Management of Neuropsychiatric Systemic Lupus Erythematosus: Current Approaches and Future Perspectives

Neuropsychiatric systemic lupus erythematosus (NPSLE) is a generic definition referring to a series of neurological and psychiatric symptoms directly related to systemic lupus erythematosus (SLE). NPSLE includes heterogeneous and rare neuropsychiatric (NP) manifestations involving both the central and peripheral nervous system. Due to the lack of a gold standard, the attribution of NP symptoms to SLE represents a clinical challenge that obligates the strict exclusion of any other potential cause. In the acute setting, management of these patients does not differ from other non-SLE subjects presenting with the same NP manifestation. Afterwards, an individualized therapeutic strategy, depending on the presenting manifestation and severity of symptoms, must be started. Clinical trials in NPSLE are scarce and most of the data are extracted from case series and case reports. High-dose glucocorticoids and intravenous cyclophosphamide remain the cornerstone for patients with severe symptoms that are thought to reflect inflammation or an underlying autoimmune process. Rituximab, intravenous immunoglobulins, or plasmapheresis may be used if response is not achieved. When patients present with mild to moderate NP manifestations, or when maintenance therapy is warranted, azathioprine and mycophenolate may be considered. When symptoms are thought to reflect a thrombotic underlying process, anticoagulation and antiplatelet agents are the mainstay of therapy, especially if antiphospholipid antibodies or antiphospholipid syndrome are present. Recent trials on SLE using new biologicals, based on newly understood SLE mechanisms, have shown promising results. Based on what we currently know about its pathogenesis, it is tempting to speculate how these new therapies may affect the management of NPSLE patients. This article provides a comprehensive and critical review of the literature on

Antibody response to SARS-CoV-2 in patients receiving glucocorticoids with or without tocilizumab for COVID-19-associated hyperinflammation

Pathophysiology and treatment of rheumatic disease

Three-month follow-up after severe COVID-19 infection: are chest CT results associated with respiratory outcomes and respiratory recovery in COVID-19 patients?

Background: CT Severity Score (CT-SS) can be used to assess the extent of severe coronavirus disease 19 (COVID-19) pneumonia. Follow-up CT-SS in patients surviving COVID-19-associated hyperinflammation and its correlation with respiratory parameters remains unknown. This study aims to assess the association between CT-SS and respiratory outcomes, both in hospital and at three months after hospitalization. Methods: Patients from the COVID-19 High-intensity Immunosuppression in Cytokine storm Syndrome (CHIC) study surviving hospitalization due to COVID-19 associated hyperinflammation were invited for follow-up assessment at three months after hospitalization. Results of CT-SS three months after hospitalization were compared with CT-SS at hospital admission. CT-SS at admission and at 3-months were correlated with respiratory status during hospitalization and with patient reported outcomes as well as pulmonary- and exercise function tests at 3-months after hospitalization. Results: A total of 113 patients were included. Mean CT-SS decreased by 40.4% (SD 27.6) in three months (P 80%pred vs. 14.3 (3.2) in those with DLCO Pathophysiology and treatment of rheumatic disease

Different phenotypes of neuropsychiatric systemic lupus erythematosus are related to a distinct pattern of structural changes on brain MRI

Objectives The underlying structural brain correlates of neuropsychiatric involvement in systemic lupus erythematosus (NPSLE) remain unclear, thus hindering correct diagnosis. We compared brain tissue volumes between a clinically well-defined cohort of patients with NPSLE and SLE patients with neuropsychiatric syndromes not attributed to SLE (non-NPSLE). Within the NPSLE patients, we also examined differences between patients with two distinct disease phenotypes: ischemic and inflammatory. Methods In this prospective (May 2007 to April 2015) cohort study, we included 38 NPSLE patients (26 inflammatory and 12 ischemic) and 117 non-NPSLE patients. All patients underwent a 3-T brain MRI scan that was used to automatically determine white matter, grey matter, white matter hyperintensities (WMH) and total brain volumes. Group differences in brain tissue volumes were studied with linear regression analyses corrected for age, gender, and total intracranial volume and expressed as B values and 95% confidence intervals. Results NPSLE patients showed higher WMH volume compared to non-NPSLE patients (p = 0.004). NPSLE inflammatory patients showed lower total brain (p = 0.014) and white matter volumes (p = 0.020), and higher WMH volume (p = 0.002) compared to non-NPSLE patients. Additionally, NPSLE inflammatory patients showed lower white matter (p = 0.020) and total brain volumes (p = 0.038) compared to NPSLE ischemic patients. Conclusion We showed that different phenotypes of NPSLE were related to distinct patterns of underlying structural brain MRI changes. Especially the inflammatory phenotype of NPSLE was associated with the most pronounced brain volume changes, which might facilitate the diagnostic process in SLE patients with neuropsychiatric symptoms.Neuro Imaging Researc

