The mediating effect of fatigue in impaired quality of life in systemic lupus erythematosus: mediation analysis of the French EQUAL cohort.

OBJECTIVES: Mediation analyses were conducted to measure the extent to which musculoskeletal (MSK) flares and depression affected physical health through excessive fatigue. METHODS: Mediation analyses were performed in a large multicentre cohort of SLE patients. Domains of the LupusQoL and SLEQOL questionnaires were selected as outcomes, MSK flares according to the SELENA-SLEDAI flare index (SFI-R) score and depression defined by Center for Epidemiologic Studies-Depression scale (CES-D) scale as exposures and different fatigue domains from MFI-20 and LupusQoL questionnaires as mediators. For each model, total, direct, indirect effects and proportion of effect mediated by fatigue (i.e. proportion of change in health-related quality of life) were determined. RESULTS: Of the 336 patients, 94 (28%) had MSK flares at inclusion and 99 (29.5%) were considered with depression. The proportion of the total effect of MSK flares on physical health impairment explained by fatigue ranged from 59.6% to 78% using the LupusQOL 'Physical health' domain and from 51.1% to 73.7% using the SLEQOL 'Physical functioning' domain, depending on the fatigue domain selected. The proportion of the total effect of depression on physical health impairment explained by fatigue ranged from 68.8% to 87.6% using the LupusQOL 'Physical health' domain and from 79.3% to 103.2% using the SLEQOL 'Physical functioning' domain, depending on the fatigue domain selected. CONCLUSIONS: The effect of MSK flares and depression on physical health impairment is largely mediated by fatigue. Thus, the patient's perception of disease activity as measured by physical health is largely influenced by fatigue. In addition, fatigue has a significant negative impact on quality of lifeof SLE patients with depression. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, NCT01904812.

Health related quality of life, remission and low lupus disease activity state in patients with systemic lupus erythematosus.

OBJECTIVES: To measure the association between systemic lupus erythematosus (SLE) remission and scores of patients reported outcome measures (PRO). METHODS: We performed a prospective cohort study of SLE patients with a 2-year follow-up, recording LupusPRO, LupusQol, SLEQOL, and SF-36 questionnaires. Remission was defined as remission-off-treatment (ROFT) and remission-on-treatment (RONT) according to the DORIS consensus. Mixed models accounting for repeated measures were used to compare groups as follow: ROFT and RONT versus no remission, and Lupus Low Disease activity state (LLDAS) versus no LLDAS. RESULTS: A total of 1478 medical visits and 2547 PRO questionnaires were collected during the follow-up from the 336 recruited patients. A between-group difference in PRO scores reaching at least 5 points on a 0-100 scale was obtained in the following domains: "lupus symptoms" (LLDAS: +5 points on the 0-100 scale, RONT: +9 and ROFT: +5), "lupus medication" (LLDAS: +5, RONT: +8 and ROFT: +9), "pain vitality" (LLDAS: +6, RONT: +9 and ROFT: +6) of LupusPRO, "role emotional" (LLDAS: +5, RONT: +8), "role physical" (RONT: +7 and ROFT: +7), "bodily pain" (RONT: +6), "mental health" (RONT: +5) and "social functioning" (RONT: +6) of SF-36. In contrast, a between-group difference reaching at least 5 points was not achieved for any of the LupusQol and SLEQOL domains. CONCLUSIONS: RONT, ROFT, and LLDAS were associated with significant and clinically relevant higher quality of life in most PRO domains of LupusPRO (disease-specific) and SF-36 (generic) questionnaires, but not with LupusQol and SLEQOL disease-specific questionnaires.

Interleukin 6 receptor inhibition in primary Sjögren syndrome: a multicentre double-blind randomised placebo-controlled trial.

OBJECTIVES: No immunomodulatory drug has been approved for primary Sjögren's syndrome, a systemic autoimmune disease affecting 0.1% of the population. To demonstrate the efficacy of targeting interleukin 6 receptor in patients with Sjögren's syndrome-related systemic complications. METHODS: Multicentre double-blind randomised placebo-controlled trial between 24 July 2013 and 16 July 2018, with a follow-up of 44 weeks, involving 17 referral centres. Inclusion criteria were primary Sjögren's syndrome according to American European Consensus Group criteria and score ≥5 for the EULAR Sjögren's Syndrome Disease activity Index (ESSDAI, score of systemic complications). Patients were randomised to receive either 6 monthly infusions of tocilizumab or placebo. The primary endpoint was response to treatment at week 24. Response to treatment was defined by the combination of (1) a decrease of at least 3 points in the ESSDAI, (2) no occurrence of moderate or severe activity in any new domain of the ESSDAI and (3) lack of worsening in physician's global assessment on a Visual Numeric Scale ≥1/10, all as compared with enrolment. RESULTS: 110 patients were randomised, 55 patients to tocilizumab (mean (SD) age: 50.9 (12.4) years; women: 98.2%) and 55 patients to placebo (54.8 (10.7) years; 90.9%). At 24 weeks, the proportion of patients meeting the primary endpoint was 52.7% (29/55) in the tocilizumab group and 63.6% (35/55) in the placebo group, for a difference of -11.4% (95% credible interval -30.6 to 9.0) (Pr[Toc >Pla]=0.14). CONCLUSION: Among patients with primary Sjögren's syndrome, the use of tocilizumab did not improve systemic involvement and symptoms over 24 weeks of treatment compared with placebo. TRIAL REGISTRATION NUMBER: NCT01782235.

