Serum protein profiling reveals distinct patient clusters in giant cell arteritis.

OBJECTIVES: We investigated the potential of serum proteins to distinguish clinical and molecular subtypes in patients with giant cell arteritis (GCA). METHODS: Proximity extension assays were used to analyse 1463 proteins in serum samples from patients with new-onset GCA (n = 16) and after achieving remission (n = 13). Unsupervised and supervised cluster analyses were performed. RESULTS: Unsupervised cluster analysis identified three distinct clusters based on the protein signature. Compared with cluster 2, patients of cluster 1 had less polymyalgia rheumatica symptoms, increased levels of macrophage migration inhibitory factor (MIF) and pronounced NF-kB, STAT5 and interleukin-1 signalling. The changes in serum proteins upon remission differed between cluster 1 and 2.Patients with cranial GCA were characterised by altered endothelial and Th17 signalling whereas patients not responding to treatment within the GUSTO-trial showed increased Th1 and diminished B cell signalling. Patients with anterior ischemic optic neuropathy displayed higher levels of CHI3L1 (YKL40), MMP12 and reduced levels of TIMP3. CONCLUSIONS: Protein profiling identifies patient clusters in GCA with distinct proteomic features and therefore likely different pathophysiology. These unique proteomic footprints might lead to more targeted treatments in future.

Musculoskeletal magnetic resonance imaging findings support a common spectrum of giant cell arteritis and polymyalgia rheumatica.

OBJECTIVES: To investigate the proportion and distribution of contrast enhancement (CE) of musculoskeletal structures with MRI of the thorax/abdomen/pelvis in giant cell arteritis (GCA). METHODS: CE at 34 musculoskeletal sites was rated with a 4-point ordinal scale. Patients were divided into groups with/without glucocorticoid (GC) treatment and with/without symptoms of polymyalgia rheumatica (PMR). Two composite scores were created: an MRI-score, including seven sites and a Limited-MRI-score, including four sites. RESULTS: Retrospectively, 90 consecutive patients with GCA were included. The population included 54 and 36 patients with and without PMR symptoms, respectively, and 45 (50%) patients were receiving GCs at the time of MRI. CE was found in 90.7% of lumbar spines, 87.5% of the pelvis, 82.2% of shoulder girdles and in 95.6% at any site in patients without GCs. The proportion of patients without and with GCs with at least moderate enhancement was 91.1%/75.6% at ≥ 1-3, 75.6%/51.1% at ≥ 4-6 and 64.4%/28.9% at ≥ 7-9 sites. The mean difference between the proportion of pathological CE in patients with and without GCs was 27.4% for synovial sites and 18.3% for periarticular/musculotendinous sites. Both composite scores captured substantial differences between groups, correlation was very strong between scores. CONCLUSIONS: MRI shows CE of musculoskeletal structures typical of PMR in most patients with GCA, supporting the concept of "GCA-PMR Spectrum Disease". Changes are more frequent at periarticular/musculotendinous sites and in the presence of PMR symptoms. A clear response to GCs is evident, less so for periarticular/musculotendinous sites.

HLA-B27, axial spondyloarthritis and survival.

INTRODUCTION: Ankylosing spondylitis (AS), and carriage of HLA-B27 gene in otherwise healthy individuals, are reportedly associated with increased mortality. We evaluated this hypothesis, using data from both a 35-year AS follow-up study and UK Biobank data. METHODS: In 1985, 363 members of the Swiss AS Patient Society and 806 relatives were screened clinically and then radiographically for AS/axial spondyloarthritis (axSpA). Life expectancy was analysed in 377 axSpA patients having available pelvic radiographs and HLA-B27 status, comparing with matched Swiss population data. Survival in relation to HLA-B27 status in the general population was studied in UK Biobank European-ancestry participants (n=407 480, n=30 419 deaths). RESULTS: AS patients have increased standardised mortality rate (SMR) compared with the general population (1.37, 95% CI 1.11 to 1.62). This increase was significant for HLA-B27-positive AS (SMR 1.38, 95% CI 1.11 to 1.65). Shortened life expectancy was observed among both HLA-B27-positive AS women (SMR 1.77, 95% CI 1.09 to 2.70) and men (SMR 1.31, 95% CI 1.02 to 1.59). Patients with non-radiographic axSpA (nr-axSpA) had significantly lower SMR: 0.44 (95% CI 0.23 to 0.77), compared with the general population. In the UK Biobank European-ancestry population cohort, HLA-B27 carriage was not significantly associated with any change in mortality (HR 1, 95% CI 0.97 to 1.1, p=0.349, adjusted by sex), in either males (HR 1, 95% CI 0.98 to 1.1, p=0.281) or females (HR 0.96, 95% CI 0.9 to 1, p=0.232), and no increase in vascular disease mortality was observed. DISCUSSION: AS patients, but not nr-axSpA patients, have a significantly shortened life expectancy. Increased mortality is particularly significant among women with HLA-B27-positive AS. HLA-B27 carriage in the European-ancestry general population does not influence survival, or the risk of death due to vascular disease.

