Successful treatment of JAK1-associated inflammatory disease.

BACKGROUND: Gain-of-function variants of JAK1 drive a rare immune dysregulation syndrome associated with atopic dermatitis, allergy, and eosinophilia. OBJECTIVES: This study sought to describe the clinical and immunological characteristics associated with a new gain-of-function variant of JAK1 and report the therapeutic efficacy of Janus kinase (JAK) inhibition. METHODS: The investigators identified a family affected by JAK1-associated autoinflammatory disease and performed clinical assessment and immunological monitoring on 9 patients. JAK1 signaling was studied by flow and mass cytometry in patients' cells at basal state or after immune stimulation. A molecular disease signature in the blood was studied at the transcriptomic level. Patients were treated with 1 of 2 JAK inhibitors: either baricitinib or upadacitinib. Clinical, cellular, and molecular response were evaluated over a 2-year period. RESULTS: Affected individuals displayed a syndromic disease with prominent allergy including atopic dermatitis, ichthyosis, arthralgia, chronic diarrhea, disseminated calcifying fibrous tumors, and elevated whole blood histamine levels. A variant of JAK1 localized in the pseudokinase domain was identified in all 9 affected, tested patients. Hyper-phosphorylation of STAT3 was found in 5 of 6 patients tested. Treatment of patients' cells with baricitinib controlled most of the atypical hyper-phosphorylation of STAT3. Administration of baricitinib to patients led to rapid improvement of the disease in all adults and was associated with reduction of systemic inflammation. CONCLUSIONS: Patients with this new JAK1 gain-of-function pathogenic variant displayed very high levels of blood histamine and showed a variable combination of atopy with articular and gastrointestinal manifestations as well as calcifying fibrous tumors. The disease, which appears to be linked to STAT3 hyperactivation, was well controlled under treatment by JAK inhibitors in adult patients.

Clinical features and long-term outcomes of patients with systemic polyarteritis nodosa diagnosed since 2005: Data from 196 patients.

BACKGROUND: The landscape of polyarteritis nodosa (PAN) has substantially changed during the last decades. Recent data regarding causes, characteristics, and prognosis of systemic PAN in the modern era are lacking. METHODS: This retrospective study included patients with systemic PAN referred to the French Vasculitis Study Group between 2005 and 2019. Characteristics, associated conditions and outcomes were collected, and predictors of relapse and death were analyzed. RESULTS: 196 patients were included. Main clinical symptoms were constitutional (84%), neurological (59%), skin (58%) and musculoskeletal (58%) manifestations. Secondary PAN accounted for 55 (28%) patients, including myelodysplastic syndrome (9%), solid cancer (7%), lymphoma (4%) and autoinflammatory diseases (4%). No patient had active HBV infection. All treated patients (98.5%) received glucocorticoids (GCs), alone (41%) or in combination with immunosuppressants (59%), with remission achieved in 90%. Relapses were independently associated with age >65 years (HR 1.85; 95% CI1.12-3.08), gastrointestinal involvement (1.95; 95% CI1.09-3.52) and skin necrotic lesions (HR 1.95; 95%CI 1.24-3.05). One-, 5- and 10-year overall survival rates were 93%, 87% and 81%, respectively. In multivariate analyses, age >65 years (HR 2.80; 95%CI 1.23-6.37), necrotic purpura (HR 4.16; 95%CI 1.62-10.70), acute kidney injury (HR 4.89; 95% 1.71-13.99) and secondary PAN (HR 2.98; 95%CI 1.29-6.85) were independently associated with mortality. CONCLUSION: Landscape of PAN has changed during the last decades, with the disappearance of HBV-PAN and the emergence of secondary PAN. Relapse rate remains high, especially in aged patients with gastrointestinal and cutaneous necrosis, as well as mortality.

"Helicobacter pylori in familial mediterranean fever: A series of 120 patients from literature and from france".

