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Zusammenfassung. Gicht, die weltweit häufigste Arthritis, wird oft nicht als schwere chronische Erkrankung angesehen, obwohl die kardiovaskuläre Morbidität und die Gesamtmortalität von Gichtpatienten gegenüber der Normalbevölkerung erhöht sind. Die Prävalenz von Gicht ist in verschiedenen Ländern sehr unterschiedlich und beträgt im Mittel 2,6%. Männer sind deutlich überrepräsentiert (3:1 bis 4:1). Umweltfaktoren wie Ernährung und Alkoholkonsum sind wichtig, aber genetische Einflüsse, z.B. bei früh einsetzender Gicht, werden zunehmend beschrieben. Trotz der breiten therapeutischen Möglichkeiten sind die Ergebnisse nach wie vor unbefriedigend, und die Krankheit führt zu oft zu behindernden strukturellen Schäden. Die gezielte Information von Patienten sowie eine gute Ausbildung von Ärzten und Pflegefachpersonen können dazu beitragen die Behandlungsziele besser zu erreichen.

Zusammenfassung. Die nach ihrem immunserologischen Marker (anti-neutrophile zytoplasmatische Antikörper – ANCA) benannten ANCA-assoziierten Vaskulitiden (AAV) werden entsprechend der Chapel-Hill-Nomenklatur (2012) von anderen systemischen Kleingefässvaskulitiden abgegrenzt. Die mikroskopische Polyangiitis (MPA), die Granulomatose mit Polyangiitis (GPA) und die Eosinophile Granulomatose mit Polyangiitis (EGPA) werden nach klinischen, histologischen und bildgebenden Befunden diagnostiziert und klassifiziert. GPA und EGPA unterscheiden sich hauptsächlich durch das Vorhandensein von granulomatösen Entzündungen im Bereich der Atemwege von der MPA. Epidemiologisch betrachtet sind alle drei Entitäten seltene Autoimmunerkrankungen, wobei die Prävalenzen geographische Unterschiede zeigen. Trotz ihrer Seltenheit ist ein Erkennen der typischen Klinik prognostisch sehr wichtig. Entscheidend ist eine rechtzeitige Diagnosestellung, da unbehandelt die Prognose bezüglich der Erhaltung von Organfunktion sowie bezüglich des Überlebens schlecht ist. Neue, nebenwirkungsärmere Therapien sind in den letzten Jahren für diese Indikation geprüft worden. Eine wichtige Rolle spielt das Rituximab, das das Cyclophosphamid weitestgehend ersetzt hat. Ziel der neuen Therapieansätze ist die Reduktion der Exposition der Patienten gegenüber Steroiden. Therapie- und insbesondere Steroidnebenwirkungen sind neben der Erkrankung selbst Hauptursache der AAV-Morbidität.

Purpose Identify chronic shoulder MRI findings in patients with known shoulder injury related to vaccine administration (SIRVA). Materials and methods Two fellowship-trained musculoskeletal radiologists retrospectively reviewed the MRI of nine patients with clinically established SIRVA. MRI was performed at least 4 weeks after vaccination and included intravenous contrast-enhanced sequences. MRI was reviewed for the presence of erosions, tendonitis, capsulitis, synovitis, bone marrow oedema, joint effusion, bursitis, cartilage defects, rotator cuff lesions, and lymphadenopathy. The number and location of focal lesions were recorded. Results Erosions of the greater tuberosity were present in 8/9 (89%), tendonitis of the infraspinatus muscle tendon in 7/9 (78%), capsulitis, synovitis, and bone marrow oedema in 5/9 (56%) cases, respectively. Effusion was found in three, and subdeltoid bursitis, rotator cuff lesions as well as cartilage defects in one patient, respectively. None of our included subjects showed axillary lymphadenopathy. Conclusion In this case series, greater humeral tuberosity erosions, infraspinatus muscle tendonitis, capsulitis, synovitis, and bone marrow oedema were common MRI findings in chronic SIRVA.

OBJECTIVES: To determine the prevalence and predictors of subclinical giant cell arteritis (GCA) in patients with newly diagnosed polymyalgia rheumatica (PMR). METHODS: PubMed, Embase, and Web of Science Core Collection were systematically searched (date of last search July 14, 2021) for any published information on any consecutively recruited cohort reporting the prevalence of GCA in steroid-naïve patients with PMR without cranial or ischemic symptoms. We combined prevalences across populations in a random-effect meta-analysis. Potential predictors of subclinical GCA were identified by mixed-effect logistic regression using individual patient data (IPD) from cohorts screened with PET/(CT). RESULTS: We included 13 cohorts with 566 patients from studies published between 1965 to 2020. Subclinical GCA was diagnosed by temporal artery biopsy in three studies, ultrasound in three studies, and PET/(CT) in seven studies. The pooled prevalence of subclinical GCA across all studies was 23% (95% CI 14%-36%, I2=84%) for any screening method and 29% in the studies using PET/(CT) (95% CI 13%-53%, I2=85%) (n=266 patients). For seven cohorts we obtained IPD for 243 patients screened with PET/(CT). Inflammatory back pain (OR 2.73, 1.32-5.64), absence of lower limb pain (OR 2.35, 1.05-5.26), female sex (OR 2.31, 1.17-4.58), temperature >37° (OR 1.83, 0.90-3.71), weight loss (OR 1.83, 0.96-3.51), thrombocyte count (OR 1.51, 1.05-2.18), and haemoglobin level (OR 0.80, 0.64-1.00) were most strongly associated with subclinical GCA in the univariable analysis but not C-reactive protein (OR 1.00, 1.00-1.01) or erythrocyte sedimentation rate (OR 1.01, 1.00-1.02). A prediction model calculated from these variables had an area under the curve of 0.66 (95% CI 0.55-0.75). CONCLUSION: More than a quarter of patients with PMR may have subclinical GCA. The prediction model from the most extensive IPD set has only modest diagnostic accuracy. Hence, a paradigm shift in the assessment of PMR patients in favour of implementing imaging studies should be discussed. ispartof: SEMINARS IN ARTHRITIS AND RHEUMATISM vol:55 ispartof: location:United States status: published