Factors predicting axial spondyloarthritis among first-degree relatives of probands with ankylosing spondylitis: a family study spanning 35 years.

OBJECTIVE: Factors predicting axial spondyloarthritis (axSpA) among first-degree relatives (FDRs) of ankylosing spondylitis (AS) patients need to be defined. We investigated the predictive value of the probands' HLA-B27 and radiographic sacroiliitis status on disease occurrence among their FDR. We also assessed the predictive value of features of the clinical history, including chronic inflammatory back pain (CIBP) and acute anterior uveitis (AAU), among the FDR and how they can be used to improve classification and diagnosis of axSpA. METHODS: In 1985, we studied 363 AS probands and 806 FDR who underwent rheumatologic examination, completed questionnaires, provided blood samples for HLA-typing and underwent radiography of sacroiliac joints. At follow-up in 2018-2019, 125 patients and 360 FDR were available for study, and completed a postal questionnaire about axSpA features. FDRs were asked to report whether after 1985 they had been diagnosed by Swiss rheumatologists as having axSpA. RESULTS: Among HLA-B27(+) FDR, axSpA occurred in 25.4%-26.3%, independent of the radiographic sacroiliitis status of the proband. AAU occurred in 13/34 (38.2%) FDR with axSpA vs 29/251 (11.6%) FDR without axSpA (p=0.00004, OR=4.74 95% CI 2.15 to 10.47). The presence of CIBP at baseline did not predict later occurrence of axSpA but combining CIBP and pain/discomfort at the thoracic spine and at anterior (ventral) chest wall ever, assessed at follow-up in 2018-2019, provided 83.1% sensitivity and 87.2% specificity for current axSpA. CONCLUSION: Occurrence of AAU among FDR of axSpA probands should prompt screening for axSpA. Moreover, co-occurrence of CIBP and pain/discomfort in the thoracic spine and at anterior chest wall as a three-question tool may further enhance clinical suspicion of axSpA among these FDR.

Comparison of drug retention of TNF inhibitors, other biologics and JAK inhibitors in RA patients who discontinued JAK inhibitor therapy.

OBJECTIVES: JAK Inhibitors (JAKi) are recommended DMARDs for patients with moderate-to-severe RA who failed first-line therapy with methotrexate. There is a lack of data allowing an evidence-based choice of subsequent DMARD therapy for patients who had discontinued JAKi treatment. We aimed to compare the effectiveness of TNF inhibitor (TNFi) therapy vs JAKi vs other mode of action (OMA) biologic DMARD (bDMARD) in RA patients who were previously treated with a JAKi. METHODS: RA patients who discontinued JAKi treatment within the Swiss RA registry SCQM were included for this observational prospective cohort study. The primary outcome was drug retention for either TNFi, OMA bDMARD or JAKi. The hazard ratio for treatment discontinuation was calculated adjusting for potential confounders. A descriptive analysis of the reasons for discontinuation was performed. RESULTS: Four hundred treatment courses of JAKi were included, with a subsequent switch to either JAKi, TNFi or OMA bDMARD. The crude overall drug retention was higher in patients switching to another JAKi as compared with TNFi and comparable to OMA. A significant difference of JAKi vs TNFi persisted after adjusting for potential confounders. CONCLUSION: In a real-world population of RA patients who discontinued treatment with a JAKi, switching to another JAKi resulted in a higher drug retention than switching to a TNFi. A switch to a second JAKi seems an effective therapeutic option.

