Primary Sjögren's syndrome independently promotes premature subclinical atherosclerosis.

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<0.001) and plaque extent (OR=1.82; 95% CI 1.14 to 2.95). Subgroup analyses of patients with pSS revealed that OI was associated with increased cIMT (p=0.025) and increased plaque occurrence compared with patients without OI (OR=1.74; 95% CI 1.02 to 3.01). OxLDL ab tended to be lower in patients with plaque (p=0.052). Correlations of higher Oxidized Low Density Lipoprotein (oxLDL) ab with EULAR Sjögren's Syndrome Disease Activity Index (p<0.001) and anti-Sjögren's-syndrome-related antigen A autoantibodies (SSA/Ro antibodies) (p=0.026) were observed. CONCLUSIONS: Subclinical atherosclerosis occurs earlier and more severely in patients with pSS. The difference in cIMT between pSS and controls seems mainly driven by patients with OI, suggesting that this subgroup is particularly at risk. OxLDL ab might protect against atherosclerotic progression in patients with pSS. CVR stratification and preventive medications such as Hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors should be discussed and further longitudinal studies are needed.

[Update on Sjögren's syndrome : Diagnostics, treatment, and challenges]. / Update Sjögren-Syndrom : Diagnostik, Therapie und Fallstricke.

Sjögren's syndrome (SjS) is the most common connective tissue disease with a prevalence of 1:200. Predominantly affecting women, SjS is associated with destruction of the exocrine glands, leading to xerophthalmia and xerostomia. In over 50% of patients, there are also extraglandular manifestations, leading to multiple organ manifestations including polyneuropathies and interstitial lung disease as well as symptoms such as fatigue and arthralgia. Diagnostic procedures include biomarkers, in particular anti-SS-A/Ro antibodies, histology of salivary glands, and salivary gland sonography. There are currently no licensed immunosuppressive drugs for SjS, so current treatment is often based on off-label use of drugs. The European League Against Rheumatism (EULAR) has recently published treatment recommendations based on the prevailing organ manifestations. Several promising controlled trials with novel compounds and concepts are currently in progress.

Investigation of an airport-associated cluster of falciparum malaria in Frankfurt, Germany, 2022.

Airport malaria is uncommon but increasing in Europe and often difficult to diagnose. We describe the clinical, epidemiological and environmental investigations of a cluster of airport malaria cases and measures taken in response. Three Frankfurt International Airport employees without travel histories to malaria-endemic areas were diagnosed with Plasmodium falciparum malaria in Germany in 2022. Two cases were diagnosed within 1 week, and the third one after 10 weeks. Two cases had severe disease, all three recovered fully. The cases worked in separate areas and no specific location for the transmissions could be identified. No additional cases were detected among airport employees. In June and July, direct flights from Equatorial Guinea, Nigeria and Angola and one parcel originating in Ghana arrived at Frankfurt airport. No vector-competent mosquitoes could be trapped to identify the source of the outbreak. Whole genome sequencing of P. falciparum genomes showed a high genetic relatedness between samples of the three cases and suggested the geographical origin closest to Ghana. A diagnosis of airport malaria should prompt appropriate and comprehensive outbreak investigations to identify the source and to prevent severe forms of falciparum malaria.

Molecular characterisation of lupus low disease activity state (LLDAS) and DORIS remission by whole-blood transcriptome-based pathways in a pan-European systemic lupus erythematosus cohort.

OBJECTIVES: To unveil biological milieus underlying low disease activity (LDA) and remission versus active systemic lupus erythematosus (SLE). METHODS: We determined differentially expressed pathways (DEPs) in SLE patients from the PRECISESADS project (NTC02890121) stratified into patients fulfilling and not fulfilling the criteria of (1) Lupus LDA State (LLDAS), (2) Definitions of Remission in SLE remission, and (3) LLDAS exclusive of remission. RESULTS: We analysed data from 321 patients; 40.8% were in LLDAS, and 17.4% in DORIS remission. After exclusion of patients in remission, 28.3% were in LLDAS. Overall, 604 pathways differed significantly in LLDAS versus non-LLDAS patients with an false-discovery rate-corrected p (q)<0.05 and a robust effect size (dr)≥0.36. Accordingly, 288 pathways differed significantly between DORIS remitters and non-remitters (q<0.05 and dr≥0.36). DEPs yielded distinct molecular clusters characterised by differential serological, musculoskeletal, and renal activity. Analysis of partially overlapping samples showed no DEPs between LLDAS and DORIS remission. Drug repurposing potentiality for treating SLE was unveiled, as were important pathways underlying active SLE whose modulation could aid attainment of LLDAS/remission, including toll-like receptor (TLR) cascades, Bruton tyrosine kinase (BTK) activity, the cytotoxic T lymphocyte antigen 4 (CTLA-4)-related inhibitory signalling, and the nucleotide-binding oligomerization domain leucine-rich repeat-containing protein 3 (NLRP3) inflammasome pathway. CONCLUSIONS: We demonstrated for the first time molecular signalling pathways distinguishing LLDAS/remission from active SLE. LLDAS/remission was associated with reversal of biological processes related to SLE pathogenesis and specific clinical manifestations. DEP clustering by remission better grouped patients compared with LLDAS, substantiating remission as the ultimate treatment goal in SLE; however, the lack of substantial pathway differentiation between the two states justifies LLDAS as an acceptable goal from a biological perspective.

