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Background: Sjögren’s syndrome is an autoimmune disease characterized by sicca symptoms and various extraglandular manifestations including vasculitis. Neurological involvement occurs frequently (Neuro-Sjögren) and often mimics immune neuropathies such as chronic inflammatory demyelinating polyneuropathy (CIDP). Objectives: We aim to assess relevant differences in vessel density (VD) in Optical Coherence Tomography Angiography (OCTA) in those diseases to use it as an easily available diagnostic tool. Design: Prospective, monocentric pilot-study. Methods: OCTA (Heidelberg Engineering OCT SPECTRALIS) of the superficial vascular plexus, intermediate capillary plexus (ICP) and deep capillary plexus (DCP) of the retina was prospectively performed in Neuro-Sjögren, age-matched CIDP patients ( n = 31, each), and healthy controls ( n = 30). Vessel density (VD) and foveal avascular zone (FAZ) was measured with Erlangen Angio Tool. Results: Significantly lower VD were found for the DCP and ICP in Neuro-Sjögren and CIDP patients compared to healthy controls ( p = 0.0002 and

Background MicroRNAs (miRNAs) can regulate gene expression, controlling numerous cellular processes. Dysregulation of miRNA function is linked to various diseases, making them attractive diagnostic and therapeutic targets. Examples include hsa-miR-92a-3p, hsa-miR-126-3p, hsa-miR-143-3p, hsa-miR-145-5p and hsa-miR-204-5p, which are associated with endothelial function. Their prevalence in Sjögren’s disease (SjD) is unknown. We assessed the prevalence of these miRNAs in serum of patients with SjD, correlating levels with cardiovascular risk factors and carotid intima-media thickness (cIMT) to evaluate their utility in risk stratification.Methods 199 patients with SjD and 100 age and sex-matched healthy controls (HC) were included in the study. Five different miRNAs (hsa-miR-92a-3p; hsa-miR-126-3p; hsa-miR143-3p; hsa-miR-145-5p; hsa-miR-204-5p) were analysed by quantitative real-time PCR. The miRNA results were compared with known clinical and disease-related parameters.Results Four miRNAs showed significantly different expressions compared with HC. MiR-92a-3p was upregulated (p=0.025) and miR-126-3p (p=0.044), miR-143-3p (p=0.006) and miR-204-5p (p=0.009) downregulated in SjD compared with HC. The comparison between HC and SjD with/without organ involvement revealed descriptively increased miR-92a-3p levels in patients with SjD with organ involvement (p=0.087). Furthermore, miR-92a-3p levels correlated positively with cIMT as an expression of subclinical atherosclerosis (r=0.148, p=0.04).Conclusion In conclusion, patients with SjD demonstrated differences in their expression of miRNAs linked to regulation of endothelial function. Reduction of specific miRNAs was associated with increased cardiovascular risk, suggesting a potentially protective role for these miRNAs. Furthermore, miR-92a-3p could be helpful for molecular detection of early-stage atherosclerosis and increased cardiovascular risk in SjD.

ObjectiveThe signal transducer and activator of transcription 3 (STAT3) gain-of-function (GOF) syndrome (STAT3-GOF) is an inborn error of immunity (IEI) characterized by diverse manifestations of immune dysregulation that necessitate systemic immunomodulatory treatment. The blockade of the interleukin-6 receptor and/or the inhibition of the Janus kinases has been commonly employed to treat diverse STAT3-GOF-associated manifestations. However, evidence on long-term treatment outcome, especially in the case of adult patients, is scarce.MethodsClinical data, including laboratory findings and medical imaging, were collected from all seven patients, diagnosed with STAT3-GOF, who have been treated at the Hannover University School, focusing on those who received a Janus kinase (JAK) inhibitor (JAKi). Previously published cases of STAT3-GOF patients who received a JAKi were evaluated, focusing on reported treatment efficacy with respect to diverse STAT3-GOF-associated manifestations of immune dysregulation and safety.ResultsFive out of seven patients diagnosed with STAT3-GOF were treated with a JAKi, each for a different indication. Including these patients, outcomes of JAKi treatment have been reported for a total of 41 patients. Treatment with a JAKi led to improvement of diverse autoimmune, inflammatory, or lymphoproliferative manifestations of STAT3-GOF and a therapeutic benefit could be documented for all except two patients. Considering all reported manifestations of immune dysregulation in each patient, complete remission was achieved in 10/41 (24.4%) treated patients.ConclusionsJAKi treatment improved diverse manifestations of immune dysregulation in the majority of STAT3-GOF patients, representing a promising therapeutic approach. Long-term follow-up data are needed to evaluate possible risks of prolonged treatment with a JAKi.

BackgroundSafety recommendations for Janus kinase inhibitors (JAKi) issued by the European Medical Agency (EMA) in 2023 could potentially influence treatment patterns for rheumatoid arthritis (RA) drugs, but little is known about the impact of these recommendations in routine clinical care.MethodsWe retrospectively analyzed the German RHADAR rheumatology database for adult patients with RA and documentation of a new therapy with a JAKi, tumor necrosis factor inhibitor (TNFi), or interleukin-6 receptor inhibitor (IL-6Ri). Data were grouped into half-yearly intervals from quarter (Q)2/2020 to Q3/2023. The period from Q4/2022 to Q1/2023 immediately followed the initial EMA endorsement of Pharmacovigilance Risk Assessment Committee (PRAC) recommendations and Q2/2023-Q3/2023 immediately followed the direct healthcare provider communication (DHPC) containing the new safety JAKi recommendations.ResultsBetween April 1, 2020 and September 23, 2023, 3008 newly initiated therapies for TNFi (1499 [49.8%]), JAKi (1126 [37.4%]), and IL-6Ri (383 [12.7%]) were documented by the treating physicians. JAKi were increasingly used in the first two half-year periods (from 29.7% of these therapies in Q2/2020-Q3/2020 to 46.7% in Q2/2021-Q3/2021; odds ratio [OR] 2.08; p3rd-line therapy in later time periods.ConclusionsThis exploratory study suggests that EMA safety recommendations for JAKi influenced treatment patterns of RA patients who received JAKi in Germany. Additional studies will be needed to confirm these findings.