IgA Triggers Cell Death of Neutrophils When Primed by Inflammatory Mediators.

IVIG preparations consisting of pooled IgG are increasingly used for the treatment of autoimmune diseases. IVIG is known to regulate the viability of immune cells, including neutrophils. We report that plasma-derived IgA efficiently triggers death of neutrophils primed by cytokines or TLR agonists. IgA-mediated programmed neutrophil death was PI3K-, p38 MAPK-, and JNK-dependent and evoked anti-inflammatory cytokines in macrophage cocultures. Neutrophils from patients with acute Crohn's disease, rheumatoid arthritis, or sepsis were susceptible to both IgA- and IVIG-mediated death. In contrast to IVIG, IgA did not promote cell death of quiescent neutrophils. Our findings suggest that plasma-derived IgA might provide a therapeutic option for the treatment of neutrophil-associated inflammatory disorders.

Functional domains of the FgfrL1 receptor.

FgfrL1 is a novel growth factor receptor that is primarily expressed in musculoskeletal tissues and the kidney. FgfrL1-deficient mice have a malformed diaphragm and no kidneys. Such animals die immediately after birth because they are not able to inflate their lungs. The FgfrL1 molecule is composed of three extracellular Ig domains, a transmembrane helix and a short intracellular domain. To investigate the contribution of each of these domains to the function of the novel receptor, we generated mice with deletions of the individual domains. Mice lacking the intracellular domain are viable and phenotypically normal. Mice lacking the first (N-terminal) Ig domain are also viable and normal, but have a reduced life span. Mice lacking the Ig2 or the Ig3 domain are born alive, but die within 24 â€‹h after birth. Ig2-deficient animals exhibit substantially smaller kidneys than wild-type littermates and contain a lower number of glomeruli. Ig3-deficient mice completely lack metanephric kidneys. Interestingly, both the Ig2 and the Ig3-deficient animals show only minor alterations in the diaphragm, which still enables them to inflate their lungs after birth. Our results demonstrate that the principal function of the FgfrL1 receptor is to control the growth of the metanephric kidneys by regulating nephrogenesis. It appears that this function is primarily accomplished by the Ig3 domain with some contribution of the Ig2 domain. It is conceivable that the two domains interact with an Fgf ligand and another molecule from the surface of neighboring cells to induce condensation of the metanephric mesenchyme to renal epithelia and glomeruli.

Cutaneous involvement in anti-HMGCR positive necrotizing myopathy.

OBJECTIVE: Anti-3-Hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) positive immune-mediated necrotizing myopathy (IMNM) is a rare disease. It is induced by exogenous substances, most often by statins. Little is known about cutaneous manifestations of HMGCR positive IMNM and about HMGCR antibody positivity in other diseases. METHODS: The characteristics of patients with anti-HMGCR autoantibodies measured at our laboratory between January 2012 and September 2020 were studied. Characteristics of patients with IMNM were compared to those patients with positive antibodies but without muscle involvement. Associations of IMNM with other organ involvements were searched for. RESULTS: Of the 32 patients studied, 23 showed characteristics of IMNM, 9 did not fulfill current classification criteria but most showed signs of connective tissue diseases. Patients with IMNM were older (66 and 35 years, respectively; 0.92 (0.73-0.98); p < 0.001), had more frequent statin exposure (87% and 33%, respectively; 0.84 (0.61-0.94); p = 0.005) and higher mean peak CK (8717U/l and 329U/l, respectively; 1.0 (0.85-1.0); p < 0.001). 13/23 (56%) of IMNM patients showed cutaneous lesions; none of the patients suffered from cancer; only three IMNM patients showed drug-free complete remission. Incidence of IMNM in the catchment area of our center is at least 2.7/Mio/year. CONCLUSION: Cutaneous lesions were found to be more frequent in anti-HMRCR positive IMNM than previously reported. Titer of anti-HMGCR antibodies and CK levels were significantly higher in IMNM than in other autoimmune connective tissue diseases. The data support the hypothesis of an antigen-driven response in IMNM, and suggests an activation of autoreactive B-lymphocytes in non-IMNM patients.