INTRODUCTION: Familial Mediterranean Fever (FMF), the most common monogenic auto-inflammatory disease, is characterized by recurrent febrile abdominal pain. Helicobacter pylori infection (HPI), one of the most frequent infections worldwide, can mimic an FMF attack. OBJECTIVES: Identify FMF patients with HPI in a cohort of French FMF patients and the literature and identify features allowing to distinguish HPI from an FMF attack. METHODS: A retrospective study of all HPI cases was performed on the cohort of FMF patients fulfilling the Livneh criteria from the French Reference Center for rare Auto-Inflammatory Diseases and Amyloidosis (CEREMAIA). A systematic literature review of HPI in FMF patients was conducted according to the PRISMA guidelines. RESULTS: Eight French patients developed HPI, whose symptoms of epigastralgia, diarrhea, anorexia/weight loss, and nausea/vomiting differed from their typical abdominal FMF attacks. A total of 112 FMF patients with HPI have been described in the literature, including 61 adults. Diagnosis of HPI was made by gastroscopy (n = 43), labelled urea test (n = 55) or IgG serology by ELISA (n = 12). When performed, C-reactive protein was always elevated. Ten cases of interaction between colchicine and antibiotic therapy for HPI (clarithromycin (n = 9) and azithromycin (n = 1)) were reported. CONCLUSION: We described a total of 120 patients with typical FMF and HPI. When FMF patients develop atypical abdominal symptoms, upper gastrointestinal endoscopy with biopsies is essential to eliminate underlying HPI. Untreated HPI can lead to misdiagnosis of colchicine resistance with inappropriate prescription of an interleukin-1 inhibitor at a non-negligible cost.

Epidemiological and clinical factors associated with post-exertional malaise severity in patients with myalgic encephalomyelitis/chronic fatigue syndrome.

BACKGROUND: Post-exertional malaise (PEM), the cardinal feature of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), occurs generally after exposure to a stressor. It is characterized by the worsening of ME/CFS symptoms and results in aggravating the course of the disease and the quality of life of patients. Due to its unpredictable onset, severity, and recovery time, identifying patients with higher risk for severe PEM would allow preventing or reducing its occurrence. We thus aimed at defining possible factors that could be associated with PEM severity. METHODS: Adult patients fulfilling ME international consensus criteria who attended the internal medicine department of University hospital Angers-France between October 2011 and December 2019 were included retrospectively. All patients were systematically hospitalized for an etiological workup and overall assessment. We reviewed their medical records for data related to the assessment: epidemiological data, fatigue features, clinical manifestations, and ME/CFS precipitants. PEM severity was appreciated by the Center for Disease Control self-reported questionnaire. The study population was classified into quartiles according to PEM severity scores. Analyses were performed with ordinal logistic regression to compare quartile groups. RESULTS: 197 patients were included. PEM severity was found to be positively associated with age at disease onset ≥ 32 years (OR 1.8 [95% CI 1.1-3.0] (p = 0.03)), recurrent infections during the course of the disease (OR 2.1 [95% CI 1.2-3.7] (p = 0.009)), and when ME/CFS was elicited by a gastrointestinal infectious precipitant (OR 5.7 [1.7-19.3] (p = 0.006)). CONCLUSION: We identified some epidemiological and clinical features, which were positively associated with PEM severity in subsets of ME/CFS patients. This could help improving disease management and patients' quality of life.

R-DHA-oxaliplatin (R-DHAOx) versus R-DHA-cisplatin (R-DHAP) regimen in B-cell lymphoma treatment: A eight-year trajectory study.