A wide range of extrapulmonary manifestations in patients with COVID-19 has been reported during the ongoing pandemic, thus making the clinical spectrum of this new disease very heterogeneous. While COVID-19-associated vasculitis and vasculopathy have been described, cutaneous leukocytoclastic vasculitis (cLcV) due to SARS-CoV-2 has rarely been reported, and if it has, with relatively mild courses. We present the case of a 93-year-old man who, after having survived classic COVID-19 infection, developed a fulminant cLcV leading to extensive skin necrosis and tissue damage that resulted in his death. Considering the negative workup for other triggers of vasculitis, we find that cLcV is a secondary manifestation of COVID-19, even though SARS-CoV-2 polymerase chain reaction in the skin biopsy was not present in the tissue. We hypothesize this by providing a pathophysiologic rationale (eg, SARS-CoV-2-induced endotheliitis, complement activation, and interleukin 6 dominant intra- and perivascular inflammation).

Background: Cardiac troponin (cTn) T and cTnI are considered cardiac specific and equivalent in the diagnosis of acute myocardial infarction. Previous studies suggested rare skeletal myopathies as a noncardiac source of cTnT. We aimed to confirm the reliability/cardiac specificity of cTnT in patients with various skeletal muscle disorders (SMDs). Methods: We prospectively enrolled patients presenting with muscular complaints (≥2 weeks) for elective evaluation in 4 hospitals in 2 countries. After a cardiac workup, patients were adjudicated into 3 predefined cardiac disease categories. Concentrations of cTnT/I and resulting cTnT/I mismatches were assessed with high-sensitivity (hs-) cTnT (hs-cTnT–Elecsys) and 3 hs-cTnI assays (hs-cTnI–Architect, hs-cTnI–Access, hs-cTnI–Vista) and compared with those of control subjects without SMD presenting with adjudicated noncardiac chest pain to the emergency department (n=3508; mean age, 55 years; 37% female). In patients with available skeletal muscle biopsies, TNNT/I1-3 mRNA differential gene expression was compared with biopsies obtained in control subjects without SMD. Results: Among 211 patients (mean age, 57 years; 42% female), 108 (51%) were adjudicated to having no cardiac disease, 44 (21%) to having mild disease, and 59 (28%) to having severe cardiac disease. hs-cTnT/I concentrations significantly increased from patients with no to those with mild and severe cardiac disease for all assays (all P P P TNNT2 , encoding cTnT (but none for TNNI3 , encoding cTnI) versus control subjects (n=16, P Wald R =0.59, P t-statistic R =0.26, P t-statistic =0.031). Conclusions: In patients with active chronic SMD, elevations in cTnT concentrations are common and not attributable to cardiac disease in the majority. This was not observed for cTnI and may be explained in part by re-expression of cTnT in skeletal muscle. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03660969.

ObjectivesTo develop an Outcome Measures in Rheumatology (OMERACT) ultrasonography score for monitoring disease activity in giant cell arteritis (GCA) and evaluate its metric properties.MethodsThe OMERACT Instrument Selection Algorithm was followed. Forty-nine members of the OMERACT ultrasonography large vessel vasculitis working group were invited to seven Delphi rounds. An online reliability exercise was conducted using images of bilateral common temporal arteries, parietal and frontal branches as well as axillary arteries from 16 patients with GCA and 7 controls. Sensitivity to change and convergent construct validity were tested using data from a prospective cohort of patients with new GCA in which ultrasound-based intima–media thickness (IMT) measurements were conducted at weeks 1, 3, 6, 12 and 24.ResultsAgreement was obtained (92.7%) for the OMERACT GCA Ultrasonography Score (OGUS), calculated as follows: sum of IMT measured in every segment divided by the rounded cut-off values of IMTs in each segment. The resulting value is then divided by the number of segments available. Thirty-five members conducted the reliability exercise, the interrater intraclass correlation coefficient (ICC) for the OGUS was 0.72–0.84 and the median intrareader ICC was 0.91. The prospective cohort consisted of 52 patients. Sensitivity to change between baseline and each follow-up visit up to week 24 yielded standardised mean differences from −1.19 to −2.16, corresponding to large and very large magnitudes of change, respectively. OGUS correlated moderately with erythrocyte sedimentation rate, C reactive protein and Birmingham Vasculitis Activity Score (corrcoeff0.37–0.48).ConclusionWe developed a provisional OGUS for potential use in clinical trials.