ObjectiveTreatment options with disease-modifying antirheumatic drugs (DMARDs) for psoriatic arthritis (PsA) have evolved over recent years. In addition to Janus kinase inhibitors (JAKi), four classes of biologic DMARDs (bDMARDs; interleukin [IL]-23 inhibitors [IL-23i], IL-12/23 inhibitors [IL-12/23i], tumor necrosis factor inhibitors [TNFi], and IL-17 inhibitors [IL-17i]) are currently approved for moderate to severe PsA treatment. There is minimal evidence of the persistence of these drugs among PsA outpatients in a real-world scenario during the period following the approval of JAKi. Therefore, we aimed to analyze the drug survival rates of biologic and JAKi therapies among German PsA outpatients during routine clinical care.MethodsWe retrospectively analyzed PsA patients with a new prescription for a biologic or JAKi in the RHADAR database between January 2015 and October 2023. Kaplan-Meier Curves and Cox regression modelling were used to compare drug survival rates.Results1352 new prescriptions with bDMARDs (IL-12/23i [n=50], IL-23i [n=31], TNFi [n=774], IL-17i [n=360]) or JAKi (n=137) were identified. The 5-year drug survival rate was 67.8% for IL-17i, 62.3% for TNFi, 53.3% for JAKi, and 46.0% for IL-12/23i. Discontinuation probabilities for JAKi and IL-12/23i were significantly higher compared with TNFi (JAKi hazard ratio [HR] 1.66, [95% CI 1.23–2.24], p=0.001; IL-12/23i HR 1.54, [95% CI 1.02–2.33], p=0.042) and IL-17i (JAKi HR 1.77, [95% CI 1.27–2.47], p=0.001; IL-12/23i HR 1.64, [95% CI 1.06–2.55], p=0.027). JAKi-treated patients had more severe disease and more osteoarthritis (OA) compared to TNFi and more OA compared to IL-17i. ConclusionGerman PsA outpatients might persist longer with TNFi and IL-17i compared with IL-12/23i or JAKi. For TNFi, differences in subgroup characteristics and comorbidities (OA) may have affected drug survival rates. For IL-17i, the longer drug survival might not only be related to less OA compared to JAKi and, therefore, might be affected by other factors.

Objectives Cardiovascular comorbidities are common in patients with autoimmune diseases. This study investigates the extent of subclinical atherosclerosis in patients with primary Sjögren’s syndrome (pSS). Correlations with clinical factors such as organ involvement (OI) or disease activity were analysed and oxLDL antibodies (oxLDL ab) were measured as potential biomarkers of vascular damage.Methods Patients with pSS were consecutively included from the rheumatology outpatient clinic. Age- and sex-matched controls were recruited (2:1 ratio). Data collection was performed by a standardised questionnaire and Doppler ultrasound to evaluate the plaque extent and carotid intima-media thickness (cIMT). Propensity score matching included all cardiovascular risk (CVR) factors and corresponding laboratory markers.Results Data were available for 299 participants (199 pSS/100 controls), aged 59.4 years (50.6–65.0), 19.1% male. After matching, the pSS cohort had greater cIMT (p

IntroductionSystemic lupus erythematosus (SLE) is a clinically heterogeneous disease that presents a challenge for clinicians. To identify potential biomarkers for diagnosis and disease activity in SLE, we investigated a selected yet broad panel of cytokines and autoantibodies in patients with SLE, healthy controls (HC), and patients with other autoimmune diseases (AIDs).MethodsSerum samples from 422 SLE patients, 546 HC, and 1223 other AIDs were analysed within the frame of the European PRECISESADS project (NTC02890121). Cytokine levels were determined using Luminex panels, and autoantibodies using different immunoassays.ResultsOf the 83 cytokines analysed, 29 differed significantly between patients with SLE and HC. Specifically, CCL8, CXCL13, and IL-1RA levels were elevated in patients with active, but not inactive, SLE versus HC, as well as in patients with SLE versus other AIDs. The levels of these cytokines also correlated with SLE Disease Activity Index 2000 (SLEDAI-2K) scores, among five other cytokines. Overall, the occurrence of autoantibodies was similar across SLEDAI-2K organ domains, and the correlations between autoantibodies and activity in different organ domains were weak.DiscussionOur findings suggest that, upon validation, CCL8, CXCL13, and IL-1RA could serve as promising serum biomarkers of activity in SLE.

Prolidase deficiency (PD) is a rare autosomal recessive inborn error of immunity caused by biallelic homozygous or compound heterozygous loss-of-function mutations in PEPD, the gene that encodes prolidase. PD typically manifests with variable dysmorphic features, chronic cutaneous ulcers, recurrent infections and autoimmune features, including systemic lupus erythematosus. So far, there is no consensus regarding treatment of PD and its autoimmune manifestations. Here, we present a 28-year-old female patient with PD due to a novel homozygous intragenic deletion in PEPD, diagnosed at the age of 6 years and 7 months with an undifferentiated connective tissue disease that, apart from its very early onset, would be consistent with the diagnosis of Sjögren’s syndrome. Steroids and diverse conventional synthetic disease-modifying antirheumatic drugs failed to control PD-associated vasculitis and mucocutaneous ulcerations and led to infectious complications, including cytomegalovirus colitis. Introduction of rituximab (RTX) treatment in this patient led to sustained recession of mucocutaneous ulceration, enabling tapering of steroids. High interleukin-1β (IL-1β) production by this patient’s monocytes, together with the detection of both IL-1β and interleukin-18 (IL-18) in her serum, suggest enhanced inflammasome activation in PD, whereas the therapeutic efficacy of RTX implies a role for CD20 positive B cells in the complex immunopathogenesis of PD.