Treatment strategies in MDA5-positive clinically amyopathic dermatomyositis: a single-center retrospective analysis.

Melanoma differentiation-associated protein 5 (MDA5) antibody positive amyopathic dermatomyositis (DM) is a rare inflammatory disease. So far, there is no official treatment guideline in MDA5 amyopathic dermatomyositis, but early and aggressive immunosuppressive combination treatment can induce a stable remission. We retrospectively analyzed a cohort of eight patients (male n = 5) that were diagnosed with MDA5-positive amyopathic DM. Patient data comprised demographics, CT-guided diagnosis of pulmonary involvement, pulmonary function testing including forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO) data on baseline and mean long-term follow-up of 51 months (24-92 months) to evaluate treatment strategies. Depending on severity of organ involvement treatments were individualized including cyclophosphamide, immunoglobulins and plasmapheresis. Simultaneously, oral treatment with tacrolimus was commenced in four of the eight patients. Most patients received remission maintenance therapy with a combination of tacrolimus, rituximab and low dose steroids. In all patients, improvement in FVC was recorded and five patients achieved an improvement in DLCO. An improvement in the CT imaging morphological findings was observed in four patients. Awareness for the entirety of all clinical and disease-related findings of amyopathic DM is crucial, and remission maintenance is often achieved with a combination of tacrolimus and rituximab.

Rheuma-VOR study: optimising healthcare of rheumatic diseases by multiprofessional coordinating centres.

OBJECTIVES: Early diagnosis of inflammatory arthritis is critical to prevent joint damage and functional incapacities. However, the discrepancy between recommendations of early diagnosis and reality is remarkable. The Rheuma-VOR study aimed to improve the time to diagnosis of patients with early arthritis by coordinating cooperation between primary care physicians, specialists and patients in Germany. METHODS: This prospective non-randomised multicentre study involved 2340 primary care physicians, 72 rheumatologists, 4 university hospitals and 4 rheumatology centres in 4 German Federal States. The two coprimary endpoints (time to diagnosis and screening performance of primary care physicians) were evaluated for early versus late implementation phase. Additionally, time to diagnosis and secondary endpoints (decrease of disease activity, increase in quality of life and overall well-being, improvement of fatigue, depression, functional ability, and work ability, reduction in drug and medical costs and hospitalisation) were compared with a reference cohort of the German Rheumatism Research Centre (DRFZ) reflecting standard care. RESULTS: A total of 7049 patients were enrolled in the coordination centres and 1537 patients were diagnosed with a rheumatic disease and consented to further participation. A follow-up consultation after 1 year was realised in 592 patients. The time to diagnosis endpoint and the secondary endpoints were met. In addition, the calculation of cost-effectiveness shows that Rheuma-VOR has a dominant cost-benefit ratio compared with standard care. DISCUSSION: Rheuma-VOR has shown an improvement in rheumatological care, patient-reported outcome parameters and cost savings by coordinating the cooperation of primary care physicians, rheumatologists and patients, in a nationwide approach.

Status of HIV and comorbidities in refugees with HIV from Ukraine.