ObjectivesTo characterise factors associated with permanent vision loss (PVL) and potential reasons for the therapeutic delay contributing to PVL in giant cell arteritis (GCA).MethodsRetrospective analysis of GCA patients diagnosed at the University Hospital Basel between December 2006 and May 2021.ResultsOf 282 patients with GCA (64% females), 49 (17.4%) experienced PVL. In 43/49 (87.8%) PVL occurred before treatment. Of these, 24 (55.8%) patients had first non-ocular symptoms and eventually sought consultation when PVL occurred in a median of 21 (IQR 14.75–31.0) days after the first symptoms. Only five of the 24 patients had consulted a physician before PVL, but GCA diagnosis was missed. Treatment was initiated rapidly after diagnosis (median 1 day (IQR 0.0–7.0)). PVL on therapy occurred in six patients in a median of 40 (IQR 20.5–67.3) days after treatment started. In two of those, glucocorticoids were tapered too quickly.In multivariable analysis, patients with PVL were older (OR 1.17, 95% CI 1.07 to 1.29, p=0.001) and reported more frequently jaw claudication (OR 3.52, 95% CI 1.02 to 13.16, p=0.051). PVL was present in 18 (42.9%) of the 42 patients with vasculitic ultrasound findings in all six temporal artery segments. The incidence of PVL over 15 years did not decline (Spearman rank=0.3, p=0.68).ConclusionThe prevalence of GCA-associated PVL remains high. Associated factors were advanced age, jaw claudication and ultrasound findings consistent with vasculitis in all six temporal artery segments. Despite preceding non-ocular GCA symptoms weeks before the onset of PVL, most patients were not seen by a rheumatologist before PVL occurred.

Current diagnostic methods in differentiating septic from non-septic arthritis are time-consuming (culture) or have limited sensitivity (Gram stain). Microcalorimetry is a novel method that can rapidly detect microorganisms by their heat production. We investigated the accuracy and time to detection of septic arthritis by using microcalorimetry. Patients older than 18 years of age with acute arthritis of native joints were prospectively included. Synovial fluid was aspirated and investigated by Gram stain, culture and microcalorimetry. The diagnosis of septic arthritis and non-septic arthritis were made by experienced rheumatologists or orthopaedic surgeons. Septic arthritis was diagnosed by considering the finding of acute arthritis together with findings such as positive Gram stain or positive culture of synovial fluid or positive blood culture. The sensitivity and specificity for diagnosing septic arthritis and the time to positivity of microcalorimetry were determined. Of 90 patients (mean age 64 years), nine had septic arthritis, of whom four (44 %) had positive Gram stain, six (67 %) positive synovial fluid culture and four (44 %) had positive blood culture. The sensitivity of microcalorimetry was 89 %, the specificity was 99 % and the mean detection time was 5.0 h (range, 2.2-8.0 h). Microcalorimetry is an accurate and rapid method for the diagnosis of septic arthritis. It has potential to be used in clinical practice in diagnosing septic arthritis.

Summary Background Primary Sjogren's syndrome is an autoimmune disease that presents as dryness of the mouth and eyes due to impairment of the exocrine glands. To our knowledge, no systemic therapies for primary Sjogren's syndrome have shown efficacy. CD40–CD154-mediated T cell–B cell interactions in primary Sjogren's syndrome contribute to aberrant lymphocyte activation in inflamed tissue, leading to sialadenitis and other tissue injury. Therefore, we investigated the safety and preliminary efficacy of iscalimab (CFZ533), a novel anti-CD40 monoclonal antibody, in patients with primary Sjogren's syndrome. Methods This multicentre, randomised, double-blind, placebo-controlled, proof-of-concept study took place at ten investigational sites across Europe (UK, n=4; Germany, Switzerland, and Hungary, n=1 each) and the USA (n=3). Eligible patients were aged 18–75 years and fulfilled the 2002 American European consensus group diagnostic classification criteria for primary Sjogren's syndrome. In the double-blind phase of the trial, patients were randomly assigned (2:1) via computer-generated unique randomisation numbers to receive subcutaneous iscalimab (3 mg/kg) or placebo at weeks 0, 2, 4, and 8 (cohort 1) or intravenous iscalimab (10 mg/kg) or placebo at weeks 0, 2, 4, and 8 (cohort 2). Randomisation was stratified according to baseline intake of oral corticosteroids. At week 12, patients in both cohorts received open-label iscalimab (same dose and route) for 12 weeks. The primary objectives of the study were to assess the safety, tolerability, and efficacy of multiple doses of iscalimab in the two sequential dose cohorts. Safety and tolerability were assessed by adverse events and efficacy of iscalimab versus placebo was assessed by clinical disease activity, as measured by the change in European League Against Rheumatism Sjogren's syndrome disease activity index (ESSDAI) score after 12 weeks of treatment. Analyses were done on a per-protocol basis. The trial was registered with ClinicalTrials.gov , NCT02291029 . Findings Between Oct 22, 2014, and June 28, 2016, we assessed 82 patients for eligibility (25 for cohort 1 and 57 for cohort 2). 38 patients were excluded because of ineligibility. In cohort 1, 12 patients were randomly assigned to receive either 3 mg/kg doses of iscalimab (n=8) or placebo (n=4), and in cohort 2, 32 patients were randomly assigned to receive either intravenous 10 mg/kg doses of iscalimab (n=21) or placebo (n=11). Adverse events were similar between iscalimab treatment groups and placebo groups, with adverse events occurring in all patients in cohort 1, and in 52% and 64% of the iscalimab and placebo groups, respectively, in cohort 2. Two serious adverse events were reported (one case of bacterial conjunctivitis in cohort 1 and one case of atrial fibrillation in cohort 2), which were unrelated to treatment with iscalimab. Intravenous treatment with iscalimab resulted in a mean reduction of 5·21 points (95% CI 0·96–9·46; one-sided p=0·0090) in ESSDAI score compared with placebo. There was no signficiant difference in ESSDAI score between subcutaneous iscalimab and placebo. Interpretation To our knowledge, this is the first randomised, placebo-controlled proof-of-concept study of a new investigational drug for primary Sjogren's syndrome that indicates preliminary efficacy. Our data suggest a role of CD40–CD154 interactions in primary Sjogren's syndrome pathology and the therapeutic potential for CD40 blockade in this disease should be investigated further. Funding Novartis Pharma.