The genetic architecture underlying Sjögren’s syndrome is not fully understood. Here, the authors perform a genome-wide association study to identify 10 new genetic risk regions, implicating genes involved in immune and salivary gland function.

Summary: Inborn errors of immunity (IEIs) are immunological disorders characterized by variable susceptibility to infections, immune dysregulation and/or malignancies, as a consequence of damaging germline variants in single genes. Though initially identified among patients with unusual, severe or recurrent infections, non-infectious manifestations and especially immune dysregulation in the form of autoimmunity or autoinflammation can be the first or dominant phenotypic aspect of IEIs. An increasing number of IEIs causing autoimmunity or autoinflammation, including rheumatic disease have been reported over the last decade. Despite their rarity, identification of those disorders provided insight into the pathomechanisms of immune dysregulation, which may be relevant for understanding the pathogenesis of systemic rheumatic disorders. In this review, we present novel IEIs primarily causing autoimmunity or autoinflammation along with their pathogenic mechanisms. In addition, we explore the likely pathophysiological and clinical relevance of IEIs in systemic rheumatic disorders.

Abstract In gout, crystallization of uric acid in the form of monosodium urate (MSU) leads to a painful inflammatory response. MSU crystals induce inflammation by activating the complement system and various immune cell types, and by inducing necrotic cell death. We previously found that the soluble pattern recognition molecule C-reactive protein (CRP) recognizes MSU crystals, while enhancing complement activation. In the absence of CRP, MSU crystals still induced complement activation, suggesting additional CRP-independent mechanisms of complement activation. In the present study, we searched for additional MSU crystal-binding complement activators. We found that all healthy individuals, even unborn children, have MSU crystal-specific immunoglobulin M (IgM) in their blood. This indicates that innate IgM, also known as natural IgM, recognizes these crystals. In serum lacking IgM and CRP, MSU crystals showed negligible complement activation as assessed by the production of the anaphylatoxins C4a, C3a, and C5a (listed in order of production via the classical complement pathway). We show that IgM and CRP both activate the classical complement pathway on MSU crystals. CRP was more efficient at fixating active C1 on the crystals and inducing release of the most inflammatory anaphylatoxin C5a, indicating non-redundant functions of CRP. Notably, while CRP recognizes MSU crystals but not the related calcium pyrophosphate dihydrate (CPPD) crystals, natural IgM bound to both, suggesting common and distinct mechanisms of recognition of individual crystal types by complement activators.

IntroductionThe characterization of the influence of the microbiota on the development and drug responses during rheumatic diseases has intensified in recent years. The role of specific bacteria during disease development has become a central research question. Notably, several lines of evidence point to distinct microbes, e.g., Prevotella copri (P. copri) being targeted by antibodies in clinical phases of rheumatic diseases.MethodsIn the present study, we compiled a broad collection of human serum samples from individuals at risk of developing RA, chronic RA patients as well as patients with new-onset of rheumatic diseases. We evaluated the presence of inflammatory biomarkers in our serum collection as well as serum antibody responses against novel, genetically distinct isolates of P. copri and several oral pathobionts.ResultsOur analysis revealed the presence of increased levels of inflammatory markers already in pre-clinical and new onset rheumatoid arthritis. However, antibody reactivity against the microbes did not differ between patient groups. Yet, we observed high variability between the different P. copri strains. We found total serum IgG levels to slightly correlate with IgG antibody responses against P. copri, but no relation between the latter and presence or prevalence of P. copri in the intestine.DiscussionIn conclusion, our work underlined the importance of strain-level characterization and its consideration during further investigations of host-microbiota interactions and the development of microbiome-based therapeutic approaches for treating rheumatic diseases.

IntroductionPrimary Sjögren's syndrome (pSS) is associated with an increased prevalence of traditional risk factors and cardiovascular diseases (CVDs). The study aimed to identify specific risk factors for CVD in pSS patients.MethodsPSS patients with and without CVD were compared. All patients fulfilled the EULAR/ACR classification criteria. Patients with CVD presented at least one of the following manifestations: myocardial infarction, transient ischemic attacks, ischemic or hemorrhagic stroke, peripheral artery disease, coronary artery disease, and carotid plaques. Data were collected by a standardized protocol and review of medical records.Results61/312 (19.6%) pSS patients presented with CVD. Traditional risk factors such as hypertension, hypercholesterinemia and diabetes (p < 0.05), pSS manifestations, in particular vasculitis (p = 0.033) and Raynaud's phenomenon (p = 0.018) were associated with CVD. Among patients with ischemic events (28/312, 9%), particularly cerebrovascular disease (n = 12/28, 42.9%), correlations with increased EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) (p = 0.039) and EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) (p = 0.048) were observed. Age at first cerebrovascular event was 55.2 [48.9–69.6] years. Multivariate analysis confirmed hypertension [odds ratio (OR) 3.7, 95% confidence interval (CI) 1.87–7.18, p < 0.001], hypercholesterinemia (OR 3.1, 95% CI 1.63–5.72, p < 0.001), male gender (OR 0.4, 95% CI 0.17–0.78, p = 0.009), Raynaud's phenomenon (OR 2.5, 95% CI 1.28–4.82, p = 0.007), and CNS involvement (OR 2.7, 95% CI 1.00–7.15, p = 0.048) as independent CVD predictors.ConclusionRaynaud's phenomen as well as vasculitis and high ESSDAI have shown a significant association to CVD. PSS patients with cerebrovascular events were younger than expected. Knowledge about risk factors may help clinicians to identify pSS patients at risk for CVD. After diagnosis of pSS, patients should be screened for risk factors such as hypertension and receive appropriate therapy to prevent or at least reduce sequelae such as infarction. However, further investigations are necessary in order to achieve a reliable risk stratification for these patients.