Patterns of fatigue and association with disease activity and clinical manifestations in systemic lupus erythematosus.

OBJECTIVE: The prevalence of fatigue is high in patients with systemic lupus erythematosus (SLE). In this study, we used latent class analysis to reveal patterns of fatigue, anxiety, depression and organ involvement in a large international cohort of SLE patients. METHODS: We used the Lupus BioBank of the upper Rhein to analyse patterns of fatigue using latent class analysis (LCA). After determining the optimal number of latent classes, patients were assigned according to model generated probabilities, and characteristics of classes were compared. RESULTS: A total of 502 patients were included. Significant fatigue, anxiety and depression were reported by 341 (67.9%), 159 (31.7%) and 52 (10.4%) patients, respectively. LCA revealed a first cluster (67.5% of patients) with low disease activity [median (25th-75th percentile interquartile range) Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA)-SLEDAI: 2 (0-4)], significant fatigue (55.5%, P < 0.0001), low anxiety (11.8%, P < 0.0001) and depression (0.9%, P < 0.0001). Cluster 2 (25.3%) also comprised patients with low disease activity [SELENA-SLEDAI: 2 (0-6)], but those patients had a very high prevalence of fatigue (100%, P < 0.0001), anxiety (89%, P < 0.0001) and depression (38.6%, P < 0.0001). Cluster 3 (7.2%) comprised patients with high disease activity [SELENA-SLEDAI: 12 (8-17), P < 0.0001] and high fatigue (72.2%, P < 0.0001) with low levels of anxiety (16.7%, P < 0.0001) and no depression (0%, P < 0.0001). CONCLUSION: LCA revealed three patterns of fatigue with important practical implications. Based on these, it is crucial to distinguish patients with active disease (in whom remission will be achieved) from those with no or mild activity but high levels of fatigue, depression and anxiety, for whom psychological counselling should be prioritized.

Disease-specific quality of life following a flare in systemic lupus erythematosus: an item response theory analysis of the French EQUAL cohort.

OBJECTIVE: To explore, at an item-level, the effect of disease activity (DA) on specific health-related quality of life (HRQoL) in SLE patients using an item response theory longitudinal model. METHODS: This prospective longitudinal multicentre French cohort EQUAL followed SLE patients over 2 years. Specific HRQoL according to LupusQoL and SLEQOL was collected every 3 months. DA according to SELENA-SLEDAI flare index (SFI) and revised SELENA-SLEDAI flare index (SFI-R) was evaluated every 6 months. Regarding DA according to SFI and each SFI-R type of flare, specific HRQoL of remitting patients was compared with non-flaring patients fitting a linear logistic model with relaxed assumptions for each domain of the questionnaires. RESULTS: Between December 2011 and July 2015, 336 patients were included (89.9% female). LupusQoL and SLEQOL items related to physical HRQoL (physical health, physical functioning, pain) were most affected by musculoskeletal and cutaneous flares. Cutaneous flares had significant influence on self-image. Neurological or psychiatric flares had a more severe impact on specific HRQoL. Patient HRQoL was impacted up to 18 months after a flare. CONCLUSION: Item response theory analysis is able to pinpoint items that are influenced by a given patient group in terms of a latent trait change. Item-level analysis provides a new way of interpreting HRQoL variation in SLE patients, permitting a better understanding of DA impact on HRQoL. This kind of analysis could be easily implemented for the comparison of groups in a clinical trial. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, NCT01904812.

Predictors of fatigue and severe fatigue in a large international cohort of patients with systemic lupus erythematosus and a systematic review of the literature.