PURPOSE: To describe the clinical characteristics of refugees with HIV from Ukraine that seek continuation of medical care in Germany. METHODS: Fourty-six refugees with HIV that had left Ukraine between 24 February and 30 December 2022 were examined. Information on patients' history was obtained using a standardized questionnaire for clinical care. Interviews were conducted in Russian during their first clinical presentation. RESULTS: Fourty-six persons (41 females and 5 males) were included and their mean age was 39.6 (±8.4) years. The mean time since HIV diagnosis was 8.0 (median, IQR 7.15) years and 70.3% of participants currently received tenfofovir-DF, lamividine and dolutegravir. Most refugees had an undetectable HIV viral load and their current mean CD4 T cell count was 702 (SD ± 289) per µL. Serology revealed previous hepatitis B infection in 50.4% without evidence for replication, with undetectable anti-hepatitis B surface antigen in the remaining refugees. Antibodies against hepatitis C were present in 23 refugees (50%), but only 10 patients had been diagnosed with hepatitis C previously. Five refugees had undergone successful antiviral treatment for hepatitis C. Detectable HCV-RNA was evident in nine patients (19.6%). Sixteen (38.6%) refugees had a positive tuberculosis (TB) interferon gamma release assay, and four were on TB treatment for previously diagnosed infection. One had been diagnosed with multidrug-resistant (MDR) TB, two with pre-extensively drug-resistant (pre-XDR) TB and two with XDR TB and were treated with combinations of second-line and novel agents according to WHO guidelines. CONCLUSIONS: Based on this preliminary analysis of a not fully representative cohort, refugees with HIV from Ukraine were young, mostly healthy females highly adherent to antiretroviral therapy. The rate of transmittable co-infections urges early diagnostic evaluation and treatment.

Rituximab to treat prolidase deficiency due to a novel pathogenic copy number variation in PEPD.

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-1ß (IL-1ß) production by this patient's monocytes, together with the detection of both IL-1ß 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 impact of C-reactive protein levels on the effectiveness of upadacitinib in patients with rheumatoid arthritis: a 12-month prospective, non-interventional German study.

OBJECTIVES: We investigated whether the effectiveness of upadacitinib in rheumatoid arthritis (RA) treatment is affected by baseline CRP levels in a real-world setting. METHODS: UPwArds was a prospective, non-interventional study. Patients had moderate-to-severe RA and an inadequate response or intolerance to ≥1 disease-modifying anti-rheumatic drug (DMARD). The primary endpoint was clinical remission (Clinical Disease Activity Index [CDAI] ≤2.8) at 6 months. Secondary endpoints at 12 months included clinical remission and low disease activity assessed by CDAI and Simple Disease Activity Index criteria, DAS28-CRP <2.6/≤3.2, and patient-reported outcomes. The impact of baseline CRP levels (normal vs. above the upper limit of normal [ULN]) on primary and secondary endpoints was evaluated. The effect of concomitant MTX and prior inadequate response to biologic or targeted synthetic DMARDs (b/tsDMARD-IR) on the effectiveness of upadacitinib was also assessed. Safety was evaluated through 12 months. RESULTS: 518 patients were included in the effectiveness analyses. At 6 months, 24.4% of patients achieved the primary endpoint (CDAI ≤2.8). At 12 months, similar proportions of patients with normal CRP and CRP above the ULN at baseline achieved CDAI ≤2.8 (27.3% and 29.1%) and other key secondary endpoints. The effectiveness of upadacitinib was comparable with and without concomitant MTX and in b/tsDMARD-naive and b/tsDMARD-IR patients. The safety results were consistent with the known safety profile of upadacitinib; no new safety signals were identified. CONCLUSIONS: Upadacitinib therapy was effective for RA in a real-world setting. Baseline CRP levels had no significant impact on the effectiveness of upadacitinib.

[What is proven in the treatment of systemic lupus erythematosus?] / Was ist gesichert in der Therapie des systemischen Lupus erythematodes?

Systemic lupus erythematosus (SLE) is an autoimmune disease with variable clinical presentation and organ involvement. Early diagnosis and rapid achievement of low disease activity or remission reduces organ damage and improves prognosis. Therapeutic principles can be divided into so-called basic measures and immunosuppressive treatment. Novel drugs have been developed in recent years, with new classes of agents being added for the treatment of SLE. These include biologic therapies and approved therapeutic options for the treatment of lupus nephritis. In light of improved treatment options, good disease control can now frequently be achieved; with savings on glucocorticoids, combination therapies are increasingly being used. Of great importance is the consistent use of basic measures, which include the use of hydroxychloroquine, optimization of cardiovascular risk factors, UV protection, bone-protective measures, and the implementation of vaccinations. In the treatment of lupus nephritis, conservative therapeutic measures for nephroprotection play a crucial role in renal prognosis. Finally, non-pharmacological therapy options such as exercise therapy are of great importance for improving quality of life.