BACKGROUND: The R-DHAP regimen (rituximab, cisplatin, dexamethasone, and high-dose cytarabine) is standardly used to treat relapsed Non-Hodgkin lymphoma (NHL). Despite scarce data, cisplatin is frequently substituted with oxaliplatin (R-DHAOx) to avoid nephrotoxicity. We compared nephrotoxicity of cisplatin and oxaliplatin based on creatinine-based trajectory modeling. METHODS: All patients with NHL treated by R-DHAP or R-DHAOx in Angers hospital between January 01, 2007, and December 31, 2014, were included. Patients received cisplatin 100 mg/m2 or oxaliplatin 130 mg/m2 (d1) with cytarabine (2000 mg/m2 , two doses, d2), dexamethasone (40 mg, d1-4), and rituximab (375 mg/m2 , d1). Creatinine levels were recorded before each cycle. Individual profiles of trajectories were clustered to detect homogeneous patterns of evolution. RESULTS: Twenty-two patients received R-DHAP, 35 R-DHAOx, 6 switched from R-DHAP to R-DHAOx due to nephrotoxicity. Characteristics of patients were similar between two groups. Patients receiving R-DHAP experienced more severe renal injury than patients receiving R-DHAOx (68% vs. 7.7%, P < .001). Two homogeneous clusters appeared: cluster A, with a majority of R-DHAOx (32, 91.4%), was less nephrotoxic than B, with a majority of R-DHAP (19, 86.4%), with a decreased average serum creatinine level (P < .0001). There were no other differences between clusters. CONCLUSIONS: Our study confirms that R-DHAOx regimen causes less nephrotoxicity than R-DHAP regimen.

Efficacy and safety of TPO receptor agonists in treatment of ITP associated with predominantly antibody deficiencies.

Predominantly antibody deficiencies have an estimated prevalence of more than 1/25,000. Their classical phenotype entails the association of autoimmune manifestations with increased susceptibility to infections. Up to 8% of these patients ultimately develop immune thrombocytopenic purpura (ITP). Reducing the risk of infections and considering non immunosuppressive treatments, such as thrombopoietin receptor agonists (TPO-RAs), are important needs in these patients. This nationwide retrospective case series assessed outcomes and safety of TPO-RAs as treatment for ITP in adults diagnosed with predominantly antibody deficiencies. Response and complete response to treatment were defined as platelet count reaching 30 x 109/L and 100 x 109/L respectively. We analyzed data from 28 patients. The median follow-up after introduction of the first TPO-RAs was 33 months (range, 2 weeks - 10,6 years). After 6 weeks of follow up, response was achieved for 24 out of 28 patients (85.7%), among which 21 patients (75%) displayed a complete response. At the last available follow-up visit only 7 patients (25%) needed second-line therapies for ITP among which only 5 patients (17.9%) received immunosuppressants. Only 3 patients (10.7%) reported hepatobiliary laboratory adverse events of light or mild severity and 3 patients (10.7%) reported thrombotic events. In conclusion, TPO-RAs appeared as an effective and safe option of treatment in these case series. Our results suggest that Eltrombopag or Romiplostim should be considered as second line therapy of ITP related to predominantly antibody deficiencies.

An immuno-lipidomic signature revealed by metabolomic and machine-learning approaches in labial salivary gland to diagnose primary Sjögren's syndrome.