Different phenotypes of neuropsychiatric systemic lupus erythematosus are related to a distinct pattern of structural changes on brain MRI

Objectives The underlying structural brain correlates of neuropsychiatric involvement in systemic lupus erythematosus (NPSLE) remain unclear, thus hindering correct diagnosis. We compared brain tissue volumes between a clinically well-defined cohort of patients with NPSLE and SLE patients with neuropsychiatric syndromes not attributed to SLE (non-NPSLE). Within the NPSLE patients, we also examined differences between patients with two distinct disease phenotypes: ischemic and inflammatory. Methods In this prospective (May 2007 to April 2015) cohort study, we included 38 NPSLE patients (26 inflammatory and 12 ischemic) and 117 non-NPSLE patients. All patients underwent a 3-T brain MRI scan that was used to automatically determine white matter, grey matter, white matter hyperintensities (WMH) and total brain volumes. Group differences in brain tissue volumes were studied with linear regression analyses corrected for age, gender, and total intracranial volume and expressed as B values and 95% confidence intervals. Results NPSLE patients showed higher WMH volume compared to non-NPSLE patients (p = 0.004). NPSLE inflammatory patients showed lower total brain (p = 0.014) and white matter volumes (p = 0.020), and higher WMH volume (p = 0.002) compared to non-NPSLE patients. Additionally, NPSLE inflammatory patients showed lower white matter (p = 0.020) and total brain volumes (p = 0.038) compared to NPSLE ischemic patients. Conclusion We showed that different phenotypes of NPSLE were related to distinct patterns of underlying structural brain MRI changes. Especially the inflammatory phenotype of NPSLE was associated with the most pronounced brain volume changes, which might facilitate the diagnostic process in SLE patients with neuropsychiatric symptoms

EULAR points to consider on pathophysiology and use of immunomodulatory therapies in COVID-19

OBJECTIVES: Severe systemic inflammation associated with some stages of COVID-19 and in fatal cases led therapeutic agents developed or used frequently in Rheumatology being at the vanguard of experimental therapeutics strategies. The aim of this project was to elaborate EULAR Points to consider (PtCs) on COVID-19 pathophysiology and immunomodulatory therapies. METHODS: PtCs were developed in accordance with EULAR standard operating procedures for endorsed recommendations, led by an international multidisciplinary Task Force, including rheumatologists, translational immunologists, haematologists, paediatricians, patients and health professionals, based on a systemic literature review up to 15 December 2020. Overarching principles (OPs) and PtCs were formulated and consolidated by formal voting. RESULTS: Two OPs and fourteen PtCs were developed. OPs highlight the heterogeneous clinical spectrum of SARS-CoV-2 infection and the need of a multifaceted approach to target the different pathophysiological mechanisms. PtCs 1-6 encompass the pathophysiology of SARS-CoV-2 including immune response, endothelial dysfunction and biomarkers. PtCs 7-14 focus on the management of SARS-CoV-2 infection with immunomodulators. There was evidence supporting the use of glucocorticoids, especially dexamethasone, in COVID-19 cases requiring oxygen therapy. No other immunomodulator demonstrated efficacy on mortality to date, with however inconsistent results for tocilizumab. Immunomodulatory therapy was not associated with higher infection rates. CONCLUSIONS: Multifactorial pathophysiological mechanisms, including immune abnormalities, play a key role in COVID-19. The efficacy of glucocorticoids in cases requiring oxygen therapy suggests that immunomodulatory treatment might be effective in COVID-19 subsets. Involvement of rheumatologists, as systemic inflammatory diseases experts, should continue in ongoing clinical trials delineating optimal immunomodulatory therapy utilisation in COVID-19

2021 update of the EULAR points to consider on the use of immunomodulatory therapies in COVID-19

OBJECTIVES: To update the EULAR points to consider (PtCs) on the use of immunomodulatory therapies in COVID-19. METHODS: According to the EULAR standardised operating procedures, a systematic literature review up to 14 July 2021 was conducted and followed by a consensus meeting of an international multidisciplinary task force. The new statements were consolidated by formal voting. RESULTS: We updated 2 overarching principles and 12 PtC. Evidence was only available in moderate to severe and critical patients. Glucocorticoids alone or in combination with tocilizumab are beneficial in COVID-19 cases requiring oxygen therapy and in critical COVID-19. Use of Janus kinase inhibitors (baricitinib and tofacitinib) is promising in the same populations of severe and critical COVID-19. Anti-SARS-CoV-2 monoclonal antibodies and convalescent plasma may find application in early phases of the disease and in selected subgroups of immunosuppressed patients. There was insufficient robust evidence for the efficacy of other immunomodulators with further work being needed in relation to biomarker-based stratification for IL-1 therapy CONCLUSIONS: Growing evidence supports incremental efficacy of glucocorticoids alone or combined with tocilizumab/Janus kinase inhibitors in moderate to severe and critical COVID-19. Ongoing studies may unmask the potential application of other therapeutic approaches. Involvement of rheumatologists, as systemic inflammatory diseases experts, should be encouraged in clinical trials of immunomodulatory therapy in COVID-19