Objective The clinical spectrum of primary antibody deficiencies (PADs) and especially common variable immunodeficiency (CVID) includes various autoimmune disorders. We studied the prevalence and the features of articular rheumatic disease in a cohort of patient with PADs.Methods In this retrospective cohort study, complete clinical data of 268 patients with PADs, mainly consisting of patients with CVID, visiting the immunology outpatient clinic of a German tertiary hospital between 2018 and 2021 were collected. Those included case history, physical examination, laboratory as well as radiological findings.Results Inflammatory arthritis was diagnosed in 16.4% of studied patients and was significantly more common among patients with PAD-associated enteropathy (OR 13.39, p=0.0001), splenomegaly (OR 6.09, p=0.0001) or atopic diseases (OR 3.31, p=0.021). Given HLA-B27 status, the involvement of the axial skeleton and the presence of features, such as anterior uveitis, inflammatory bowel disease, psoriasis and/or dactylitis, 75% of studied patients fulfilled the Assessment of Spondyloarthritis International Society classification criteria.Conclusion PAD-associated arthritis frequently shares features with spondyloarthritis (SpA) and enteropathic arthritis. The latter may suggest the interconnected pathomechanisms of inflammatory arthritis in SpA and PADs.

Objectives Besides adaptive immunity genes, genetic risk factors for psoriatic arthritis (PsA) include innate immunity loci, which suggests an autoinflammatory disease mechanism, at least in a subset of patients. Here, we aimed at investigating the autoinflammatory genetic background of PsA.Methods A total of 120 patients with PsA visiting the outpatient clinics of the Hannover University hospital underwent targeted next-generation sequencing, searching for variations in genes linked with inborn errors of immunity classified as autoinflammatory disorders (AIDs). Deleteriousness of rare variants was evaluated through in silico analysis.Results We found 45 rare predicted deleterious variants in 37 out of 120 (30.8%) patients with PsA. Relatively common were variants in AP1S3, PLCG2, NOD2 and NLRP12. All 45 variants were monoallelic and 25 of them, identified in 20 out of 120 (16.7%) patients, were localised in genes associated with autosomal dominant (AD) disorders. Detection of those variants is associated with pustular psoriasis or a coexisting inflammatory bowel disease (IBD).Conclusions Approximately 30% of patients with PsA harboured at least one variant in a gene associated with an AID, suggesting an autoinflammatory disease mechanism. Detection of variants in genes linked to AD-AIDs may explain extra-articular manifestations of PsA, such as pustular psoriasis and IBD.

Sjögren’s syndrome, a disease that primarily affects women, is poorly understood. Here, the authors combine data from a large cohort of patients and healthy controls to identify biomarkers that distinguish patient subgroups to improve our understanding of the disease and facilitate drug development.

Abstract Background Serology testing is explored for epidemiological research and to inform individuals after suspected infection. During the coronavirus disease 2019 (COVID-19) pandemic, frontline healthcare professionals (HCP) may be at particular risk for infection. No longitudinal data on functional seroconversion in HCP in regions with low COVID-19 prevalence and low pre-test probability exist. Methods In a large German university hospital, we performed weekly questionnaire assessments and anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunoglobulin G (IgG) measurements with various commercial tests, a novel surrogate virus neutralisation test, and a neutralisation assay using live SARS-CoV-2. Results From baseline to week 6, 1080 screening measurements for anti-SARS CoV-2 (S1) IgG from 217 frontline HCP (65% female) were performed. Overall, 75.6% of HCP reported at least one symptom of respiratory infection. Self-perceived infection probability declined over time (from mean 20.1% at baseline to 12.4% in week 6, p

Abstract Objective Extraglandular neurological manifestations of Sjögren’s syndrome are increasingly recognized, defining the disease entity of Neuro‐Sjögren. Neuropsychological assessment of patients with Sjögren’s syndrome has hitherto been performed on predominantly rheumatological cohorts. These studies revealed a wide variety of prevalence rates for cognitive impairment (22–80%), while variable cut‐off criteria for detection of cognitive impairment were applied. Attentional functions have not yet been thoroughly investigated in these patients, although they clearly represent relevant aspects of cognitive functioning in daily life. Methods We therefore conducted extensive neuropsychological assessment based on two neuropsychological test batteries [i.e., the extended German version of the Consortium to Establish a Registry for Alzheimer’s Disease Neuropsychological Assessment Battery (CERAD‐PLUS), and the test battery for attentional performance (TAP) as a well‐established assessment of attentional functions in the German‐speaking part of Europe]. Results Sixty‐four patients with Neuro‐Sjögren, who were treated at our university hospital between December 2016 and January 2019, were included. Evidence for the presence of cognitive impairment was found in 55% of patients with Neuro‐Sjögren. The degree of cognitive impairment ranged from mild (38%) to severe (17%). Attentional and mnemonic subtests showed pronounced cognitive impairment in patients with Neuro‐Sjögren. Interpretation Our results suggest that a substantial proportion of patients with Neuro‐Sjögren suffer from cognitive impairment, putatively as a corollary of attentional deficits, which might exert adverse effects on occupational abilities, other cognitive functions, and social role functioning.