OBJECTIVE: Fatigue is reported in up to 90% of patients with SLE. This study was conducted to identify the determinants associated with fatigue in a large cohort of patients with SLE, as well as to provide a systematic review of the literature. METHODS: Patients from the Lupus BioBank of the upper Rhein, a large German-French cohort of SLE patients, were included in the FATILUP study if they fulfilled the 1997 ACR criteria for SLE and had Fatigue Scale for Motor and Cognitive Functions scores collected. Multivariate logistic regression analyses were performed to assess the determinants of fatigue and severe fatigue. RESULTS: A total of 570 patients were included (89.1% female). The median age was 42 years (interquartile range 25-75: 34-52). The median value of the SAfety of Estrogens in Lupus Erythematosus National Assessment (SELENA)-SLEDAI was 2 (0-4). Fatigue was reported by 386 patients (67.7%) and severe fatigue by 209 (36.7%). In multivariate analyses, fatigue was associated with depression [odds ratio (OR): 4.72 (95% CI: 1.39-16.05), P = 0.01], anxiety [OR: 4.49 (95% CI: 2.60-7.77), P < 0.0001], glucocorticoid treatment [OR: 1.59 (95% CI 1.05-2.41), P = 0.04], SELENA-SLEDAI scores [OR: 1.05 (95% CI: 1.00-1.12) per 1 point increase, P = 0.043] and age at sampling [OR: 1.01 (95% CI: 1.00-1.03) per 1 year increase, P = 0.03]. Severe fatigue was independently associated with anxiety (P < 0.0001), depression (P < 0.0001), glucocorticoid treatment (P = 0.047) and age at sampling (P = 0.03). CONCLUSION: Both fatigue and severe fatigue are common symptoms in SLE, and are strongly associated with depression and anxiety. Disease activity and the use of glucocorticoids were also independently associated with fatigue, although more weakly.

Extra-haematological manifestations related to human parvovirus B19 infection: retrospective study in 25 adults.

BACKGROUND: To describe extra-haematological manifestations associated with human parvovirus B19 (HPV-B19) infection. METHODS: We conducted a nationwide multicentre study to retrospectively describe the characteristics and outcome of extra-haematological manifestations in French adults. RESULTS: Data from 25 patients followed from 2001 to 2016 were analysed. Median age was 37.9 years (range: 22.7-83.4), with a female predominance (sex ratio: 4/1). Only 3 patients had an underlying predisposing condition (hemoglobinopathy or pregnancy). The most common manifestations were joint (80%) and skin (60%) involvement. Four patients (16%) had renal involvement (endocapillary proliferative or membranoproliferative glomerulonephritis, focal segmental glomerulosclerosis). Three patients (12%) had peripheral nervous system involvement (mononeuritis, mononeuritis multiplex, Guillain-Barré syndrome) and 2 (8%) presented muscle involvement. Other manifestations included hemophagocytic lymphohistiocytosis (n = 1), myopericarditis and pleural effusion (n = 1), and lymphadenopathy and splenomegaly mimicking lymphoma with spleen infarcts (n = 1). Immunological abnormalities were frequent (56.5%). At 6 months, all patients were alive, and 54.2% were in complete remission. In 2 patients, joint involvement evolved into rheumatoid arthritis. Six patients (24%) received intravenous immunoglobulin (IVIg), with a good response in the 3 patients with peripheral nervous system involvement. CONCLUSIONS: HPV-B19 infection should be considered in a wide range of clinical manifestations. Although the prognosis is good, IVIg therapy should be discussed in patients with peripheral nerve involvement. However, its efficacy should be further investigated in prospective studies.

Angioedema due to Acquired C1-Inhibitor Deficiency Associated With Monoclonal Gammopathies of Undetermined Significance Characteristics of a French National Cohort.

BACKGROUND: No specific description of monoclonal gammopathies of undetermined significance (MGUS)-associated angioedema due to acquired C1 inhibitor deficiency (AAE-C1-INH) has been reported yet. OBJECTIVE: To describe the biological and clinical characteristics, evolution, and response to treatment of MGUS-associated AAE-C1-INH. MATERIALS AND METHODS: We conducted a French national retrospective observational study on MGUS-associated acquired angioedema spanning a 30-year period. RESULTS: Forty-one patients with MGUS-associated AAE-C1-INH at diagnosis were included; 68% displayed anti-C1-INH antibodies. The monoclonal component was an IgM in 24 patients, IgG in 11, and IgA in 6 patients. The mean age at first angioedema attack was 63 years (standard deviation [SD] = 13 years) and at diagnosis 66 years (SD = 11 years). A total of 88% patients benefited from acute attack treatments, and 77% from long-term prophylaxis, either danazol, tranexamic acid, or lanadelumab. Median follow-up was 7 years, during which 14 patients (33%) evolved into well-defined malignant hemopathies. Fifty percent of patients were given a hematological treatment, either rituximab alone, indicated by recurrent attacks of angioedema in patients with AAE-C1-INH with anti-C1-INH antibodies, or validated combinations of chemotherapies, indicated by evolution into a lymphoma in 7 patients and a myeloma in 3 patients. Fifteen patients (35%) were in clinical complete remission of angioedema at last visit, of whom 60% had an undetectable serum monoclonal immunoglobulin. CONCLUSIONS: Complete remission of AAE-C1-INH is correlated to complete remission of the underlying hematological malignancy, as defined by an undetectable serum monoclonal immunoglobulin. In our MGUS-associated acquired angioedema cohort, we recorded an incidence of evolution into hematological malignancy of 4% per patient-year. It is therefore crucial to conduct full hematological workup during follow-up at an annual rate, and earlier if AAE relapses or if acute attack frequency increases.