Background: COVID-19 has led to a change in care for patients with chronic conditions, involving a transfer of drug administration from an outpatient to a community setting. Aim: To investigate patient preferences for treatment settings in the light of the current pandemic. Methods: Patients, who prior to the pandemic had attended two different outpatient clinics in a university hospital for their infusions or injections, were interviewed by telephone. The semi-structured interviews were analyzed using qualitative and quantitative methods. Results: Out of 49 patients with either anti-inflammatory or immunoglobulin treatments (response rate: 83 %), 24 (49.0 %) switched from subcutaneous (sc) injections in the hospital to the community setting, 18 (36.7 %) from intravenous infusions (iv) in the hospital to sc administration at home and 7 (14.3 %) moved to iv at home. During the pandemic 38 (80.9 %) wanted to continue their treatment at home, but after the pandemic 22 (46.8 %) would opt to go back to the hospital. Satisfaction was high with both settings, slightly favoring drug administration in hospital. Qualitative data shows that patients while emphasizing the importance of the relationship with the healthcare team, had increased concerns about safety as a result of COVID-19. Conclusions: The experience during the COVID-19 pandemic has increased self-management-skills in some patients, but long-term follow-up is needed. It has repercussions for future shared decision making for patients and their healthcare teams.

Myelodysplastic syndromes (MDS) and associated diseases, like chronic myelomonocytic leukemias (CMML), are heterogeneous, clonal disorders affecting the hematopoietic stem cells. They are characterized by dysplasia and a propensity to evolve toward acute myeloid leukemia. Systemic inflammatory and autoimmune manifestations (SIAMs) occur with a prevalence of 10% to 20% in myeloid malignancies, but the underlying pathogenetic mechanisms remain obscure. In this study, we aimed to characterize patient- and disease-based differences in MDS and CMML patients with and without SIAMs and explore the impact of SIAMs on progression and survival. We performed a retrospective, single-centre, and case-control study in a cohort of 93 patients diagnosed with MDS and CMML between 01/2008 and 12/2015. Thirty patients (32%) were identified with SIAMs: musculoskeletal and connective tissue (26.8%), vascular (19.5%), systemic autoinflammation (17%), skin (12.2%), gastrointestinal (9.8%), and others (14.6%). SIAMs were treated with glucocorticoids (60%), methotrexate (16.7%), biologicals (13.3%), and cyclosporine (3.3%). No significant differences between the SIAM and non-SIAM patients were observed in age, gender, or previous exposure to cancer treatment. Cardiovascular comorbidities were significantly more frequent in patients with SIAMs (63.1% vs 90%; OR 5.5; P < .01), but no differences were observed for other comorbidities or IPSS and IPSS-R risk scores. CMML and refractory anemia with excess blasts 1/2 subtypes were by tendency more frequent in patients with and refractory cytopenia with multilineage dysplasia (RCMD) in those without SIAMs. Finally, time to progression, leukemia free survival and overall survival were similar for both groups. Despite patient heterogeneity and small cohort size, we were able to identify a significant association of SIAMs with cardiovascular comorbidities but without influence on progression or survival.

Uber die letzten Jahre hat die Wichtigkeit der Bildgebung bei der Frage nach Vorliegen einer Grosgefasvaskulitis massiv zugenommen. Der Ultraschall hat trotz gewisser Limitationen (z. B. fehlende Beurteilbarkeit der thorakalen Aorta) dank der raschen Verfugbarkeit, fehlender Strahlenbelastung, aber auch wegen seiner im Vergleich geringen Kosten einen nicht mehr wegzudenkenden Platz im Abklarungsalgorithmus. Es sollen die Validitat, aber auch potenzielle Fallstricke bei der Ultraschalluntersuchung anhand der Literatur aufgezeigt werden. Die „konventionelle“ Form der Gefasultraschallabklarung mit B‑Bild, Farb- und gepulstem Doppler hat einen sehr hohen Stellenwert in der Abklarung der Grosgefasvaskulitis. Die Summe ihrer Vorteile hat dazu gefuhrt, dass sie in immer mehr aufkommenden „fast track clinics“ in der Erstabklarung, fokal angewendet, zum Standard gehort. Der kontrastmittelunterstutzte Ultraschall birgt das Potenzial einer hilfreichen Erganzung in der initialen Beurteilung, aber auch im Verlauf bei Frage nach Rezidiv zu werden.