Introduction: Assessing labial salivary gland exocrinopathy is a cornerstone in primary Sjögren's syndrome. Currently this relies on the histopathologic diagnosis of focal lymphocytic sialadenitis and computing a focus score by counting lym=phocyte foci. However, those lesions represent advanced stages of primary Sjögren's syndrome, although earlier recognition of primary Sjögren's syndrome and its effective treatment could prevent irreversible damage to labial salivary gland. This study aimed at finding early biomarkers of primary Sjögren's syndrome in labial salivary gland combining metabolomics and machine-learning approaches. Methods: We used a standardized targeted metabolomic approach involving high performance liquid chromatography coupled with mass spectrometry among newly diagnosed primary Sjögren's syndrome (n=40) and non- primary Sjögren's syndrome sicca (n=40) participants in a prospective cohort. A metabolic signature predictive of primary Sjögren's syndrome status was explored using linear (logistic regression with elastic-net regularization) and non-linear (random forests) machine learning architectures, after splitting the data set into training, validation, and test sets. Results: Among 126 metabolites accurately measured, we identified a discriminant signature composed of six metabolites with robust performances (ROC-AUC = 0.86) for predicting primary Sjögren's syndrome status. This signature included the well-known immune-metabolite kynurenine and five phospholipids (LysoPC C28:0; PCaa C26:0; PCaaC30:2; PCae C30:1, and PCaeC30:2). It was split into two main components: the first including the phospholipids was related to the intensity of lymphocytic infiltrates in salivary glands, while the second represented by kynurenine was independently associated with the presence of anti-SSA antibodies in participant serum. Conclusion: Our results reveal an immuno-lipidomic signature in labial salivary gland that accurately distinguishes early primary Sjögren's syndrome from other causes of sicca symptoms.

Factors Influencing the Prognosis of Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a long-term debilitating multisystem condition with poor prognosis. Studies that examined predictors of ME/CFS outcomes yielded contradictory results. We aimed to explore epidemiological and clinical prognostic factors of ME/CFS using operationalized criteria for recovery/improvement. Adult ME/CFS patients who attended the Internal Medicine Department of Angers University Hospital, Angers, France between October 2011 and December 2019, and were followed up until December 2020, were included retrospectively. Their medical records were reviewed for data collection. Patients were classified into two groups according to the presence or absence of recovery/improvement (R/I) and compared for epidemiological characteristics, fatigue features, post-exertional malaise severity, clinical manifestations, and comorbidities. The subgroups of recovered and significantly improved patients were then compared. 168 patients were included. Recovery and improvement rates were 8.3% and 4.8%, respectively. Older age at disease onset was associated with R/I (OR 1.06 [95% CI 1.007-1.110] (p = 0.028)), while diagnostic delay was inversely associated with R/I (OR 0.98 [95% CI 0.964-0.996] (p = 0.036)). The study findings confirmed the poor prognosis of ME/CFS and the deleterious effect of diagnostic delay on disease progression. Interestingly, being older at disease onset was associated with better outcomes, which offers hope to patients for recovery/improvement even at an advanced age.

Discordant Predictions of Extraglandular Involvement in Primary Sjögren's Syndrome According to the Anti-SSA/Ro60 Antibodies Detection Assay in a Cohort Study.

Electrophoresis-derived techniques for anti-SSA/Ro60 KDa (anti-SSA) antibodies detection have been progressively replaced by methods using non-native antigens. We aimed to compare the patients' phenotypes and the occurrence of extraglandular manifestations in primary Sjögren's syndrome according to the method used to detect anti-SSA antibodies. Sera from patients with a diagnosis of pSS according to ACR/EULAR 2016 criteria between 2008 and 2017 were tested for anti-SSA antibodies using methods with non-native antigens (magnetic bead multiplex assay; line immunoassays) and one with native antigens (counterimmunoelectrophoresis (CIE)). The population was split into three groups according to anti-SSA antibodies status: absence (SSA-), presence in any method except for CIE (SSA+CIE-), and presence in CIE (SSA+CIE+). The patients in the SSA+CIE+ group (n = 70, 42.7%) were ten years younger and presented more immunological activity compared with both the SSA- (n = 80, 48.8%) and SSA+CIE- groups (n = 14, 8.5%). The SSA- and SSA+CIE- groups were poorly distinct. The presence of anti-SSA antibodies solely in CIE was significantly associated with the occurrence of extraglandular manifestations of pSS (HR = 4.45 (2.35-8.42)). Contrary to CIE, methods using non-native antigens to detect anti-SSA antibodies were unable to predict the occurrence of systemic expression of pSS.

Evolution of plasma vitamin B12 in patients with solid cancers during curative versus supportive care.