Quantitative ultrasound to monitor the vascular response to tocilizumab in giant cell arteritis.

OBJECTIVES: To characterize the effect of ultra-short glucocorticoids followed by Tocilizumab monotherapy on the intima-media thickness (IMT) in GCA. METHODS: Eighteen GCA patients received 500 mg for 3 consecutive days (total of 1500mg) i.v. methylprednisolone on days 0-2, followed by i.v. Tocilizumab (8 mg/kg) on day 3 and thereafter weekly s.c. Tocilizumab injections (162 mg) over 52 weeks. US of temporal (TAs), axillary (AAs) and subclavian (SAs) arteries was performed at baseline, on days 2-3, and at weeks 4, 8, 12, 24 and 52. The largest IMT of all segments and IMT at landmarks of AA/SA were recorded. IMT was scaled by mean normal values and averaged. Each segment was classified according to diagnostic cut-offs. RESULTS: Of the 18 GCA patients, 16 patients had TA and 6 had extracranial large artery involvement. The IMT showed a sharp decline on day 2/3 in the TAs and AAs/SAs. In TAs, this was followed by an increase to baseline levels at week 4 and a subsequent slow decrease, which was paralleled by decreasing symptoms and achievement of clinical remission. The AAs/SAs showed a new signal of vasculitis at week 4 in three patients, with an IMT increase up to week 8. CONCLUSION: Glucocorticoid pulse therapy induced a transient decrease of the IMT in TAs and AAs/SAs. Tocilizumab monotherapy resulted in a slow and steady decrease in IMT of the TAs and a smaller and delayed effect on the AAs/SAs. The data strongly support a remission-inducing effect of Tocilizumab and argue the case for US having an important role in monitoring disease activity in GCA. TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT03745586.

Accuracy of serological testing for SARS-CoV-2 antibodies: First results of a large mixed-method evaluation study.

BACKGROUND: Serological immunoassays that can identify protective immunity against SARS-CoV-2 are needed to adapt quarantine measures, assess vaccination responses, and evaluate donor plasma. To date, however, the utility of such immunoassays remains unclear. In a mixed-design evaluation study, we compared the diagnostic accuracy of serological immunoassays that are based on various SARS-CoV-2 proteins and assessed the neutralizing activity of antibodies in patient sera. METHODS: Consecutive patients admitted with confirmed SARS-CoV-2 infection were prospectively followed alongside medical staff and biobank samples from winter 2018/2019. An in-house enzyme-linked immunosorbent assay utilizing recombinant receptor-binding domain (RBD) of the SARS-CoV-2 spike protein was developed and compared to three commercially available enzyme-linked immunosorbent assays (ELISAs) targeting the nucleoprotein (N), the S1 domain of the spike protein (S1), and a lateral flow immunoassay (LFI) based on full-length spike protein. Neutralization assays with live SARS-CoV-2 were performed. RESULTS: One thousand four hundred and seventy-seven individuals were included comprising 112 SARS-CoV-2 positives (defined as a positive real-time PCR result; prevalence 7.6%). IgG seroconversion occurred between day 0 and day 21. While the ELISAs showed sensitivities of 88.4% for RBD, 89.3% for S1, and 72.9% for N protein, the specificity was above 94% for all tests. Out of 54 SARS-CoV-2 positive individuals, 96.3% showed full neutralization of live SARS-CoV-2 at serum dilutions ≥ 1:16, while none of the 6 SARS-CoV-2-negative sera revealed neutralizing activity. CONCLUSIONS: ELISAs targeting RBD and S1 protein of SARS-CoV-2 are promising immunoassays which shall be further evaluated in studies verifying diagnostic accuracy and protective immunity against SARS-CoV-2.