Background Viral infections may trigger autoimmunity in genetically predisposed individuals. Immunizations mimic viral infections immunologically, but only in rare instances vaccinations coincide with the onset of autoimmunity. Inadvertent vaccine injection into periarticular shoulder tissue can cause inflammatory tissue damage (‘shoulder injury related to vaccine administration, SIRVA). Thus, this accident provides a model to study if vaccine-induced pathogen-specific immunity accompanied by a robust inflammatory insult may trigger autoimmunity in specific genetic backgrounds. Methods We studied 16 otherwise healthy adults with suspected SIRVA occurring following a single work-related influenza immunization campaign in 2017. We performed ultrasound, immunophenotypic analyses, HLA typing, and influenza- and self-reactivity functional immunoassays. Vaccine-related bone toxicity and T cell/osteoclast interactions were assessed in vitro. Findings Twelve of the 16 subjects had evidence of inflammatory tissue damage on imaging, including bone erosions in six. Tissue damage was associated with a robust peripheral blood T and B cell activation signature and extracellular matrix-reactive autoantibodies. All subjects with erosions were HLA-DRB1*04 positive and showed extracellular matrix-reactive HLA-DRB1*04 restricted T cell responses targeting heparan sulfate proteoglycan (HSPG). Antigen-specific T cells potently activated osteoclasts via RANK/RANK-L, and the osteoclast activation marker Trap5b was high in sera of patients with an erosive shoulder injury. In vitro, the vaccine component alpha-tocopheryl succinate recapitulated bone toxicity and stimulated osteoclasts. Auto-reactivity was transient, with no evidence of progression to rheumatoid arthritis or overt autoimmune disease. Conclusion Vaccine misapplication, potentially a genetic predisposition, and vaccine components contribute to SIRVA. The association with autoimmunity risk allele HLA-DRB1*04 needs to be further investigated. Despite transient autoimmunity, SIRVA was not associated with progression to autoimmune disease during two years of follow-up.

Aims The usefulness of [18F] fluorodeoxyglucose-positron emission tomography/computed tomography ([18F]FDG-PET/CT) for diagnosing giant cell arteritis (GCA) has been previously reported. Yet, the interpretation of PET scans is not clear-cut. The present study aimed at determining the best method to analyse PET/CT in a large, real-life cohort of patients presenting with suspicion of GCA. Methods and results One hundred and three patients with clinical suspicion of GCA undergoing PET/CT between 2006 and 2012 were included. Clinical data were retrieved from patients' charts. PET/CT was categorized by visual scoring of the uptake and by the artery/liver standardized uptake values (SUV) ratios. Diagnosis of GCA was confirmed in 68 patients and excluded in 35 patients, which served as the controls. GCA patients were older (median age 75 vs. 68 years), and presented more often with ischaemic symptoms. The best discrimination between GCA patients and controls was achieved for PET/CT findings within the supra-aortic arteries (sensitivity 0.71, specificity 0.91 for a SUV/LE cut-off value of 1.0). Specificity of PET/CT for the aorta and the iliofemoral arteries was lower (

Objective: To characterize patients with both monosodium urate (MSU) and calcium pyrophosphate (CPP) crystals in their synovial fluid (SF).Method: Forty-nine gout patients with acute arthritis were included. Those patients with MSU crystals only in their SF were compared to those patients with both MSU and CPP crystals in their SF.Results: A total of 36 out of 49 patients (73.5%) had only MSU crystals, whereas 13 out of 49 (26.5%) had both MSU and CPP crystals in their SF. Co-deposition of CPP crystals was associated with long-standing gout disease (p = 0.022), kidney dysfunction (p = 0.024), and erosive arthritis (p = 0.049), but not with age.Conclusion: Long-standing gout may be a risk factor for CPP deposition disease, and the frequency of CPP co-deposition may be higher than expected.

Tocilizumab (TCZ) has been approved for giant cell arteritis (GCA). Interleukin-6 (IL-6) receptor blockade suppresses clinical disease and is steroid sparing.1 2 Since IL-6 induces the acute-phase response, the clinically used inflammation markers (C reactive protein (CRP), erythrocyte sedimentation rate (ESR)) are suppressed during TCZ treatment. Whether serum IL-6 is useful in monitoring disease activity and detecting infections in TCZ-treated GCA is unknown. We longitudinally measured IL-6 in 23 patients with intravenous TCZ–treated GCA, two patients with polymyalgia rheumatica and one patient with Takayasu arteritis of our GCA cohort (EKBB-239/09), and in 13/26 patients additionally before TCZ treatment. Patient characteristics are shown in table 1. At each visit, clinical and laboratory parameters (white blood cell (WBC), CRP, ESR) were assessed. Relapse was defined as the need for treatment intensification following new or increasing symptoms, or rising CRP/ESR not otherwise explained.2 View this table: Table 1 Patient characteristics of ‘relapser’ and ‘non-relapser’ During TCZ therapy, CRP, ESR and WBC rapidly declined and were sustainably suppressed. IL-6 levels rose and remained elevated throughout TCZ treatment (figure 1). Daily prednisone doses were successfully tapered after TCZ was initiated (figure 1C). During 23.8 patient-years of TCZ therapy, eight infections were documented with available IL-6 levels (online supplementary table S1). IL-6, but not CRP, ESR …