INTRODUCTION: The direction of the causal link between solid cancers and elevated plasma vitamin B12 (B12) remains uncertain. METHODS: We retrospectively included patients having two B12 measurements with a B12 initially ≥ 1000 ng/l and a solid cancer diagnosed between the measurements. Patients were included in the Curative or Supportive group according to their treatments. RESULTS: B12 changes over time differed between groups (p = 0.001): +157.4 ng/l/month in the Supportive care group versus -171.6 ng/l/month in the Curative care group. CONCLUSIONS: The decrease of plasma B12 in cases of curative care could suggest that this B12 elevation is secondary to solid cancers.

Warning Signals of Post-Exertional Malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Retrospective Analysis of 197 Patients.

Post-exertional malaise (PEM), the key feature of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), is characterized by baseline symptom exacerbation after exposure to a stressor, and some patients can experience new or non-typical symptoms. We hypothesized that new or non-typical symptoms occurring long enough before onset of baseline symptom exacerbation could be warning signals predicting PEM. Adult ME/CFS patients who attended the internal medicine department of Angers University Hospital (France) between October 2011 and December 2019 were included in a retrospective medical records review. Patients who experienced one or more new or non-typical symptoms before baseline symptom exacerbation were compared with the rest of the study population for PEM features, epidemiological characteristics, fatigue features, and comorbidities. New or non-typical symptoms preceded baseline symptom exacerbation in 27/197 (13.7%) patients, and the most frequent ones were mood disorders (37%). When compared to the rest of the study population, only PEM intensity was significantly lower in these patients (p = 0.004), even after adjustment for sex and age at disease onset (p = 0.007). New or non-typical symptoms preceding baseline symptom exacerbation in some ME/CFS patients could be warning signals for PEM. Their identification could help preventing PEM occurrences or reducing their intensity leading to improving disease prognosis.

Persistent elevation of plasma vitamin B12 is strongly associated with solid cancer.

Elevated plasma vitamin B12 has been associated with solid cancers, based on a single B12 measurement. We evaluated the incidence of solid cancers following B12 measurement in patients with persistent elevated B12, compared to patients without elevated B12 and to patients with non-persistent elevated B12. The study population included patients with at least two plasma B12 measurements without already known elevated-B12-related causes. Patients with elevated plasma B12 (≥ 1000 ng/L) at first measurement (n = 344) were matched for age and sex with patients having 2 normal B12 measurements (< 1000 ng/L) (NN group, n = 344). The patients with elevated plasma B12 at first measurement were split into 2 groups, according to the presence (EE group, n = 144) or the absence (EN group, n = 200) of persistent elevated plasma B12 at second measurement. We compared the cancer-free survival during 60 months between the groups after adjustment for the other elevated-B12-related causes in a survival competing risk model. Compared to the NN group, a persistent elevated plasma B12 ≥ 1000 ng/mL was strongly associated with the occurrence of solid cancer (HR 5.90 [95% CI 2.79-12.45], p < 0.001), contrary to non-persistent plasma B12 elevation (p = 0.29). These results could help to select patients in whom the screening for solid cancers would be of interest.

Differences in clinical features between small fiber and sensitive large fiber neuropathies in Sjögren's syndrome.