2018 Update of the EULAR recommendations for the management of large vessel vasculitis.

BACKGROUND: Since the publication of the European League Against Rheumatism (EULAR) recommendations for the management of large vessel vasculitis (LVV) in 2009, several relevant randomised clinical trials and cohort analyses have been published, which have the potential to change clinical care and therefore supporting the need to update the original recommendations. METHODS: Using EULAR standardised operating procedures for EULAR-endorsed recommendations, the EULAR task force undertook a systematic literature review and sought opinion from 20 experts from 13 countries. We modified existing recommendations and created new recommendations. RESULTS: Three overarching principles and 10 recommendations were formulated. We recommend that a suspected diagnosis of LVV should be confirmed by imaging or histology. High dose glucocorticoid therapy (40-60 mg/day prednisone-equivalent) should be initiated immediately for induction of remission in active giant cell arteritis (GCA) or Takayasu arteritis (TAK). We recommend adjunctive therapy in selected patients with GCA (refractory or relapsing disease, presence of an increased risk for glucocorticoid-related adverse events or complications) using tocilizumab. Methotrexate may be used as an alternative. Non-biological glucocorticoid-sparing agents should be given in combination with glucocorticoids in all patients with TAK and biological agents may be used in refractory or relapsing patients. We no longer recommend the routine use of antiplatelet or anticoagulant therapy for treatment of LVV unless it is indicated for other reasons. CONCLUSIONS: We have updated the recommendations for the management of LVV to facilitate the translation of current scientific evidence and expert opinion into better management and improved outcome of patients in clinical practice.

The links of hepcidin and erythropoietin in the interplay of inflammation and iron deficiency in a large observational study of rheumatoid arthritis.

Anaemia affects quality of life and radiographic outcome in rheumatoid arthritis (RA). In a cross-sectional study with 779 patients, we assessed the prognostic potential of the major haematopoietic regulators, hepcidin and erythropoietin, comparing their serum concentrations with respect to different anaemia types, inflammatory activity, anti-cytokine-specific treatment effects and iron deficiency (ID) indices. The results showed that clinical disease activity was more closely associated with haemoglobin levels than with anti-tumour necrosis factor-alpha or interleukin 6 receptor effects. In ID, hepcidin was suppressed, independently of inflammation. Erythropoietin levels were inappropriately low in relation to the degree of anaemia, but, in contrast to low haemoglobin, not directly associated with joint damage progression. Hepcidin and erythropoietin levels are intimately connected with inflammation and ID. Interventional studies on these important targets are already in progress.

Risk of relapse after discontinuation of tocilizumab therapy in giant cell arteritis.

OBJECTIVE: It is currently unknown how long GCA should be treated with tocilizumab. In the first randomized controlled trial, the biologic agent was stopped after 52 weeks. We therefore studied what proportion of patients relapsed, when relapses occurred and whether factors might predict relapse after tocilizumab treatment discontinuation. METHODS: All patients in the tocilizumab arm who had received a 52-week treatment were evaluated. In case of lasting remission, magnetic resonance angiography (MRA) was performed and sera were taken to search for biomarkers associated with subclinical disease activity. RESULTS: Seventeen of 20 patients randomized to the tocilizumab treatment arm were in lasting remission without any co-medication at week 52. Mean follow-up after study end was 28.1 months (range 17-44). Eight patients relapsed after a mean of 6.3 months (range 2-14) (six within the first 5 months, two patients at months 13 and 14, respectively). Relapsing patients were younger and showed more signs of mural enhancement in MRA compared with non-relapsing patients. MRA documented low-intensity vessel wall signals in all subjects. No morphological changes such as formation of aneurysm of aorta occurred. Biomarkers in sera did not indicate subclinical disease activity: levels of IL-6, MMP-3, soluble TNF receptor 2, soluble CD163, soluble intercellular adhesion molecule-1 and Pentraxin-3 did not differ from matched healthy controls. CONCLUSION: The data show that a 52-week treatment with tocilizumab induces a lasting remission that persists in half of the patients after treatment stop. None of the clinical, serological or MRA findings qualify to predict relapse. Remarkably, MRA revealed a persisting wall enhancement of the descending aorta.

Safety and immunogenicity of tetanus/diphtheria vaccination in patients with rheumatic diseases-a prospective multi-centre cohort study.