ObjectiveThe aim of this study was to investigate the prevalence of cancer and associating clinical, immunological, and genetic factors in a German cohort of patients with common variable immunodeficiency (CVID).MethodsIn this retrospective monocenter cohort study, we estimated the standardized incidence ratio (SIR) for different forms of cancer diagnosed in CVID patients. Furthermore, we evaluated the likely association of infectious and non-infectious CVID-related phenotypes with the diagnosis of cancer by calculation of the odds ratio. The genetic background of CVID in patients with cancer was evaluated with sequential targeted next-generation sequencing (tNGS) and whole-exome sequencing (WES). Patients’ family history and WES data were evaluated for genetic predisposition to cancer.ResultsA total of 27/219 patients (12.3%) were diagnosed with at least one type of cancer. Most common types of cancer were gastric cancer (SIR: 16.5), non-melanoma skin cancer (NMSC) (SIR: 12.7), and non-Hodgkin lymphoma (NHL) (SIR: 12.2). Immune dysregulation manifesting as arthritis, atrophic gastritis, or interstitial lung disease (ILD) was associated with the diagnosis of cancer. Furthermore, diagnosis of NMSC associated with the diagnosis of an alternative type of cancer. Studied immunological parameters did not display any significant difference between patients with cancer and those without. tNGS and/or WES yielded a definite or likely genetic diagnosis in 11.1% of CVID patients with cancer. Based on identified variants in cancer-associated genes, the types of diagnosed cancers, and family history data, 14.3% of studied patients may have a likely genetic susceptibility to cancer, falling under a known hereditary cancer syndrome.ConclusionsGastric cancer, NMSC, and NHL are the most frequent CVID-associated types of cancer. Manifestations of immune dysregulation, such as arthritis and ILD, were identified as risk factors of malignancy in CVID, whereas studied immunological parameters or the identification of a monogenic form of CVID appears to have a limited role in the evaluation of cancer risk in CVID.

Background: Sicca syndrome represents a heterogeneous group of conditions, such as Sjögren syndrome, causing xerophthalmiaand xerostomia. This study characterizes in depth patients with Sicca syndrome and evaluates salivary gland ultrasound (SGUS).Methods: Principal component analysis and hierarchical clustering of clinical parameters, such as ESSPRI, ESSDAI and laboratory data, were performed on all referrals for assessment of Sicca symptoms between October 2018 and March 2021. SGUS and labial gland biopsies were compared across groups.Results: A total of 583 patients were assessed. Objective dryness was confirmed in 73% of the patients. Cluster analysis identified 3 groups with post-hoc analysis confirming distinct phenotypes: Somatic Group (283/583; 49%) with more frequent symptoms but limited objective dryness; Dry Without Autoimmune Features (DAFneg, 206/584; 35%), and Dry With Autoimmune Features (DAFpos, 94/584;16%). DAFpos patients had highest autoantibody titers (anti-SSA(Ro) 240 vs. 3.6 vs. 3.8; p < 0.001), most extra-glandular manifestations (p < 0.001), and highest median SGUS Score (DAFpos: 8 [IQR 4–10] vs. SG: 2 [1–4] vs. DAFneg 4 [2–5]; p < 0.001). No tangible correlation with primary Sjögren syndrome criteria was observed.Discussion: SGUS score correlated with a subset of patients with Sjögren syndrome, identified in the DAFpos cluster. This study highlights heterogeneity within sicca and, indeed, Sjögren syndrome, highlighting the need for further studies.

NF-κB1 deficiency is suggested to be the most common cause of common variable immunodeficiency (CVID). NFKB1 encodes for the p105 precursor protein of NF-κB1, which is converted into the active transcriptional subunit p50 through proteasomal processing of its C-terminal half upon stimulation and is implicated in the canonical NF-kB pathway. Rare monoallelic NFKB1 variants have been shown to cause (haplo) insufficiency. Our report describes a novel NFKB1 missense variant (c.691C>T, p.R230C; allele frequency 0.00004953) in a family vulnerable to meningitis, sepsis, and late-onset hypogammaglobulinemia. We investigated the pathogenic relevance of this variant by lymphocyte stimulation, immunophenotyping, overexpression study and immunoblotting. The ectopic expression of p50 for c.691 C>T restricted transcriptionally active p50 in the cytoplasm, and immunoblotting revealed reduced p105/50 expression. This study shows that the deleterious missense variant in NFKB1 adversely affects the transcriptional and translational activity of NFκB1, impairing its function. Patients immunological parameters show a progressive course of hypogammaglobulinemia, which may partially account for the incomplete disease penetrance and suggest the need for closer immunological monitoring of those mutation carriers.

Objective: To identify a spectrum of perspectives on functioning and health of patients with primary Sjögren's syndrome (pSS) from the five European countries in order to reveal commonalities and insights in their experiences.Methods: A multicenter focus group study on the patients with pSS about their perspectives of functioning and health was performed. Focus groups were chaired by trained moderators based on an interview guide, audiotaped, and transcribed. After conducting a meaning condensation analysis of each focus group, we subsequently combined the extracted concepts from each country and mapped them to the International Classification of Functioning, Disability and Health (ICF).Results: Fifty-one patients with pSS participated in 12 focus groups. We identified a total of 82 concepts meaningful to people with pSS. Of these, 55 (67%) were mentioned by the patients with pSS in at least four of five countries and 36 (44%) emerged in all the five countries. Most concepts were assigned to the ICF components activities and participation (n = 25, 30%), followed by 22 concepts (27%) that were considered to be not definable or not covered by the ICF; 15 concepts (18%) linked to body structures and functions. Participants reported several limitations in the daily life due to a mismatch between the capabilities of the person, the demands of the environment and the requirements of the activities.Conclusion: Concepts that emerged in all the five non-English speaking countries may be used to guide the development and adaption of the patient-reported outcome measures and to enhance the provision of treatment options based on the aspects meaningful to patients with pSS in clinical routine.