[Delegation of medical duties to qualified rheumatology assistants : Effect on depression and anxiety in patients with rheumatoid arthritis]. / Delegation ärztlicher Leistungen an rheumatologische Fachassistenten : Effekte auf Depression und Angst bei Patienten mit rheumatoider Arthritis.

BACKGROUND: At least 1 comorbidity occurs in 80% of patients with rheumatoid arthritis (RA). In addition to cardiovascular comorbidities psychological comorbid conditions are common. The prevalence of depression and anxiety is higher in patients than in the general population. Screening for comorbidities is crucial. A shortage of outpatient specialist care barely allows resources for this. The implementation of team-based care holds the potential to improve the standard of care while simultaneously working against the shortage of care. OBJECTIVE: The aim of the study was to examine the effects of care on the course of depression and anxiety in patients with seropositive RA and active disease. MATERIAL AND METHODS: A multicenter pragmatic randomized controlled trial was conducted over the course of 1 year with 224 patients. After baseline, five more visits followed. In the intervention group (IG), three were initially carried out by qualified rheumatological assistants. Depression, anxiety and patient satisfaction with outpatient care were looked at in detail. RESULTS: In the IG the anxiety symptoms significantly improved over 12 months (p = 0.036). The proportions of patients with anxiety also significantly changed in the IG (p < 0.001), while there was no change in the control group between baseline and month 12. The values of the depression scale did not differ significantly (p = 0.866). In terms of the information dimension of the satisfaction questionnaire, patients in the IG felt significantly better informed after 6 months (p = 0.013) and 12 months (p = 0.003). CONCLUSION: A positive effect of team-based care on the course of depression and anxiety in patients with seropositive RA and active disease could be shown.

Janus kinase-inhibition modulates hepatitis E virus infection.

Hepatitis E virus (HEV) usually causes a self-limiting disease, but especially immunocompromised individuals are at risk to develop a chronic and severe course of infection. Janus kinase (JAK) inhibitors (JAKi) are a novel drug class for the treatment of autoimmune inflammatory rheumatic disease (AIRD). As JAKs play a key role in innate immunity, viral infections and reactivations are frequently reported during JAKi treatment in AIRD patients. The aim of this study was to characterize the influence of JAKis on HEV replication. To this end, we evaluated liver enzymes of an AIRD patient under JAKi therapy with hepatitis E. Further, experiments with HEV (Kernow-C1 p6) were performed by infection of primary human hepatocytes (PHHs) followed by immunofluorescence staining of viral markers and transcriptomic analysis. Infection experiments in PHHs displayed an up to 50-fold increase of progeny virus production during JAKi treatment and transcriptomic analysis revealed induction of antiviral programs during infection. Upregulation of interferon-stimulated genes (ISG) was perturbed in the presence of JAKis, concomitant with elevated HEV RNA levels. The obtained results suggest that therapeutic JAK inhibition increases HEV replication by modulating the HEV-triggered immune response. Therefore, JAKi treatment and the occurrence of elevated liver enzymes requires a monitoring of potential HEV infections.

Corrigendum: Vulnerability to meningococcal disease in immunodeficiency due to a novel pathogenic missense variant in NFKB1.

[This corrects the article DOI: 10.3389/fimmu.2021.767188.].

What is the best referral strategy for axial spondyloarthritis? A prospective multicenter study in patients with suspicious chronic low back pain.

OBJECTIVE: To assess the value of referral strategies for axial spondyloarthritis (axSpA) in patients with suspicious chronic inflammatory low back pain (LBP), to estimate the value of inflammatory back pain (IBP) for referral, and to identify the predictive factors of the final diagnosis of axSpA in Middle Eastern Arab countries. METHODS: The study was multicentric, prospective, and conducted in LBP first-line clinics (rheumatology, internal, family medicine, orthopedic surgery, neurosurgery, and neurology). Consecutive adult patients aged under 45years were included in case of LBP suspicious of inflammatory nature according to the first-line physician. The rheumatologist's final diagnosis was the gold standard. The diagnostic properties of ten referral strategies (Brandt I, II, III, Hermann, RADAR, RADAR 2/3, MASTER, Braun, CAFASPA, and ASAS) and of IBP were calculated. A multivariable logistic regression identified the clinical predictive factors of axSpA. RESULTS: In 515 referred patients, axSpA was confirmed in 48%, refuted in 43%, and diagnosis remained inconclusive in 9%. The optimal referral strategy was the MASTER (PLR 3.3), which comprises IBP, good response to NSAIDs, positive HLA-B27, and SpA family history. Considering strategies without HLA-B27, the RADAR 2/3 had a PLR of 2.9 (IBP, good response to NSAIDs, any extra-musculoskeletal manifestation). The predictive factors for axSpA were MRI sacroiliitis, positive HLA-B27, high CRP, psoriasis, IBP, and longer symptom duration. Of all patients, 35% were self-referred, 16% were referred by primary care physicians, and 15% by neuro/orthopedic surgeons. CONCLUSION: Optimizing physicians' awareness of these clinical features may enhance referral in axSpA.