BACKGROUND: To distinguish large (LFN) and small fiber neuropathies (SFN) in Sjögren's syndrome (SS) requires electroneuromyography (EMG) first, but this is time-consuming and has sometimes a limited accessibility, which can lead to a diagnostic delay. We aimed to identify clinical features that could distinguish SFN from sensitive LFN in SS. METHODS: The study included patients with SS who were monitored in the internal medicine and neurology departments at Angers University Hospital between 2010 and 2016, and who were tested for suspected peripheral neuropathy. Patients with clinical motor involvement were excluded. LFN diagnosis was based on EMG. SFN diagnosis was based on intraepidermal nerve fiber density on skin biopsies in patients with no abnormality on EMG. RESULTS: LFN and SFN were diagnosed respectively in 22 (6.9%) and 17 (5.4%) patients among 317 patients with SS. Prevalence of anti-SSA antibodies was lower in the SFN group compared to the LFN group (p=0.002). The types of paresthesia did not differ between the 2 groups. After adjustment for age and sex, SFN was associated with dysautonomia (p=0.01, OR 8.4 [CI 95%: 1.7-42.4]) and without length-dependent topography (p=0.03, OR 0.2 [0.04-0.8] in comparison with the LFN group. CONCLUSIONS: An association of non-length-dependent pattern and dysautonomia seems to predict the absence of LFN in SS and encourages the search for SFN. In contrary, patients with length-dependent involvement and without dysautonomia should be prioritized for EMG.

Unstimulated whole saliva flow for diagnosis of primary Sjögren's syndrome: time to revisit the threshold?

BACKGROUND: Unstimulated whole saliva (UWS) flow rate is one of the ACR/EULAR 2016 criteria for primary Sjögren's syndrome (pSS). With a single threshold of ≤ 0.1 mL/min, UWS flow does not take into account the age- and sex-related physiological variations. Furthermore, it has a low sensitivity for the diagnosis of pSS (about 50%), contrary to the screening test for xerophthalmia, Schirmer's test (sensitivity of about 70%). We aimed to identify UWS thresholds allowing better performances for a screening test for pSS comparable to Schirmer's test, and considering age- and sex-related variations. METHODS: A prospective cohort of 185 patients with oral and/or ocular dryness was classified into 3 groups: men, women < 50 (< 50 years old), and women ≥ 50 (≥ 50 years old). The diagnostic performances of UWS flow rate in these groups were compared in terms of sensitivity, specificity, positive and negative predictive values, and ROC curves. The identification of thresholds that optimize diagnostic performances was carried out using Youden's index. RESULTS: The diagnostic performances of UWS flow rate varied according to age and sex. UWS had poor diagnostic performances whatever the threshold in the women ≥ 50 group. The threshold of 0.2 mL/min had a sensitivity of ≥ 70% and a specificity of ≥ 50% in both men and women < 50 groups. In the whole population and compared to the current cutoff, a threshold of 0.2 mL/min increased sensitivity (+ 19.8%) and positive (+ 2.3%) and negative (+ 7.0%) predictive values, with a better specificity (65.2%) than Schirmer's test. CONCLUSION: For objective assessment of xerostomia, raising the threshold of the UWS flow rate to 0.2 mL/min would optimize its screening performances for pSS.

Elevated blood lactate in resting conditions correlate with post-exertional malaise severity in patients with Myalgic encephalomyelitis/Chronic fatigue syndrome.

Elevated blood lactate after moderate exercise was reported in some of patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). We hypothesised that blood lactate could be also elevated in resting conditions. We aimed investigating the frequency of elevated lactate at rest in ME/CFS patients, and comparing characteristics of ME/CFS patients with and without elevated lactate. Patients fulfilling international consensus criteria for ME/CFS who attended the internal medicine department of University hospital Angers-France between October 2011 and December 2017 were included retrospectively. All patients were systematically hospitalised for an aetiological workup and overall assessment. We reviewed their medical records for data related to the assessment: clinical characteristics, comorbidities, fatigue features, post-exertional malaise (PEM) severity, and results of 8 lactate measurements at rest. Patients having ≥1 lactate measurement ≥2 mmol/L defined elevated lactate group. The study included 123 patients. Elevated (n = 55; 44.7%) and normal (n = 68; 55.3%) lactate groups were comparable except for PEM, which was more severe in the elevated lactate group after adjusting for age at disease onset, sex, and comorbidities (OR 2.47, 95% CI: 1.10-5.55). ME/CFS patients with elevated blood lactate at rest may be at higher risk for more severe PEM. This finding may be of interest in ME/CFS management.