Objective: To explore potential subclinical involvement of the axial skeleton by magnetic resonance imaging (MRI) of the sacroiliac (SI) joints and the entire spine in patients with skin psoriasis without clinical evidence of peripheral or axial inflammation. Methods: Twenty patients with skin psoriasis but no clinical evidence of peripheral or axial inflammation and 22 healthy controls underwent standardized dermatologic and rheumatologic clinical examination and unenhanced 1.5T MRI of the SI joint and the entire spine. Two blinded readers globally assessed the presence or absence of SI joint inflammation simultaneously on T1-weighted and short tau inversion recovery MRI sequences with a confidence estimate. Bone marrow edema, fat metaplasia, erosion, and ankylosis of the SI joint, and vertebral corner inflammatory lesions and fat lesions were recorded using standardized modules. The prevalence of each lesion type was calculated in both groups, averaged across 2 readers. The number of subjects with lesions in the SI joint and spine (≥1, 2, 3, 4, or 5 lesions) as concordantly assessed by both readers was recorded. Results: The median duration of skin psoriasis was 23.0 years, the median age of patients was 48.5 years, and 25.0% of patients and 9.1% of healthy controls were concordantly classified by both readers as having SI joint inflammation (P = 0.23). The prevalence of bone marrow edema and structural lesions was comparable across patients and controls, both on SI joint and spine MRI. Conclusion: In this controlled study, patients with skin psoriasis but no clinical arthritis or spondylitis showed limited evidence of concomitant subclinical axial involvement by SI joint and spine MRI. These findings do not support routine screening for subclinical axial inflammation in patients with longstanding skin psoriasis.

Latent Epstein-Barr virus (EBV) infection can clinically reactivate in immunosuppressed individuals causing lymphoproliferative disease and rarely hepatitis. In this study, we provide in vivo and in vitro evidence that Treponema pallidum infection can cause EBV reactivation with hepatitis in an immunocompetent patient. We report the diagnostic challenges and immunological findings of coinciding syphilis and EBV-associated hepatitis. Using an in vitro EBV-reactivation assay, we demonstrate that T pallidum reactivates latent EBV in a Toll-like receptor (TLR)2/B-cell receptor signaling-dependent manner. Epstein-Barr virus-associated reactivation or lymphoproliferation should be considered in infections with pathogens that activate TLR2.

Background: Primary Sjogren’s syndrome (pSS) is a systemic progressive autoimmune disease characterised by formation of lymphoid structures and germinal centres within glandular tissue. Iscalimab (CFZ533) is a novel monoclonal antibody that potently and selectively blocks CD40, a co-stimulatory pathway receptor important for germinal centre reactions and B cell activation. Iscalimab showed clinical efficacy in a Proof of Concept randomised controlled trial at a dose of 10 mg/kg intravenously (IV), whereas subcutaneous (SC) dosing at 3 mg/kg was associated with unexpectedly low plasma concentrations and reduced efficacy, likely due to efficient pre-systemic target-mediated clearance. Objectives: To test IV versus SC loading doses of iscalimab followed by SC maintenance dosing, as a means of achieving target drug exposure and clinical efficacy. Methods: Patients with clinically active pSS [EULAR Sjogren’s Syndrome Disease Activity Index (ESSDAI) ≥6] were randomised to receive either 600 mg SC iscalimab weekly on 4 occasions, followed by 300 mg SC weekly until week 12, or a single IV dose of 10 mg/kg iscalimab on study Day 1, followed by 300 mg SC weekly until week 12. Subjects and investigator staff remained blinded to study treatment allocation until first dosing. Results: Twenty-five patients were randomised; 13 in the SC loading and 12 in the IV loading arms. Baseline characteristics were similar to the previous phase IIa cohorts with mean ESSDAI scores of 12.7 (SD 6.1) and 10.4 (5.9) in the SC and IV loading arms respectively. In Arm 1 (SC) and Arm 2 (IV), the mean trough plasma concentrations were 169 μg/mL (SD 64.1, CV 38%) and 135 μg/mL (SD 70.9, CV 53%) on Day 85, respectively. Both values were well above levels previously reported to be sufficient for suppression of germinal centre development and T dependent antigen responses in cynomolgus monkeys. Consistent with this finding, clinically important improvements were seen in both arms with a mean decrease in ESSDAI scores of -5.5 (+/- SD: 5.5) and -7.6 (+/- 7.1) points from baseline to Day 85 in the SC and IV dosing arms. Improvements were also seen in EULAR Sjogren’s Syndrome Patient Reported Index (ESSPRI) scores: -1.67 (+/- 1.8) and -1.17 (+/- 2.3), respectively. Other secondary efficacy outcomes showed similar patterns of improvement. Treatment with iscalimab was associated with a reduction in the germinal centre-related serum biomarker CXCL13 in both groups. Overall, iscalimab was safe and well-tolerated with no new safety signal emerging. One subject experienced three SAEs (hemarthrosis, worsening of right knee pain and swelling requiring arthroscopy) in the safety follow-up period, all unrelated to study drug. Conclusion: These results further support the safety and efficacy of iscalimab in pSS and the suitability of SC dosing for future development. Disclosure of Interests: Benjamin Fisher Consultant for: Novartis, Roche, MedImmune, Bristol-Myers Squibb, Antonia Szanto: None declared, Wan Fai Ng: None declared, Michele Bombardieri Grant/research support from: Celgene, Consultant for: Medimmune, Maximilian Posch: None declared, Athena Papas Grant/research support from: Novartis, Consultant for: Novartis, Arwa Farag: None declared, Thomas Daikeler: None declared, Bettina Bannert: None declared, Alan Kivitz Shareholder of: Novartis, Consultant for: Abbvie, Janssen, Pfizer, UCB, Genzyme, Sanofi, Regeneron, Boehringer Ingelheim, Sun Pharma Advanced Research, Flexion., Paid instructor for: Celgene, Horizon, Merck, Novartis, Pfizer, Genzyme, Sanofi, Regeneron, Speakers bureau: Celgene, Horizon, Merck and Genetech, Flexion, Steven Carsons Grant/research support from: Novartis, David Isenberg: None declared, Francesca Barone Grant/research support from: GlaxoSmithKline, Roche, UCB Pharma, Actelion, ONO Pharmaceutical, Consultant for: GlaxoSmithKline, Roche, Actelion, ONO Pharmaceutical, Simon J. Bowman Grant/research support from: Previously UCB Pharma (to University of Birmingham) and Roche, Consultant for: 2016-7: Novartis, Mitsubishi Tanabe Pharma 2017-8: AstraZeneca, MedImmune, GFK, Xtlbio, ONO Pharmaceutical 2018-9: Novartis, AstraZeneca, UCB Pharma, Pascal Espie Employee of: Novartis, Grazyna Wieczorek Employee of: Novartis, Pierre Moulin Employee of: Novartis, David Floch Employee of: Novartis, Cyrielle Dupuy Employee of: Novartis, Amanda Nguyen Employee of: Novartis, Andrew Wright Shareholder of: Novartis, Employee of: Novartis, Michael Rotte Employee of: Novartis, James Rush Employee of: Novartis, Peter Gergely Employee of: Novartis