Identification of the PTPN22 functional variant R620W as susceptibility genetic factor for giant cell arteritis

Objective: To analyse the role of the PTPN22 and CSK genes, previously associated with autoimmunity, in the predisposition and clinical phenotypes of giant cell arteritis (GCA). Methods: Our study population was composed of 911 patients diagnosed with biopsy-proven GCA and 8136 unaffected controls from a Spanish discovery cohort and three additional independent replication cohorts from Germany, Norway and the UK. Two functional PTPN22 polymorphisms (rs2476601/R620W and rs33996649/R263Q) and two variants of the CSK gene (rs1378942 and rs34933034) were genotyped using predesigned TaqMan assays. Results: The analysis of the discovery cohort provided evidence of association of PTPN22 rs2476601/R620W with GCA (PFDR=1.06E-04, OR=1.62, CI 95% 1.29 to 2.04). The association did not appear to follow a specific GCA subphenotype. No statistically significant differences between allele frequencies for the other PTPN22 and CSK genetic variants were evident either in the case/control or in stratified case analysis. To confirm the detected PTPN22 association, three replication cohorts were genotyped, and a consistent association between the PTPN22 rs2476601/R620W variant and GCA was evident in the overall meta-analysis (PMH=2.00E-06, OR=1.51, CI 95% 1.28 to 1.79). Conclusions: Our results suggest that the PTPN22 polymorphism rs2476601/R620W plays an important role in the genetic risk to GCA

EULAR points to consider on pathophysiology and use of immunomodulatory therapies in COVID-19

Objectives Severe systemic inflammation associated with some stages of COVID-19 and in fatal cases led therapeutic agents developed or used frequently in Rheumatology being at the vanguard of experimental therapeutics strategies. The aim of this project was to elaborate EULAR Points to consider (PtCs) on COVID-19 pathophysiology and immunomodulatory therapies. Methods PtCs were developed in accordance with EULAR standard operating procedures for endorsed recommendations, led by an international multidisciplinary Task Force, including rheumatologists, translational immunologists, haematologists, paediatricians, patients and health professionals, based on a systemic literature review up to 15 December 2020. Overarching principles (OPs) and PtCs were formulated and consolidated by formal voting. Results Two OPs and fourteen PtCs were developed. OPs highlight the heterogeneous clinical spectrum of SARS-CoV-2 infection and the need of a multifaceted approach to target the different pathophysiological mechanisms. PtCs 1–6 encompass the pathophysiology of SARS-CoV-2 including immune response, endothelial dysfunction and biomarkers. PtCs 7–14 focus on the management of SARS-CoV-2 infection with immunomodulators. There was evidence supporting the use of glucocorticoids, especially dexamethasone, in COVID-19 cases requiring oxygen therapy. No other immunomodulator demonstrated efficacy on mortality to date, with however inconsistent results for tocilizumab. Immunomodulatory therapy was not associated with higher infection rates. Conclusions Multifactorial pathophysiological mechanisms, including immune abnormalities, play a key role in COVID-19. The efficacy of glucocorticoids in cases requiring oxygen therapy suggests that immunomodulatory treatment might be effective in COVID-19 subsets. Involvement of rheumatologists, as systemic inflammatory diseases experts, should continue in ongoing clinical trials delineating optimal immunomodulatory therapy utilisation in COVID-19

2021 update of the EULAR points to consider on the use of immunomodulatory therapies in COVID-19

Objectives: To update the EULAR points to consider (PtCs) on the use of immunomodulatory therapies in COVID-19. Methods: According to the EULAR standardised operating procedures, a systematic literature review up to 14 July 2021 was conducted and followed by a consensus meeting of an international multidisciplinary task force. The new statements were consolidated by formal voting. Results: We updated 2 overarching principles and 12 PtC. Evidence was only available in moderate to severe and critical patients. Glucocorticoids alone or in combination with tocilizumab are beneficial in COVID-19 cases requiring oxygen therapy and in critical COVID-19. Use of Janus kinase inhibitors (baricitinib and tofacitinib) is promising in the same populations of severe and critical COVID-19. Anti-SARS-CoV-2 monoclonal antibodies and convalescent plasma may find application in early phases of the disease and in selected subgroups of immunosuppressed patients. There was insufficient robust evidence for the efficacy of other immunomodulators with further work being needed in relation to biomarker-based stratification for IL-1 therapy Conclusions: Growing evidence supports incremental efficacy of glucocorticoids alone or combined with tocilizumab/Janus kinase inhibitors in moderate to severe and critical COVID-19. Ongoing studies may unmask the potential application of other therapeutic approaches. Involvement of rheumatologists, as systemic inflammatory diseases experts, should be encouraged in clinical trials of immunomodulatory therapy in COVID-19