Fatigue is independently associated with disease activity assessed using the Physician Global Assessment but not the SLEDAI in patients with systemic lupus erythematosus.

OBJECTIVES: To analyse whether reported fatigue, one of the most challenging manifestations of systemic lupus erythematosus (SLE), may bias the assessment of disease activity in SLE according to the Physician Global Assessment (PGA). METHODS: Patients from the Lupus BioBank of the upper Rhein database, a cross-sectional multicentre collection of detailed clinical and biological data from patients with SLE, were included. Patients had to fulfil the 1997 American College of Rheumatology criteria for SLE and the PGA (0-3 scale) at the time of inclusion had to be available. Fatigue was assessed according to the Fatigue Scale for Motor and Cognitive Functions. Univariate and multivariate regression models were built to determine which variables were associated with the PGA. RESULTS: A total of 350 patients (89% female; median age: 42 years, IQR: 34-52) were included. The median Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score was 4 (IQR: 2-6). Of these 350 patients, 257 (73%) reported significant fatigue. The PGA (p=0.004) but not the SELENA-SLEDAI (p=0.43) was significantly associated with fatigue. Both fatigue and SELENA-SLEDAI were independently associated with the PGA in two different multivariate models. CONCLUSION: Fatigue is independently associated with disease activity assessed using the PGA but not the SLEDAI. These findings highlight the fact that the PGA should capture only objectively active disease manifestations in order to improve its reliability.

Evaluation of Rituximab for Induction and Maintenance Therapy in Patients 75 Years and Older With Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

Importance: Older patients are underrepresented in studies of rituximab for the treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Little is known about outcomes and adverse events associated with the use of rituximab therapy among patients 75 years and older with ANCA-associated vasculitis. Objective: To examine outcomes and adverse events associated with the use of rituximab therapy in patients 75 years and older with ANCA-associated vasculitis, specifically granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA). Design, Setting, and Participants: This multicenter cohort study involved 93 patients 75 years and older with ANCA-associated vasculitis from 36 university and nonuniversity hospitals in France. Data were obtained from the French Vasculitis Study Group database between January 1, 2000, and July 1, 2018, and a call for observation sent to French Vasculitis Study Group members on June 6, 2019. Data analysis was performed from November 15 to December 31, 2021. Inclusion criteria included a diagnosis of GPA or MPA according to European Medicines Agency classification criteria and receipt of treatment with rituximab after age 75 years. Patients were excluded if they were missing relevant clinical or biological data. Data on race and ethnicity were not reported because inclusion of this information was not authorized by the ethics committee. Exposure: At least 1 infusion of rituximab as induction or maintenance therapy. Main Outcomes and Measures: Occurrence of remission, relapse, drug discontinuation, death, and serious infections (including types of serious infections). Results: Of 238 patients screened, 93 were included (median [IQR] age, 79.4 [76.7-83.1] years; 51 women [54.8%]); 52 patients (55.9%) had a diagnosis of GPA, and 41 (44.1%) had a diagnosis of MPA. Thirty patients (32.3%) received rituximab as induction therapy in combination with high-dose glucocorticoid regimens, 27 (29.0%) received rituximab as maintenance therapy, and 36 (38.7%) received rituximab as both induction and maintenance therapy. The median (IQR) follow-up was 2.3 (1.1-4.0) years. Among 66 patients who received rituximab as induction therapy, 57 (86.4%) achieved remission, and 2 (3.0%) experienced relapses. The incidence of serious infection was significantly higher when rituximab was used as induction therapy vs maintenance therapy (46.6 [95% CI, 24.8-79.7] per 100 patient-years vs 8.4 [95% CI, 3.8-15.9] per 100 patient-years; P = .004). Most infections (12 of 22 [54.5%]) were gram-negative bacterial infections. The incidence of death was 19.7 (95% CI, 7.2-42.9) per 100 patient-years among those who received rituximab as induction therapy and 5.3 (95% CI, 1.9-11.6) per 100 patient-years among those who received rituximab as maintenance therapy. Conclusions and Relevance: In this cohort study, rituximab therapy was associated with achievement and maintenance of remission in most patients 75 years and older with ANCA-associated vasculitis. The incidence of serious infections and death was high when rituximab was used as induction therapy in combination with high-dose glucocorticoid regimens but not when rituximab was used as maintenance therapy. Efforts might focus on reducing serious infections during the first months of therapy.