OBJECTIVES: We aimed to assess the safety and immunogenicity of a diphtheria/tetanus vaccine booster dose in three different patient groups with rheumatic diseases on a variety of immunosuppressive/immunomodulatory medications compared with healthy controls (HCs). METHODS: We conducted a multi-centre prospective cohort study in Switzerland. We enrolled patients with RA, axial SpA/PsA, vasculitis (Behçet's disease, ANCA-associated vasculitis) and HCs. Diphtheria/tetanus vaccination was administered according to the Swiss vaccination recommendations. Blood samples were drawn before vaccination, and 1 month and 3 months afterwards. Antibody concentrations against vaccine antigens were measured by ELISA. Immunogenicity was compared between patient and medication groups. A mixed model was applied for multivariate analysis. Missing data were dealt with using multiple imputation. RESULTS: Between January 2014 and December 2015, we enrolled 284 patients with rheumatic diseases (131 RA, 114 SpA/PsA, 39 vasculitis) and 253 HCs. Of the patients, 89% were on immunosuppressive/immunomodulatory medication. Three months post-vaccination 100% of HCs vs 98% of patients were protected against tetanus and 84% vs 73% against diphtheria. HCs and SpA/PsA patients had significantly higher responses than RA and vasculitis patients. Assessing underlying diseases and medications in a multivariate model, rituximab was the only factor negatively influencing tetanus immunogenicity, whereas only MTX treatment had a negative influence on diphtheria antibody responses. No vaccine-related serious adverse events were recorded. CONCLUSION: Diphtheria/tetanus booster vaccination was safe. Tetanus vaccination was immunogenic; the diphtheria component was less immunogenic. Vaccine responses were blunted by rituximab and MTX. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, Identifier: NCT01947465.

Developing a rare disease chronic care model: Management of systemic sclerosis (MANOSS) study protocol.

AIM: The aim of the management of systemic sclerosis (MANOSS) study described in this protocol is to develop a chronic care model, based on a contextual analysis and stakeholder involvement, for patients living with the rare disease systemic sclerosis (SSc) in Switzerland. DESIGN: Applying an implementation science approach, this study starts with an explanatory sequential mixed method study for contextual analysis, followed by broad stakeholder involvement for model development and a Delphi study to reach consensus. METHODS: First, a quantitative cross-sectional survey with patients and healthcare professionals (HPs) will be conducted to identify current practice patterns of chronic illness management and technology readiness. Second, qualitative interviews with patients, family members and HPs will be performed to gain a deeper understanding of care needs identified in the quantitative survey. Third, a model of care will be co-created with input from patients, HPs and other experts. The eHealth enhanced Chronic Care Model will serve as a guiding framework. The new model and corresponding outcome parameters will be refined using a Delphi-study approach to reach consensus on a testable model of care for persons living with SSc. The protocol has received research ethics committee approval in September 2018 by the Swiss Ethics Committee. DISCUSSION: The MANOSS study's participatory approach is essential for contextual fit of the model for patients with SSc in this setting. Subsequent feasibility testing and implementation are planned to evaluate the model's value in relation to health disparities faced by this patient population. IMPACT: Patients living with this rare disease lack access to coordinated, specialized care and self-management support from qualified HPs. Reengineering of current care, with consideration for technological opportunities, is warranted to meet patients' and families' needs.

Risk for adverse pregnancy outcome in axial spondyloarthritis and rheumatoid arthritis: disease activity matters.

OBJECTIVE: To analyse pregnancy outcome and delivery mode in patients with RA and axial spondyloarthritis (axSpA) in relation to disease activity and anti-rheumatic drugs. METHODS: Patients with RA and axSpA were compared with age-matched healthy controls (HCs) with respect to pregnancy outcome and delivery mode. Disease activity (DAS28, ASDAS, CRP) and medication use of patients was assessed once at each trimester. ORs with 95% CI were calculated with univariate and multivariate regression models. RESULTS: We analysed 244 pregnancies, of which 96 occurred in patients with RA, 78 in patients with axSpA and 70 in HCs. The adjusted analysis showed that pregnant women with RA and axSpA had a higher risk of pregnancy complications (gestational diabetes, preeclampsia, infection, preterm premature rupture of membranes), small for gestational age infants and preterm deliveries (all P < 0.05). Active disease was a predictor for preterm delivery in both RA [odds ratio (OR) = 3.9, 95% CI: 1.25, 12.15] and axSpA (OR = 13.8, 95% CI: 1.33, 143.94). Regarding delivery mode, most patients had vaginal deliveries. However, women with RA revealed an increased risk of caesarean section compared with HC (P < 0.05), which was not seen in patients with axSpA. CONCLUSION: Our findings show that disease activity of RA and axSpA during pregnancy influences pregnancy outcome. To allow for successful pregnancy a treatment strategy that targets inactive disease beyond conception should be followed.