Objectives [18F]Fluorodeoxyglucose (FDG)-PET/CT and US are both well established for diagnosing GCA. The present study investigates their accuracy and whether they provide overlapping or complementary information in a cohort of patients presenting with suspicion of GCA. Methods We selected consecutive patients from our cohort of suspected GCA cases that underwent both extended vascular US and PET/CT for diagnostic work-up between December 2006 and August 2012. Results A total of 102 patients were included. Diagnosis of GCA was confirmed in 68 patients and excluded in 34 patients (controls). Vasculitic changes in US were most often found in the temporal artery with 32 positive findings on each side, followed by the popliteal artery (10 right, 9 left) and the subclavian/axillary artery (7 right, 8 left). By contrast, PET/CT showed vasculitis most frequently in the vertebral (23 right, 33 left) and common carotid arteries (32 right, 24 left), followed by the subclavian arteries (16 right, 18 left), and the thoracic (17) and abdominal aorta (23). In 37/68 GCA patients PET/CT and US both revealed vasculitic findings, 11/68 had positive findings in US only and 14/68 in PET/CT only. Specificity of US was higher (one false-positive vs five false-positive in PET/CT). On a single segment level, only 20 of 136 positive segments were positive in both imaging modalities. Conclusion PET/CT measuring vessel wall metabolism and US vessel wall morphology showed a comparable diagnostic accuracy for GCA. However PET/CT and US were often discrepant within single vascular regions. Thus PET/CT and US should be considered as complementary methods, with a second imaging modality increasing the diagnostic yield by 16–20%.