Improving patient pathways for systemic lupus erythematosus: a multistakeholder pathway optimisation study.

OBJECTIVE: Among the most significant challenges in SLE are the excessive diagnosis delay and the lack of coordinated care. The aim of the study was to investigate patient pathways in SLE in order to improve clinical and organisational challenges in the management of those with suspected and confirmed SLE. METHODS: We conducted a cross-sectional study of patients with SLE, healthcare providers and other representative stakeholders. Focus groups were conducted, and based on the collected data the most impactful disruption points in SLE patient pathways were identified. A novel framework to improve individual patient pathways in SLE was developed, discussed and validated during a consensus meeting with representative stakeholders. RESULTS: Six thematic clusters regarding disruption in optimal patient pathways in SLE were identified: appropriate and timely referral strategy for SLE diagnosis; the need for a dedicated consultation during which the diagnosis of SLE would be announced, and following which clarifications and psychological support offered; individualised patient pathways with coordinated care based on organ involvement, disease severity and patient preference; improved therapeutic patient education; prevention of complications such as infections, osteoporosis and cancer; and additional patient support. During the consensus meeting, the broader panel of stakeholders achieved consensus on these attributes and a framework for optimising SLE patient pathways was developed. CONCLUSIONS: We have identified significant disruption points and developed a novel conceptual framework to improve individual patient pathways in SLE. These data may be of valuable interest to patients with SLE, their physicians, health organisations as well as policy makers.

Intravenous Immunoglobulins Tapering and Withdrawal in Systemic Capillary Leak Syndrome (Clarkson Disease).

BACKGROUND: The systemic capillary leak syndrome (SCLS), also known as Clarkson disease, is a very rare condition characterized by recurrent life-threatening episodes of vascular hyperpermeability in the presence of a monoclonal gammopathy. Extended intravenous immunoglobulin (IVIG) treatment is associated with fewer recurrences and improved survival, but the optimal treatment dosage and duration remain unknown. OBJECTIVE: We aim to evaluate the safety of IVIG tapering and withdrawal in patients with SCLS. METHODS: We conducted a retrospective multicenter study including all adult patients with monoclonal gammopathy-associated SCLS from the EurêClark registry who received at least 1 course of IVIG. The primary end point was overall survival according to IVIG withdrawal. RESULTS: Fifty-nine patients of mean ± SD age 51 ± 13 years were included. Overall cumulative probabilities of 2-, 5-, 10- and 15-year survival were 100%, 85%, 72%, 44%, respectively. The IVIG was withdrawn at least once in 18 patients (31%; W+ group) and never in 41 patients (69%; W- group). Cumulative probabilities of 10-year survival in W+ versus W- groups were 50% and 83% (log rank test, P = .02), respectively. Relapse rate and the median number of relapses in the W+ versus the W- groups were 72% versus 58% (P = 0.3) and 2.5 (0.3-4) versus 1 (0-2) (P = .03), respectively. The IVIG tapering was not statistically associated with increased person-year incidence of attacks using a mixed linear model. CONCLUSIONS: The IVIG withdrawal was associated with increased mortality and higher rate of recurrence in SCLS patients. The IVIG tapering might be cautiously considered in stable SCLS patients.

Characteristics of Adult Patients with Idiopathic Retroperitoneal Fibrosis and Assessment of Risk of Relapse at Diagnosis.

OBJECTIVES: To compare adult patients' characteristics suffering from idiopathic retroperitoneal fibrosis between "relapse-free" and relapsing patients at the diagnosis and identify factors associated with relapse at initial presentation. METHODS: We conducted a retrospective multicentric study in four hospitals in Eastern France, from 1993 to 2020, of adult patients suffering from idiopathic retroperitoneal fibrosis. We analyzed clinical, biological, and radiological features at diagnosis and during a forty-month follow-up. RESULTS: Of 47 patients suffering from retroperitoneal fibrosis, 21 patients had idiopathic retroperitoneal fibrosis. Among them, 13 experienced one or more relapses during follow-up. At diagnosis, clinical characteristics, relevant comorbidities, biological and radiological features were similar between groups. Smoking cessation seems associated with decreased relapse risk (p: 0.0624). A total of 8 patients developed chronic renal failure during follow-up. Ureteral infiltration at diagnosis was associated with evolution to chronic renal failure (p: 0.0091). CONCLUSION: No clinical, biological, or radiological features could predict relapse at retroperitoneal fibrosis diagnosis, but smoking cessation may prevent relapse.