Immuno-monitoring reveals an extended subclinical disease activity in tocilizumab-treated giant cell arteritis.

Objective: Tocilizumab is effective in inducing and maintaining remission of GCA. Despite clinical and serological control of disease, magnetic resonance angiography may show persistence of inflammatory signals of unknown significance in arterial walls. Thus, there is an unmet need for tools to detect subclinical disease activity. Methods: Immune-inflammatory markers were measured in prospectively collected sera of the first randomized, double-blind, placebo-controlled trial investigating the use of tocilizumab in GCA. As a comparison, immune-inflammatory markers were also measured in sera from age- and sex-matched healthy volunteers. The biomarkers were quantified using luminex technology. Results: Of all the parameters determined, only MMP-3, pentraxin-3 and sTNFR2 were significantly elevated, while ICAM-1 and CD163 were significantly decreased during the early stages of the study, at time points of full clinical remission under treatment with tocilizumab plus glucocorticoids. In contrast, tocilizumab monotherapy towards the end of the study resulted in an almost complete normalization of immune-inflammatory molecules, as defined by the healthy controls. MMP-3 levels showed a weak association with magnetic resonance signal intensity; none of the biomarkers predicted relapse occurring within 6 months after study end. Conclusion: The data documented a subclinical disease activity in GCA that was more pronounced during the early stages of treatment and almost disappeared towards the study end. They indicated that tocilizumab treatment of at least 52 weeks is necessary in order to reset a broad range of immune-inflammatory pathways. Trial registration: ClinicalTrials.gov, http://clinicaltrials.gov, NCT01450137.

Magnetic resonance angiography in giant cell arteritis: results of a randomized controlled trial of tocilizumab in giant cell arteritis.

Objective: To analyse magnetic resonance angiographic (MRA) vessel wall signals from a randomized controlled trial of tocilizumab (TCZ) to treat GCA. Methods: Participants were assigned in a 2:1 ratio to receive either TCZ + glucocorticoids (GCs) or placebo + GC infusions at 4-week intervals for 52 weeks. GCs were started at 1 mg/kg/day, then tapered to 0.1 mg/kg/day at week 12 and thereafter down to zero. Patients with initial positive MRA findings underwent control MRA at weeks 12 and 52. Vessel wall signals were scored from 0 (normal) to 3 (intense late enhancement). Outcomes were the number of patients with complete MRA remission at weeks 12 and 52, and changes in vasculitis score, vessel anatomy and atherosclerosis. Results: Of the 30 randomized participants, nine TCZ and two placebo patients had no vessel wall enhancement on initial MRA. At week 12, MRAs were performed in nine TCZ and four placebo patients (nine and three in clinical remission, respectively). Three (33%) TCZ patients showed normalization of vessel wall signals compared with one (25%) placebo patient. At week 52, there was additional MRA improvement in some TCZ patients, but one-third showed persistent or increased late vessel wall enhancement. There was no formation of aneurysms or stenosis and no increase in atherosclerosis. Conclusions: Although TCZ resulted in complete clinical and laboratory remission of GCA over 52 weeks, MRA signals in vessel walls normalized in only one-third of patients. Whether these signals are of prognostic importance remains to be determined.

Postoperative morbidity of complete mesocolic excision and central vascular ligation in right colectomy: a retrospective comparative cohort study.