Background:GCA is characterized by cranial symptoms but imaging techniques show that patients with non-specific symptoms such as systemic inflammation or PMR may have undiagnosed large vessel (LV) GCA1. Although silent GCA in patients with clinically isolated PMR may have consequences for patients’ outcome, little is known about its prevalence and characteristics of affected patients.Objectives:To review data on the prevalence of silent GCA in newly diagnosed PMR patients without cranial GCA symptoms and to analyze which characteristics are associated with vascular involvement among PMR patients.Methods:We systematically screened PubMed, Embase and Web of Science databases and included studies screening for GCA in steroid naïve PMR patients without cranial symptoms consistent with GCA. Authors of the publications that used PET for vasculitis screening were invited to share their individual patient data (IPD) for a meta-analysis. We sought to define patient characteristics that were associated with vasculitis using univariable mixed effects logistic regression models with vascular involvement as the outcome, missing values were imputed using multilevel joint modeling multiple imputation. To fit a multivariable model with the candidate predictors we excluded variables that were hypothesized to have less medical relevance for the outcome and highly correlated inflammation markers (ESR, Lc).Results:Out of the 3047 studies screened independently by 2 authors (DG and TD), 13 fulfilled the inclusion criteria. These studies (published 1963-2019) reported on 543 PMR patients examined by temporal artery biopsy (n=175), ultrasound (n=110), PET or PET-CT (n=258). 115 PMR patients were diagnosed with GCA (21.2%), with prevalence ranging from 0-92%.We collected IPD for 243 patients from 4 cohorts using PET and 3 using PET/CT for GCA diagnosis. The overall median age of patients was 72.3 years (IQR 66.4-78.0) and vasculitis was found in 65 patients (26.7%) (table 1).Table 1.OverallPMRPMR+GCAn (%)243178 (73.3)65 (26.7)Female sex (%)146 (60.1)98 (55.1)48 (73.8)Shoulder girdle pain (%)236 (97.1)174 (97.8)62 (95.4)Pelvic girdle pain (%)174 (71.6)127 (71.3)47 (72.3)Inflammatory back pain (%)No107 (44.0)83 (46.6)24 (36.9)Yes106 (43.6)70 (39.3)36 (55.4)Lower limb pain (%)No87 (35.8)61 (34.3)26 (40.0)Yes81 (33.3)68 (38.2)13 (20.0)Weight loss (%)112 (46.1)78 (43.8)34 (52.3)CRP (mg/l) (median [IQR])46.0 [19.0, 77.7]44.0 [16.9, 74.2]52.0 [27.9, 85.0]ESR (mm/h) (mean (SD))65.2 (30.3)62.7 (30.2)72.3 (29.7)Hemoglobin (g/dl) (mean (SD))12.1 (1.5)12.2 (1.5)11.7 (1.6)Thrombocytes (1e+09/ml) (mean (SD))341.9 (106.3)323.9 (103.2)375.8 (104.6)In the univariable analyses the following factors were most strongly associated with vasculitic PET findings: female sex (OR 2.31, CI 1.17-4.58), inflammatory back pain (OR 2.73, CI 1.32-5.64), temperature >37° (OR 1.83, CI 0.90-3.7), weight loss (OR 1.83, CI 0.96-3.51), thrombocytosis (i.e., patients with a thrombocyte count 1 SD above mean have an OR of 1.51, CI 1.05-2.18), anemia (i.e., 1 g/dl decrease in Hb below mean corresponds to an OR of 1.25, CI 1.00-1.56). Patients with lower limb pain were less likely to have vasculitis (OR 0.43, CI 0.19–0.95). The estimated ORs were very similar in the multivariable model although the 95%CIs became wider.Conclusion:Although the prevalence across published studies showed substantial variation, 6 out of 13 studies reported a prevalence of silent GCA in 18-40% of all PMR patients. The exploratory analysis of the collected IPD identified female sex, inflammatory back pain, fever, weight loss, absence of lower leg pain, thrombocytosis and anemia as factors associated with LV-GCA. These findings should be validated in future prospective cohort studies. The presence or absence of these factors may further aid in diagnosing LV-GCA in PMR patients.References:[1]Buttgereit F, Dejaco C, Matteson EL, Dasgupta B. Polymyalgia Rheumatica and Giant Cell Arteritis: A Systematic Review. JAMA. 2016 Jun 14;315(22):2442–58.Acknowledgements:The study is funded by the “Schweizerische Stiftung für die Erforschung der Muskelkrankheiten (SSEM)”.Disclosure of Interests:Daniele Silvio Gozzoli: None declared, Andrea Hemmig: None declared, Lars Hemkens: None declared, Laura Werlen: None declared, Hannah Ewald: None declared, Christoph Berger: None declared, Diego Kyburz Grant/research support from: DK reports personal fees from Abbvie, Gilead, Lilly, Novartis and Pfizer, outside of the submitted work, Stephan Imfeld: None declared, Markus Aschwanden: None declared, Mihaela Stegert: None declared, Dario Camellino: None declared, Marco Amedeo Cimmino: None declared, Corrado Campochiaro Grant/research support from: personal fees from Roche, Alessandro Tomelleri: None declared, Liesbet Henckaerts: None declared, Daniel Blockmans Speakers bureau: Paid speaker for Roche, Consultant of: Paid consultant for Roche, Patricia Moya: None declared, Hector Corominas: None declared, Russell Buchanan: None declared, Claire Owen Speakers bureau: CO has received speaking honoraria from Roche, Janssen, Novartis and Pfizer, and meeting sponsorship from Roche, UCB and Janssen, Yannick van Sleen: None declared, Elisabeth Brouwer Speakers bureau: E. Brouwer as an employee of the UMCG received speaker fees and consulting fees from Roche in 2017, 2018 which were paid to the UMCG, Consultant of: E. Brouwer as an employee of the UMCG received speaker fees and consulting fees from Roche in 2017, 2018 which were paid to the UMCG, Hiroyuki Ymashita: None declared, Thomas Daikeler: None declared

Major advances have been made in understanding the pathogenesis of Erdheim Chester disease (ECD) leading to novel treatment strategies. Targeted therapies such as BRAF inhibition have shown a significant impact on disease management emphasizing the importance of the activated mitogen associated protein kinase pathway in this disease. However incomplete responsiveness potentially limiting adverse effects and the occurrence of treatment resistance to BRAF inhibition observed in other BRAF mutant malignancies imply the importance of therapeutic strategies beyond BRAF inhibition. We report a patient with ECD who carried the BRAF(V600E) mutation and developed treatment resistance under BRAF inhibition despite initial treatment response. Genetic analyses of a newly developing ECD lesion revealed a somatic KRAS(Q61H) mutation without the presence of BRAF(V600E) Accordingly the addition of MEK inhibiting trametinib to BRAF inhibiting dabrafenib was able to overcome acquired partial treatment resistance. This is the first report of treatment resistance as a result of a secondary MAPK pathway activating mutation during BRAF inhibition in ECD. This case contributes to the ongoing efforts of simultaneous BRAF/MEK inhibition as a promising strategy in ECD.