Background The determination of kappa free light chains (KFLC) in cerebrospinal fluid (CSF) is an upcoming biomarker for the detection of an intrathecal immunoglobulin synthesis. Since renal function impairment leads to altered serum KFLC and albumin concentrations, interpretation of KFLC in CSF may be influenced by these parameters. Methods In this two-center study, the influence of renal function (according to the CKD-EPI creatinine equation) on KFLC and albumin concentrations was investigated in patients with “physiological” (n = 139), “non-inflammatory” (n = 146), and “inflammatory” (n = 172) CSF profiles in respect to the KFLC index and the evaluation in quotient diagrams in reference to the hyperbolic reference range (KFLC IF). Results All sample groups displayed declining KFLC indices and KFLC IF values with decreasing renal function ( P -values between

Background: Sjögren’s syndrome (SS) is an autoimmune disease characterized by sicca symptoms and various extra-glandular manifestations. The diagnosis of SS requires sicca symptoms, anti-SSA(Ro)-antibody positivity, and/or pathological focus scores on a minor salivary gland biopsy. Previous studies have investigated different biomarkers in order to avoid invasive diagnostic procedures. It was found that kappa and lambda free light chains (KFLC and LFLC) in saliva are specific for SS. Methods: FLC concentrations in saliva and serum were determined in 130 patients—50 with SS and neurological involvement (Neuro-Sjögren) and 80 neurological controls. The EULAR SS disease activity index and patient reported index (ESSPRI) were determined in patients with SS. Results: Patients with SS revealed increased pain and decreased saliva production according to the ESSPRI and Saxon test, respectively, with increasing FLC concentrations in the saliva. No significant differences in serum and salivary protein concentrations were observed between patients with SS and controls. Conclusion: KFLC and LFLC concentrations in saliva are not suitable to distinguish patients with Neuro-Sjögren and neurological control subjects, thus a diagnostic biopsy is still required. The association of salivary KFLC and LFLC concentrations with saliva production and ESSPRI pain score suggests a complex relationship between dryness and pain in patients with SS.

Background: The intrathecal humoral response is the characteristic diagnostic finding in the cerebrospinal fluid (CSF) analysis of patients with multiple sclerosis (MS). Although the average age of MS patients increases, little is known about the sensitivity of diagnostic markers in elderly MS patients. Methods: In this retrospective two-center study, intrathecal free light chains kappa fraction (FLCk IF) and oligoclonal bands (OCB) were studied in a large cohort of patients with early and late onset relapsing (RMS) and progressive (PMS) MS. Furthermore, the humoral immune profile in CSF was analyzed, including the polyspecific intrathecal immune response measured as the MRZ reaction. Results: While the frequency of CSF-specific OCB did not differ between early and late onset RMS and PMS, the sensitivity of positive FLCk IF and absolute FLCk IF values were lower in PMS. The positivity of the MRZ reaction was equally frequent in early and late onset RMS and PMS. PMS patients had higher local IgA concentrations than RMS patients (p = 0.0123). Conclusions: OCB are slightly superior to FLCk IF in progressive MS in terms of sensitivity for detecting intrathecal immunoglobulin synthesis. The MRZ reaction, as the most specific parameter for MS, is also applicable in patients with late onset and progressive MS.

[This corrects the article DOI: 10.1371/journal.ppat.1008560.].

Objective To determine the non-inferiority of nurse-led care (NLC) in patients with anticitrullinated protein antibody (ACPA)-positive and/or rheumatoid factor (RF)-positive rheumatoid arthritis (RA) with active disease who are starting disease-modifying antirheumatic drug therapy, following treat-to-target (T2T) recommendations.Methods A multicentre, pragmatic randomised controlled trial was conducted to assess clinical effectiveness, anxiety, depression and patient satisfaction following a non-inferiority design. The participants were 224 adults with ACPA/RF-positive RA who were randomly assigned to either NLC or rheumatologist-led care (RLC). The primary outcome was the Disease Activity Score in 28 Joints measured with C reactive protein (DAS28-CRP) assessed at baseline and after 3, 6, 9 and 12 months. A DAS28-CRP difference of 0.6 was set as the non-inferiority margin. Mean differences between the groups were assessed following per-protocol and intention-to-treat strategies.Results Demographic data and baseline characteristics of patients in the NLC group (n=111) were comparable to those of patients in the RLC group (n=113). The improvement in disease activity (change in DAS28-CRP, primary outcome) over the course of 12 months was significant in both groups (p

Background: Oligoclonal bands represent intrathecal immunoglobulin G (IgG) synthesis and play an important role in the diagnosis of multiple sclerosis (MS). Kappa free light chains (KFLC) are increasingly recognized as an additional biomarker for intrathecal Ig synthesis. However, there are limited data on KFLC in neurological diseases other than MS. Methods: This study, conducted at two centers, retrospectively enrolled 346 non-MS patients. A total of 182 patients were diagnosed with non-inflammatory and 84 with inflammatory neurological diseases other than MS. A further 80 patients were classified as symptomatic controls. Intrathecal KFLC production was determined using different approaches: KFLC index, Reiber’s diagram, Presslauer’s exponential curve, and Senel’s linear curve. Results: Matching results of oligoclonal bands and KFLC (Reiber’s diagram) were frequently observed (93%). The Reiber’s diagram for KFLC detected intrathecal KFLC synthesis in an additional 7% of the patient samples investigated (4% non-inflammatory; 3% inflammatory), which was not found by oligoclonal band detection. Conclusions: The determination of both biomarkers (KFLC and oligoclonal bands) is recommended for routine diagnosis and differentiation of non-inflammatory and inflammatory neurological diseases. Due to the high sensitivity and physiological considerations, the assessment of KFLC in the Reiber’s diagram should be preferred to other evaluation methods.

