood culture and echocardiogram in every patient with SI.

Physical Training in a Medical Fitness Room for Patients with Chronic Diseases: Functional and Metabolic Outcomes.

BACKGROUND: Physical inactivity is a pivotal factor in the development and progression of various chronic diseases. However, most fitness facilities exclude unhealthy individuals. Therefore, an exercise program that admits such patients is imperative. OBJECTIVES: To evaluate the effectiveness of a fitness facility that admits adult subjects with multiple chronic diseases. METHODS: We conducted a retrospective screening of patient records from the Medical Fitness Facility at Meir Medical Center, Israel. Intake of subjects was done by a multidisciplinary team. For each individual, personalized diet and exercise plans were developed and patients attended the facility twice a week. Each participant was evaluated at enrolment and after 4 months for well-being, metabolic parameters, exercise capacity, and laboratory blood tests. RESULTS: A total of 838 individuals were enrolled, mean age 57 years. Their medical conditions included dyslipidemia (48.8%), hypertension (37.6%), and diabetes mellitus (24.9%), followed by musculoskeletal problems (arthropathy 19%, lower back pain 16.1%) and ischemic heart disease (13.4%). Less common diagnoses were vascular diseases, pulmonary diseases, and malignancy. Only 40.5% of participants adhered to the regimen with advanced age being the best predictor for adherence. At the follow-up visit, body mass index was lower (31.2 vs. 30.2 kg/m2, P <0.0001), exercise capacity increased (measured as maximal MET; 7.1 vs. 8.1, P < 0.0001), and well-being improved (measured by Short Form Survey [SF-36]; 69.3 vs. 76.0, P <0.0001). CONCLUSIONS: We show that a fitness program for patients with multiple chronic diseases is feasible and effective in improving prognostic parameters, albeit significantly challenged by adherence limitations.

Refractory macrophage activation syndrome in a patient with SLE and APLA syndrome - Successful use of PET- CT and Anakinra in its diagnosis and treatment.

A patient with antiphospholipid syndrome, SLE and refractory fever is described. The cause for the fever was macrophage activation syndrome (MAS). The diagnosis of MAS was made with the help of PET-CT. Since the syndrome was refractory to conventional therapy with high-dose steroids and cyclosporin, anakinra was administered with complete recovery of the patient. The present case illustrates the difficulties in diagnosing MAS when multiple bone marrow biopsies fail to show hemophagocytosis. It emphasizes the significance of PET-CT in the diagnosis and evaluation of treatment of MAS. Finally, it describes the important role of Anakinra in treating refractory cases of MAS.

Cogan's syndrome--clinical guidelines and novel therapeutic approaches.

Cogan's syndrome (CS) is a rare chronic inflammatory disorder, classically characterized by interstitial keratitis and sensorineural hearing loss. Recurrent episodes of inner ear disease might result in deafness. In some patients, it may also be accompanied by systemic vasculitis. Diagnosis of CS is often missed or delayed due to its rarity, the nonspecific clinical signs at onset, and the lack of a confirmatory diagnostic test. The mechanisms responsible for CS are unknown; however, in the last decade, the pathogenesis has been somewhat elucidated, suggesting that the disease is a result of inner ear autoimmunity. The autoimmune hypothesis postulates the triggering of the disease by a viral infection via a number of mechanisms, which are mainly as follows: antigenic mimicry, self-perpetuating inflammation by cytokine release, and unveiling hidden epitopes. Aside from its clinical resemblance to other autoimmune disorders, some autoantigen has apparently been identified, namely, CD148 and connexine 26. Treatment should begin as early as possible. While treatment is based primarily on glucocorticoids, there is no standard alternative for patients who respond poorly. Failure of conventional treatment could lead to profound sensorineural hearing loss. From the limited data we have, infliximab seems to be the most promising biological remedy, enabling steroid tapering and leading to improvement in auditory/ocular disease, with better results when administered in early stages. Proposed guidelines for the use of infliximab in CS are found in the last table of the review, in an attempt to define the proper timing for initiating infliximab treatment in order to avoid permanent disability.

Major vessel thrombosis in Behçet's disease: the dilemma of anticoagulant therapy - the approach of rheumatologists from different countries.

OBJECTIVES: The best treatment for patients with Behçet's disease (BD) with major vessel thrombosis has not been fully determined. Our objective was to raise this therapeutic dilemma and to call for controlled studies to help establish guidelines to address this problem. METHODS: Three patients with BD and major vessel thrombosis whom we recently encountered are described. Their cases were presented to rheumatologists from Turkey, Israel and the USA. The physicians were asked about the kind of treatment they would give each patient at diagnosis of thrombosis and if they chose to give anticoagulation and for long. RESULTS: Fifty-five Turkish, 33 Israeli and 25 American rheumatologists responded to the questionnaire. More than 87% of the Israeli and American rheumatologists would give anticoagulation at the time of diagnosis for the cases of venous thrombosis compared with only 40-44% of the Turkish physicians. In these cases 56% of the American and 45% of the Israeli rheumatologists would give warfarin for life compared with only 5-18% of the Turkish physicians. Regarding a case with intra-cardiac thrombus, 96% of American, 94% of Israeli, and 60% of Turkish rheumatologists would start anticoagulation at diagnosis while 70%, 39% and 33%, respectively would give this treatment for life. CONCLUSIONS: The therapeutic approach towards thrombosis in Behçet's disease differs significantly among rheumatologists from different countries. The different prevalence of the disease in these countries may explain this difference. A randomised controlled prospective trial is needed in order to determine the exact role of anticoagulant treatment in BD.

Familial mediterranean Fever and hypercoagulability.

Familial Mediterranean fever (FMF) is an autosomal recessive hereditary disease which is characterized by recurrent attacks of fever and peritonitis, pleuritis, arthritis, or erysipelas-like skin disease. As such, FMF is a prototype of autoinflammatory diseases where genetic changes lead to acute inflammatory episodes. Systemic inflammation - in general - may increase procoagulant factors, and decrease natural anticoagulants and fibrinolytic activity. Therefore, it is anticipated to see more thrombotic events among FMF patients compared with healthy subjects. However, reviewing the current available literature and based upon our personal experience, thrombotic events related purely to FMF are very rare. Possible explanation for this discrepancy is that along with the procoagulant activity during FMF acute attacks, anticoagulant and fibrinolytic changes are also taking place. Colchicine which is the treatment of choice in FMF may also play a role in reducing inflammation thereby decreasing hypercoagulability.

Gemcitabine-induced supraventricular tachycardia.

The superior toxicity profile is one of the major reasons for the widespread use of gemcitabine in cancer treatment. Bone marrow suppression is the most common side effect, while non-hematological events are relatively infrequent. Cardiac toxicity is a rare complication and cardiac arrhythmia is even rarer. We report the case of a 67-year-old woman with metastatic breast cancer without a history of cardiac arrhythmia or ischemic heart disease who developed supraventricular tachycardia. The symptoms had started immediately after gemcitabine treatment. The arrhythmia responded poorly to common treatment and was eventually controlled by oral propranolol five days after admission. The present case suggests that supraventricular tachycardia may be triggered by gemcitabine even without underlying significant heart disease and may be resistant to conventional therapy.