Prevalence of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis and Spatial Association With Quarries in a Region of Northeastern France: A Capture-Recapture and Geospatial Analysis.

OBJECTIVE: Silica is an environmental substance strongly linked with autoimmunity. The aim of this study was to assess the prevalence of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), including granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and renal limited vasculitis, in a northeastern region of France and to evaluate whether there was a geospatial association between the localization of quarries in the region and the prevalence of these AAVs. METHODS: Potential AAV patients were identified using 3 sources: hospital records, immunology laboratories, and the French National Health Insurance System. Patients who resided in the Alsace region of France as of January 1, 2016 and who fulfilled the American College of Rheumatology criteria for GPA or the 2012 Chapel Hill Consensus Conference definitions for GPA or MPA were included. Incomplete case ascertainment was corrected using a capture-recapture analysis. The spatial association between the number of cases and the presence of quarries in each administrative entity was assessed using regression analyses weighted for geographic region. RESULTS: Among 910 potential AAV patients, we identified 185 patients fulfilling inclusion criteria: 120 patients with GPA, 35 patients with MPA, and 30 patients with renal limited vasculitis. The number of cases missed by any source as estimated by capture-recapture analysis was 6.4 (95% confidence interval [95% CI] 3.6-11.5). Accordingly, the estimated prevalence in Alsace in 2016 was 65.5 GPA cases per million inhabitants (95% CI 47.3-93.0), 19.1 MPA cases per million inhabitants (95% CI 11.3-34.3), and 16.8 renal limited vasculitis cases per million inhabitants (95% CI 8.7-35.2). The risk of AAV was significantly increased in communities with quarries (odds ratio 2.51 [95% CI 1.66-3.80]), and geographic-weighted regression analyses revealed a significant spatial association between the proximity to quarries and the number of GPA cases (P = 0.039). In analyses stratifying the AAV patients by ANCA serotype, a significant association between the presence of quarries and positivity for both proteinase 3 ANCAs (P = 0.04) and myeloperoxidase ANCAs (P = 0.03) was observed. CONCLUSION: In a region with a high density of quarries, the spatial association between the presence of and proximity to quarries and the prevalence of AAVs supports the idea that silica may have a role as a specific environmental factor in this disease.

Absence of Anti-Glomerular Basement Membrane Antibodies in 200 Patients With Systemic Lupus Erythematosus With or Without Lupus Nephritis: Results of the GOODLUPUS Study.

Introduction: Anti-glomerular basement membrane (GBM) antibodies are pathogenic antibodies first detected in renal-limited anti-GBM disease and in Goodpasture disease, the latter characterized by rapidly progressive crescentic glomerulonephritis combined with intra-alveolar hemorrhage. Studies have suggested that anti-GBM antibody positivity may be of interest in lupus nephritis (LN). Moreover, severe anti-GBM vasculitis cases in patients with systemic lupus erythematosus (SLE) have been described in the literature, but few studies have assessed the incidence of anti-GBM antibodies in SLE patients. Objective: The main study objective was to determine if positive anti-GBM antibodies were present in the serum of SLE patients with or without proliferative renal damage and compared to a healthy control group. Methodology: This retrospective study was performed on SLE patients' sera from a Franco-German European biobank, developed between 2011 and 2014, from 17 hospital centers in the Haut-Rhin region. Patients were selected according to their renal involvement, and matched by age and gender. The serum from healthy voluntary blood donors was also tested. Anti-GBM were screened by fluorescence enzyme immunoassay (FEIA), and then by indirect immunofluorescence (IIF) in case of low reactivity detection (titer >6 U/ml). Results: The cohort was composed of 100 SLE patients with proliferative LN (27% with class III, 67% with class IV, and 6% with class V), compared to 100 SLE patients without LN and 100 controls. Patients were mostly Caucasian and met the ACR 1997 criteria and/or the SLICC 2012 criteria. Among the 300 tested sera, no significant levels of anti-GBM antibodies were detected (>10 U/ml) by the automated technique, three sera were found "ambivalent" (>7 U/ml): one in the SLE with LN group and two in the SLE without LN group. Subsequent IIF assays did not detect anti-GBM antibodies. Conclusion: Anti-GBM antibodies were not detected in the serum of Caucasian patients with SLE, even in case of renal involvement, a situation favoring the antigenic exposure of glomerular basement membranes. Our results reaffirm the central role of anti-GBM antibodies as a specific diagnostic biomarker for Goodpasture vasculitis and therefore confirm that anti-GBM antibody must not be carried out in patients with SLE (with or without LN) in the absence of disease-suggestive symptoms.