Human cytomegalovirus (HCMV) causes serious complications to immune compromised hosts. Dendritic cells (iDCgB) expressing granulocyte-macrophage colony-stimulating factor, interferon-alpha and HCMV-gB were developed to promote de novo antiviral adaptive responses. Mice reconstituted with a human immune system (HIS) were immunized with iDCgB and challenged with HCMV, resulting into 93% protection. Immunization stimulated the expansion of functional effector memory CD8+ and CD4+ T cells recognizing gB. Machine learning analyses confirmed bone marrow T/CD4+, liver B/IgA+ and spleen B/IgG+ cells as predictive biomarkers of immunization (≈87% accuracy). CD8+ and CD4+ T cell responses against gB were validated. Splenic gB-binding IgM-/IgG+ B cells were sorted and analyzed at a single cell level. iDCgB immunizations elicited human-like IgG responses with a broad usage of various IgG heavy chain V gene segments harboring variable levels of somatic hypermutation. From this search, two gB-binding human monoclonal IgGs were generated that neutralized HCMV infection in vitro. Passive immunization with these antibodies provided proof-of-concept evidence of protection against HCMV infection. This HIS/HCMV in vivo model system supported the validation of novel active and passive immune therapies for future clinical translation.

Interstitial lung disease (ILD) represents a frequent extra-glandular manifestation of primary Sjögren's Syndrome (pSS). Limited published data regarding phenotyping and treatment exists. Advances in managing specific ILD phenotypes have not been comprehensively explored in patients with coexisting pSS. This retrospective study aimed to phenotype lung diseases occurring in a well-described pSS-ILD cohort and describe treatment course and outcomes. Between April 2018 and February 2020, all pSS patients attending our Outpatient clinic were screened for possible lung involvement. Clinical, laboratory and high-resolution computed tomography (HRCT) findings were analyzed. Patients were classified according to HRCT findings into five groups: usual interstitial pneumonia (UIP), non-specific interstitial pneumonia (NSIP), desquamative interstitial pneumonia (DIP), combined pulmonary fibrosis and emphysema (CPFE), and non-specific-ILD. Lung involvement was confirmed in 31/268 pSS patients (13%). One-third (10/31) of pSS-ILD patients were Ro/SSA antibody negative. ILD at pSS diagnosis was present in 19/31 (61%) patients. The commonest phenotype was UIP n = 13 (43%), followed by NSIP n = 9 (29%), DIP n = 2 (6 %), CPFE n = 2 (6 %), and non-specific-ILD n = 5 (16%). Forced vital capacity (FVC) and carbon monoxide diffusion capacity (DLCO) appeared lower in UIP and DIP, without reaching a significant difference. Treatment focused universally on intensified immunosuppression, with 13/31 patients (42%) receiving cyclophosphamide. No anti-fibrotic treatments were used. Median follow-up was 38.2 [12.4–119.6] months. Lung involvement in pSS is heterogeneous. Better phenotyping and tailored treatment may improve outcomes and requires further evaluation in larger prospective studies.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic keeps the world in suspense. In addition to the fundamental challenges for the health care system, the individual departments must decide how to deal with patients at risk. Neurologists are confronted with the question, how they should advise their patients regarding immunosuppressive treatment. In particular, the large number of different disease-modifying therapies (DMTs) in the treatment of neuroimmunological diseases such as multiple sclerosis poses a challenge. To a limited extent, it might be useful to transfer knowledge from previous SARS- and Middle East respiratory syndrome (MERS) coronavirus outbreaks in 2002/2003 and 2012 to the current situation. Overall, immunosuppressive therapy does neither seem to have a major impact on infection with SARS- and MERS-CoV nor does it seem to lead to a severe disease course in many cases. Considering the immunological responses against infections with novel coronaviruses in humans, interferons, glatiramer acetate, and teriflunomide appear to be safe. As lymphopenia seems to be associated with a more severe disease course, all DMTs causing lymphopenia, such as cladribine, alemtuzumab, and dimethyl fumarate, need to be reviewed more thoroughly. As they are, in general, associated with a higher risk of infection, depleting anti-CD20 antibodies may be problematic drugs. However, it has to be differentiated between the depletion phase and the phase of immune reconstitution. In summary, previous coronavirus outbreaks have not shown an increased risk for immunocompromised patients. Patients with severe neuroimmunological diseases should be kept from hasty discontinuation of immunotherapy.

Abstract Background Osteoarticular tuberculosis is rare in Germany. In particular, trochanteric bursitis is an extremely rare manifestation of osteoarticular tuberculosis. We describe a case of tuberculous coxitis with trochanteric bursitis, successfully treated with a fourfold tuberculostatic therapy. Case presentation We report the case of a 43-year-old human immunodeficiency virus-negative Sudanese man with osteoarticular tuberculosis, who was originally admitted with the suspected diagnosis of ankylosing spondylitis. Low grade fever together with the positive result of an interferon-gamma release assay test as well as findings from magnetic resonance imaging provided clues to the diagnosis. A definitive diagnosis could be set after a computed tomography-guided biopsy. Conclusions Apart from a rare involvement pattern of osteoarticular tuberculosis, including trochanteric bursitis, this case highlights the increasing importance of osteoarticular tuberculosis as a differential diagnosis of rheumatic disorders. With the growing migration flows from tuberculosis-endemic African countries, clinicians in central and northern Europe may be more frequently confronted with atypical involvement patterns of osteoarticular tuberculosis.