[Practicable diagnostics of Sjögren's syndrome in interstitial lung disease-A discussion article]. / Praktikable Sjögren-Diagnostik bei interstitieller Lungenerkrankung ­ ein Diskussionsbeitrag.

Sjögren's syndrome (SjS) is a possible autoimmune cause of interstitial lung disease. The diagnostic pathway for SjS, however, is largely undefined in comparison to other systemic autoimmune diseases. Subjective sicca symptoms, anti-SS-A/Ro antibodies and even ANA as screening tests all have relevant limitations in sensitivity and/or specificity. Against this background, in an interdisciplinary discussion we have developed a consensus for the clarification of SjS, which is presented here for broader discussion. In addition to ANA and anti-SS-A/Ro antibodies, antibodies against alpha-fodrin should be included. Objective measures of dryness, such a Schirmer and Saxon tests are important, as is a salivary gland biopsy in the absence of typical autoantibodies.

Treatment of autoimmunity: The impact of disease-modifying therapies in multiple sclerosis and comorbid autoimmune disorders.

More than 10 disease-modifying therapies (DMT) are approved by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) for the treatment of multiple sclerosis (MS) and new therapeutic options are on the horizon. Due to different underlying therapeutic mechanisms, a more individualized selection of DMTs in MS is possible, taking into account the patient's current situation. Therefore, concomitant treatment of various comorbid conditions, including autoimmune mediated disorders such as rheumatoid arthritis, should be considered in MS patients. Because the pathomechanisms of autoimmunity partially overlap, DMT could also treat concomitant inflammatory diseases and simplify the patient's treatment. In contrast, the exacerbation and even new occurrence of several autoimmune diseases have been reported as a result of immunomodulatory treatment of MS. To simplify treatment and avoid disease exacerbation, knowledge of the beneficial and adverse effects of DMT in other autoimmune disorders is critical. Therefore, we conducted a literature search and described the beneficial and adverse effects of approved and currently studied DMT in a large number of comorbid autoimmune diseases, including rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel diseases, cutaneous disorders including psoriasis, Sjögren´s syndrome, systemic lupus erythematosus, systemic vasculitis, autoimmune hepatitis, and ocular autoimmune disorders. Our review aims to facilitate the selection of an appropriate DMT in patients with MS and comorbid autoimmune diseases.

MPO-ANCA-positive granulomatosis with polyangiitis and concurrent IgG4-related disease with periaortitis and tubulointerstitial nephritis: A case report of a new overlap syndrome?

Immunoglobulin G4-related disease (IgG4-RD) is a fibroinflammatory condition that was first recognized as a unique disease entity in the early 2000s. Its diagnosis is based on specific pathologic, serologic, and clinical features, and the exclusion of several differential diagnoses, such antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). However, emerging evidence suggests that these 2 conditions may overlap in some cases. Here, we report a new case of overlapping IgG4-RD and AAV. The patient was diagnosed with IgG4-RD owing to the presence of periaortitis and IgG4 positive tubulointerstitial nephritis. Myeloperoxidase (MPO)-ANCA positivity, chronic paranasal sinusitis, and glomerulonephritis with granuloma led to a concurrent diagnosis of MPO-ANCA-positive granulomatosis with polyangiitis. Our case supports the hypothesis that diagnoses of IgG4-RD and AAV are not mutually exclusive but can overlap. It can be assumed that an overlap with IgG4-RD typically affects the granulomatous form of AAV, suggesting a common pathophysiological pathway for these 2 conditions.

The link between rheumatic disorders and inborn errors of immunity.

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.