Systemic lupus erythematosus and neutropaenia: a hallmark of haematological manifestations.

OBJECTIVE: Systemic lupus is a chronic autoimmune disease characterised by its phenotypic heterogeneity. Neutropaenia is a frequent event in SLE occurring in 20%-40% of patients depending on the threshold value of neutrophil count. On a daily basis, the management of neutropaenia in SLE is difficult with several possible causes. Moreover, the infectious consequences of neutropaenia in SLE remain not well defined. METHODS: 998 patients from the Lupus BioBank of the upper Rhein (LBBR), a large German and French cohort of patients with SLE, mostly of Caucasian origin (83%), were included in this study. Neutropaenia was considered when neutrophil count was below 1800×106/L. An additional analysis of detailed medical records was done for 65 LBBR patients with neutropaenia. RESULTS: 208 patients with neutropaenia (21%) were compared with 779 SLE patients without neutropaenia. Neutropaenia in SLE was significantly associated with thrombocytopaenia (OR 4.11 (2.57-10.3)), lymphopaenia (OR 4.41 (2.51-11.5)) and low C3 (OR 1.91 (1.03-4.37)) in multivariate analysis. 65 representative patients with neutropaenia were analysed. Neutropaenia was moderate to severe in 38%, chronic in 31%, and both severe and chronic in 23% of cases. Moderate to severe and chronic neutropaenia were both associated with lymphopaenia and thrombopaenia. Chronic neutropaenia was also associated anti-Ro/SSA antibodies and moderate to severe neutropaenia with oral ulcers. CONCLUSION: This study is to date the largest cohort to describe neutropaenia in SLE. Neutropaenia displays a strong association with other cytopaenias, suggesting a common mechanism. Chronic neutropaenia is associated with anti-Ro/SSA antibodies with or without identified Sjögren's disease.

Idiopathic Pulmonary Embolism in a case of Severe Family ANKRD26 Thrombocytopenia.

Venous thrombosis affecting thrombocytopenic patients is challenging. We report the case of a woman affected by deep vein thrombosis and pulmonary embolism in a thrombocytopenic context leading to the discovery of a heterozygous mutation in the gene encoding ankyrin repeat domain 26 (ANKRD26) associated with a heterozygous factor V (FV) Leiden mutation. This woman was diagnosed with lower-limb deep vein thrombosis complicated by pulmonary embolism. Severe thrombocytopenia was observed. The genetic study evidenced a heterozygous FV Leiden mutation. Molecular study sequencing was performed after learning that her family had a history of thrombocytopenia. Previously described heterozygous mutation c-127C>A in the 5'untranslated region (5'UTR) of the ANKRD26 gene was detected in the patient, her aunt, and her grandmother. ANKRD26-related thrombocytopenia and thrombosis are rare. This is, to our knowledge, the first case reported in the medical literature. This mutation should be screened in patients with a family history of thrombocytopenia.

Central nervous system involvement in eosinophilic granulomatosis with polyangiitis (Churg-Strauss): Report of 26 patients and review of the literature.

BACKGROUND: Although peripheral nervous system involvement is common in eosinophilic granulomatosis with polyangiitis (EGPA), central nervous system (CNS) manifestations are poorly described. This study aimed to describe CNS involvement in EGPA. PATIENTS AND METHODS: This retrospective, observational, multicenter study included patients with EGPA and CNS involvement affecting cranial nerves, brain and/or spinal cord. We also undertook a systematic literature review. RESULTS: We analyzed 26 personal cases and 62 previously reported cases. At EGPA diagnosis, asthma was noted in 97%, eosinophilia in 98%, peripheral neuropathy in 55% and cardiac involvement in 41%. 38/71 (54%) were ANCA-positive, with a perinuclear-labeling pattern and/or anti-MPO specificity. CNS was involved in 86% at EGPA diagnosis, preceded EGPA in 2%, and occurred during follow-up in 12% after a median of 24months. Main neurological manifestations were ischemic cerebrovascular lesions in 46 (52%), intracerebral hemorrhage and/or subarachnoid hemorrhage in 21 (24%), loss of visual acuity in 28 (33%) (15 with optic neuritis, 9 with central retinal artery occlusion, 4 with cortical blindness), and cranial nerves palsies in 18 (21%), with 25 patients having ≥1 of these clinical CNS manifestations. Among the 81 patients with assessable neurological responses, 43% had complete responses without sequelae, 43% had partial responses with long-term sequelae and 14% refractory disease. After a mean follow-up of 36months, 11 patients died including 5 from intracerebral hemorrhages. CONCLUSION: EGPA-related CNS manifestations form 4 distinct neurological pictures: ischemic lesions, intracerebral hemorrhages, cranial nerve palsies and loss of visual acuity. Such manifestation should prompt practitioners to consider EGPA in such conditions. Long-term neurological sequelae were common, and intracerebral hemorrhages had the worst prognostic impact.