Abstract Background Anti-CD74 IgG antibodies are reported to be elevated in patients with axial spondyloarthritis (axSpA). This study assessed the diagnostic value of anti-CD74 antibodies in patients with early axSpA. Methods Anti-CD74 IgG and IgA antibodies were first measured in an exploratory cohort of patients with radiographic axSpA (138 patients with ankylosing spondyloarthritis (AS)) and 57 healthy controls and then were measured in patients with early axSpA (n = 274) and with non-SpA chronic back pain (CBP) (n = 319), participating in the spondyloarthritis caught early (SPACE) prospective cohort study of patients under 45 years old with early back pain (for ≥ 3 months, but ≤ 2 years). Results In the exploratory cohort, anti-CD74 IgG antibodies were present in 79.7% of patients with AS vs. 43.9% of healthy controls (p

F-18 fluorodeoxyglucose (F-18 FDG) PET/CT plays an increasing role in the diagnostic workup of large vessel vasculitis (LVV); however, information on the relationship between immunosuppressive drugs and vessel wall uptake is limited. In 94 patients with a confirmed diagnosis of LVV, the vessel wall-to-liver ratio (VLR) was assessed in eight vessel segments. Patients were grouped according to intake of immunomodulatory drugs (Group 1, prednisone; Group 2, prednisone + methotrexate; and Group 3, prednisone + others) and compared to treatment-naïve individuals. A total of 54/94 (57.4%) were treated with immunomodulatory drugs (Group 1, 29/49 (53.7%); Group 2, 9/54 (16.7%); Group 3, 11/54 (20.4%); and Group 4, 5/54 (9.3%)), whereas the remainder received no therapy (40/94 (42.6%)). The mean VLR of the arterial segments correlated significantly with the hematopoietic organs (r ≥ 0.22, p ≤ 0.05), c-reactive protein (r ≥ 0.25, p ≤ 0.05), and prednisone dosage (r ≥ −0.4, p ≤ 0.05). Relative to treatment-naïve patients, a significantly lower VLR was recorded in 5/8 (62.5%) of the investigated vessel segments in Group 1 (p ≤ 0.02), in 6/8 of the vessel segments in Group 2 (75.0%, p ≤ 0.006), and in 7/8 of the segments in Group 3 (87.5%, p ≤ 0.05). In LVV, the F-18 FDG uptake in vessel wall as a marker of inflammatory activity was attenuated by immunomodulatory drugs, which provides a foundation for future serial monitoring of treatment efficacy.

Objective: Sjögren's syndrome is a heterogeneous inflammatory disorder frequently involving peripheral nerves with a wide spectrum of sensory modalities and distribution patterns. The objective of this cross-sectional study was to determine characteristics of Sjögren's syndrome as a cause for severe neuropathy with limb weakness.Methods: One hundred and eighty four patients with polyneuropathy associated with limb weakness underwent routine diagnostics including investigations for Sjögren's syndrome. Forty-four patients with Sjögren's syndrome (ACR-EULAR classification criteria) and severe neuropathy were identified.Results: Sjögren's syndrome was found at a median age of 63 years and the gender distribution showed a balanced female-male ratio of 1:1. Anti-SSA(Ro) antibodies were detected in 48% while seronegative patients were diagnosed with Sjögren's syndrome based on sialadenitis on minor salivary gland biopsy with a focus score ≥1. The majority of patients (93%) were diagnosed with Sjögren's syndrome after neurological symptoms appeared. Limbs were symmetrically involved in 84% of patients (57% tetraparesis, 27% paraparesis). Sensory function was not affected in 11% of patients indicating that Sjögren's syndrome associated neuropathy can present as a pure motor syndrome. Electrophysiological measurements did not reveal pathognomonic findings (23% demyelinating pattern, 36% axonal pattern, 41% both demyelinating and axonal damage signs). More than half of our patients fulfilled the European Federation of Neurological Societies (EFNS) diagnostic criteria for CIDP indicating that distinction between Neuro-Sjögren and other causes of neuropathy such as CIDP is challenging.Interpretation: Our findings show that severe neuropathy with limb weakness is often associated with Sjögren's syndrome. This is of great importance in identifying and understanding the causes of immune mediated polyneuropathy.

Axial spondyloarthritis (axSpA) is often diagnosed late due to the non-specific nature of its main symptom [chronic back pain (CBP)] and to the paucity of diagnostic markers, particularly in regions with low HLA-B27 prevalence, such as the Middle-East. We tested the performance of IgG4 and IgA anti-CD74 antibodies as an early diagnostic marker for axSpA, compared with the performance of HLA-B27, in Lebanon. Sera of axSpA patients diagnosed by the rheumatologist and also fulfilling the imaging arm of the ASAS criteria (patients) and of blood donors (BD) (controls) were analyzed for HLA-B27, IgG4 and IgA anti-CD74, blinded to clinical characteristics. Receiver Operating Characteristic curves were constructed to identify an optimal cut-off point for anti-CD74 antibodies. Diagnostic properties were calculated (sensitivity, specificity, positive, and positive predictive values (PPV, NPV), Likelihood ratios) for each marker. Forty-nine axSpA patients and 102 BD were included in the final analysis. IgA anti-CD74 correlated poorly with axSpA (Area Under the Curve (AUC) 0.657), whereas IgG4 anti-CD74 had a good discriminative value (AUC 0.837). Respectively, for HLA-B27, IgG4 anti-CD74, and the combination of both, we found a sensitivity of 33-92-33%, specificity of 96-79-98%, PPV 80-68-89%, NPV 75-95-75%, and LR+ 8.2-4.4-16.5. IgG4 anti-CD 74 were positive in 88% of HLA-B27 negative axSpA patients, and correlated with BASDAI. In this first study in a population with low HLA-B27 prevalence, IgG4 anti-CD74 antibodies combined with HLA-B27 showed higher diagnostic value than HLA-B27 alone for early axSpA. IgG4 anti-CD74 should be considered for further evaluation as an early axSpA diagnostic marker in future dedicated research, particularly in patients with CBP.