BACKGROUND: To investigate morbidity and mortality following complete mesocolic excision (CME) and central vascular ligation (CVL) in patients undergoing right colectomy. METHODS: Data from consecutive patients undergoing elective right colectomy at a university-affiliated referral centre were retrospectively analysed. Patients who underwent conventional right-sided colonic cancer surgery (January 2001-April 2009, n = 84) were compared to patients who underwent CME/CVL (May 2009-January 2015, n = 71). The primary end point was anastomotic leak. Secondary end points were delayed gastric emptying, severe respiratory failure, mortality and length of hospital stay. RESULTS: No significant difference was found in the rate of anastomotic leak (1.2% in the conventional versus 5.6% in the CME/CVL group, p = 0.108). Patients in the CME/CVL group had a higher 90-day mortality rate (7.0% versus 0.0%, p = 0.019). Four out of five deceased patients suffered from aspiration with consecutive respiratory failure. There was a tendency towards delayed gastric emptying in the CME/CVL group (12.7% versus 7.1%, p = 0.246). Clavien-Dindo complication grades ≥ 2 were similar in both groups with 16 (19%) in the conventional and 15 (21.1%) in the CME/CVL group (p = 0.747). CME/CVL patients had a shorter mean length of stay with 11 versus 14 days (p <  0.001). CONCLUSIONS: Complete mesocolic excision with central vascular ligation in right colectomy seems to have a higher aspiration rate leading to severe respiratory failure and to higher mortality compared to conventional resection methods. Patient selection for this procedure may therefore be crucial.

Tocilizumab for induction and maintenance of remission in giant cell arteritis: a phase 2, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Giant cell arteritis is an immune-mediated disease of medium and large-sized arteries that affects mostly people older than 50 years of age. Treatment with glucocorticoids is the gold-standard and prevents severe vascular complications but is associated with substantial morbidity and mortality. Tocilizumab, a humanised monoclonal antibody against the interleukin-6 receptor, has been associated with rapid induction and maintenance of remission in patients with giant cell arteritis. We therefore aimed to study the efficacy and safety of tocilizumab in the first randomised clinical trial in patients with newly diagnosed or recurrent giant cell arteritis. METHODS: In this single centre, phase 2, randomised, double-blind, placebo-controlled trial, we recruited patients aged 50 years and older from University Hospital Bern, Switzerland, who met the 1990 American College of Rheumatology criteria for giant cell arteritis. Patients with new-onset or relapsing disease were randomly assigned (2:1) to receive either tocilizumab (8 mg/kg) or placebo intravenously. 13 infusions were given in 4 week intervals until week 52. Both groups received oral prednisolone, starting at 1 mg/kg per day and tapered down to 0 mg according to a standard reduction scheme defined in the study protocol. Allocation to treatment groups was done using a central computerised randomisation procedure with a permuted block design and a block size of three, and concealed using central randomisation generated by the clinical trials unit. Patients, investigators, and study personnel were masked to treatment assignment. The primary outcome was the proportion of patients who achieved complete remission of disease at a prednisolone dose of 0·1 mg/kg per day at week 12. All analyses were intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01450137. RESULTS: Between March 3, 2012, and Sept 9, 2014, 20 patients were randomly assigned to receive tocilizumab and prednisolone, and ten patients to receive placebo and glucocorticoid; 16 (80%) and seven (70%) patients, respectively, had new-onset giant cell arteritis. 17 (85%) of 20 patients given tocilizumab and four (40%) of ten patients given placebo reached complete remission by week 12 (risk difference 45%, 95% CI 11-79; p=0·0301). Relapse-free survival was achieved in 17 (85%) patients in the tocilizumab group and two (20%) in the placebo group by week 52 (risk difference 65%, 95% CI 36-94; p=0·0010). The mean survival-time difference to stop glucocorticoids was 12 weeks in favour of tocilizumab (95% CI 7-17; p<0·0001), leading to a cumulative prednisolone dose of 43 mg/kg in the tocilizumab group versus 110 mg/kg in the placebo group (p=0·0005) after 52 weeks. Seven (35%) patients in the tocilizumab group and five (50%) in the placebo group had serious adverse events. INTERPRETATION: Our findings show, for the first time in a trial setting, the efficacy of tocilizumab in the induction and maintenance of remission in patients with giant cell arteritis. FUNDING: Roche and the University of Bern.