Long-term efficacy and safety of antitumour necrosis factor alpha treatment in rhupus: an open-label study of 15 patients.

BACKGROUND: The efficacy of antitumour necrosis factor alpha (anti-TNF-α) treatment is well recognised in rheumatoid arthritis (RA) but remains controversial in systemic lupus erythematosus (SLE). Therefore, the role of anti-TNF-α treatment in 'Rhupus', a disease sharing features of RA and SLE, is still debated. OBJECTIVE: To evaluate the efficacy and tolerance of anti-TNF-α in patients with rhupus. METHODS: Fifteen patients with rhupus with Disease Activity Score 28 (DAS 28) >3.2 despite conventional disease-modifying anti-rheumatic drugs were included in an open-label study. Patients were monitored at months (M) 3, 6, 12, 24 and 60 with SLE Disease Activity Index (SLEDAI) and DAS 28. Statistical analyses were performed using Bayesian methods and Prob >97.5% was considered significant. RESULTS: Twelve patients were treated with etanercept for a median duration of 62.5 (range: 6-112) months and three patients by adalimumab during 36.0 (range: 4-52) months. At baseline, median DAS 28 and SLEDAI were 5.94 (4.83-8.09) and 6 (4-8), respectively. DAS 28 and SLEDAI decreased significantly after 3 months, respectively, to 3.70 (1.80-6.42) and 4 (0-6) (Prob >99.9%, for both). These changes persisted at M6, M12, M24 and M60 (Prob >99.9%, for all). Median prednisone dose decreased significantly from 15 (5-35) mg/day to 5 (0-20) mg/day after 6 months and over the follow-up (Prob >99.9%, for all). Tolerance was acceptable, with a severe infection rate of 3.0 per 100 patient-years. CONCLUSION: This pilot study suggests that anti-TNF-α is effective in patients with rhupus with refractive arthritis and has an acceptable safety profile.

Intravenous Immunoglobulins Improve Survival in Monoclonal Gammopathy-Associated Systemic Capillary-Leak Syndrome.

BACKGROUND: Monoclonal gammopathy-associated systemic capillary-leak syndrome, also known as Clarkson disease, is a rare condition characterized by recurrent life-threatening episodes of capillary hyperpermeability in the context of a monoclonal gammopathy. This study was conducted to better describe the clinical characteristics, natural history, and long-term outcome of monoclonal gammopathy-associated systemic capillary-leak syndrome. METHODS: We conducted a cohort analysis of all patients included in the European Clarkson disease (EurêClark) registry between January 1997 and March 2016. From diagnosis to last follow-up, studied outcomes (eg, the frequency and severity of attacks, death, and evolution toward multiple myeloma) and the type of preventive treatments administered were monitored every 6 months. RESULTS: Sixty-nine patients (M/F sex ratio 1:1; mean ± SD age at disease onset 52 ± 12 years) were included in the study. All patients had monoclonal gammopathy of immunoglobulin G type, with kappa light chains in 47 (68%). Median (interquartile range) follow-up duration was 5.1 (2.5-9.7) years. Twenty-four patients (35%) died after 3.3 (0.9-8) years. Fifty-seven (86%) patients received at least one preventive treatment, including intravenous immunoglobulins (IVIg) n = 48 (73.8%), theophylline n = 22 (33.8%), terbutaline n = 22 (33.8%), and thalidomide n = 5 (7.7%). In the 65 patients with follow-up, 5- and 10-year survival rates were 78% (n = 35) and 69% (n = 17), respectively. Multivariate analysis found preventive treatment with IVIg (hazard ratio 0.27; 95% confidence interval, 0.10-0.70; P = .007) and terbutaline (hazard ratio 0.35; 95% confidence interval, 0.13-0.96; P = .041) to be independent predictors of mortality. CONCLUSIONS: We describe the largest cohort to date of patients with well-defined monoclonal gammopathy-associated systemic capillary-leak syndrome. Preventive treatment with IVIg was the strongest factor associated with survival, suggesting the use of IVIg as the first line in prevention therapy.