Bhaskar Dasgupta

Trial of Tocilizumab in Giant-Cell Arteritis

Background Giant‐cell arteritis commonly relapses when glucocorticoids are tapered, and the prolonged use of glucocorticoids is associated with side effects. The effect of the interleukin‐6 receptor alpha inhibitor tocilizumab on the rates of relapse during glucocorticoid tapering was studied in patients with giant‐cell arteritis. Methods In this 1‐year trial, we randomly assigned 251 patients, in a 2:1:1:1 ratio, to receive subcutaneous tocilizumab (at a dose of 162 mg) weekly or every other week, combined with a 26‐week prednisone taper, or placebo combined with a prednisone taper over a period of either 26 weeks or 52 weeks. The primary outcome was the rate of sustained glucocorticoid‐free remission at week 52 in each tocilizumab group as compared with the rate in the placebo group that underwent the 26‐week prednisone taper. The key secondary outcome was the rate of remission in each tocilizumab group as compared with the placebo group that underwent the 52‐week prednisone taper. Dosing of prednisone and safety were also assessed. Results Sustained remission at week 52 occurred in 56% of the patients treated with tocilizumab weekly and in 53% of those treated with tocilizumab every other week, as compared with 14% of those in the placebo group that underwent the 26‐week prednisone taper and 18% of those in the placebo group that underwent the 52‐week prednisone taper (P<0.001 for the comparisons of either active treatment with placebo). The cumulative median prednisone dose over the 52‐week period was 1862 mg in each tocilizumab group, as compared with 3296 mg in the placebo group that underwent the 26‐week taper (P<0.001 for both comparisons) and 3818 mg in the placebo group that underwent the 52‐week taper (P<0.001 for both comparisons). Serious adverse events occurred in 15% of the patients in the group that received tocilizumab weekly, 14% of those in the group that received tocilizumab every other week, 22% of those in the placebo group that underwent the 26‐week taper, and 25% of those in the placebo group that underwent the 52‐week taper. Anterior ischemic optic neuropathy developed in one patient in the group that received tocilizumab every other week. Conclusions Tocilizumab, received weekly or every other week, combined with a 26‐week prednisone taper was superior to either 26‐week or 52‐week prednisone tapering plus placebo with regard to sustained glucocorticoid‐free remission in patients with giant‐cell arteritis. Longer follow‐up is necessary to determine the durability of remission and safety of tocilizumab. (Funded by F. Hoffmann–La Roche; ClinicalTrials.gov number, NCT01791153.)

A Large-Scale Genetic Analysis Reveals a Strong Contribution of the HLA Class II Region to Giant Cell Arteritis Susceptibility

We conducted a large-scale genetic analysis on giant cell arteritis (GCA), a polygenic immune-mediated vasculitis. A case-control cohort, comprising 1,651 case subjects with GCA and 15,306 unrelated control subjects from six different countries of European ancestry, was genotyped by the Immunochip array. We also imputed HLA data with a previously validated imputation method to perform a more comprehensive analysis of this genomic region. The strongest association signals were observed in the HLA region, with rs477515 representing the highest peak (p = 4.05xa0× 10(-40), OR = 1.73). A multivariate model including class II amino acids of HLA-DRβ1 and HLA-DQα1 and one class I amino acid of HLA-B explained most of the HLA association with GCA, consistent with previously reported associations of classical HLA alleles like HLA-DRB1(∗)04. An omnibus test on polymorphic amino acid positions highlighted DRβ1 13 (p = 4.08xa0× 10(-43)) and HLA-DQα1 47 (p = 4.02xa0× 10(-46)), 56, and 76 (both p = 1.84xa0× 10(-45)) as relevant positions for disease susceptibility. Outside the HLA region, the most significant loci included PTPN22 (rs2476601, p = 1.73xa0× 10(-6), OR = 1.38), LRRC32 (rs10160518, p = 4.39xa0× 10(-6), OR = 1.20), and REL (rs115674477, p = 1.10xa0× 10(-5), OR = 1.63). Our study provides evidence of a strong contribution of HLA class I and II molecules to susceptibility to GCA. In the non-HLA region, we confirmed a key role for the functional PTPN22 rs2476601 variant and proposed other putative risk loci for GCA involved in Th1, Th17, and Treg cell function.

Defining conditions where long-term glucocorticoid treatment has an acceptably low level of harm to facilitate implementation of existing recommendations: viewpoints from an EULAR task force

There is convincing evidence for the known and unambiguously accepted beneficial effects of glucocorticoids at low dosages. However, the implementation of existing recommendations and guidelines on the management of glucocorticoid therapy in rheumatic diseases is lagging behind. As a first step to improve implementation, we aimed at defining conditions under which long-term glucocorticoid therapy may have an acceptably low level of harm. A multidisciplinary European League Against Rheumatism task force group of experts including patients with rheumatic diseases was assembled. After a systematic literature search, breakout groups critically reviewed the evidence on the four most worrisome adverse effects of glucocorticoid therapy (osteoporosis, hyperglycaemia/diabetes mellitus, cardiovascular diseases and infections) and presented their results to the other group members following a structured questionnaire for final discussion and consensus finding. Robust evidence on the risk of harm of long-term glucocorticoid therapy was often lacking since relevant study results were often either missing, contradictory or carried a high risk of bias. The group agreed that the risk of harm is low for the majority of patients at long-term dosages of ≤5u2005mg prednisone equivalent per day, whereas at dosages of >10u2005mg/day the risk of harm is elevated. At dosages between >5 and ≤10u2005mg/day, patient-specific characteristics (protective and risk factors) determine the risk of harm. The level of harm of glucocorticoids depends on both dose and patient-specific parameters. General and glucocorticoid-associated risk factors and protective factors such as a healthy lifestyle should be taken into account when evaluating the actual and future risk.

Autoimmunizing mechanisms in thymoma and thymus.

Autoimmunizing mechanisms are very hard to study in humans, so we have focused on vital clues in thymomas and hyperplastic thymuses in myasthenia gravis (MG). According to our multi‐step hypothesis: thymic epithelial cells (TEC) present epitopes from the isolated acetylcholine receptor (AChR) subunits they express, and autoimmunize helper T cells; subsequently, these evoke “early antibodies” that then attack rare thymic myoid cells expressing intact AChR; in the resulting germinal centers, autoantibodies diversify to recognize native AChR. We have studied: 1) thymomas, to identify autoimmunizing cell types, focusing on IFN‐α, against which many patients have high titer autoantibodies, as in another highly informative autoimmune syndrome. Although IFN‐α is much easier to label than the sparse and delicate AChR subunits, we have not yet located obviously autoimmunizing micro‐environments; 2) hyperplastic MG thymuses, where we find (a) upregulation of complement receptors and regulators on hyperplastic TEC and deposition of activated C3b complement component on them, (b) absence of complement regulators from almost all myoid cells, indicating vulnerability to attack, and (c) deposition of C3b, and even of the terminal membrane attack complex, especially on the myoid cells close to the infiltrating germinal centers. The changes are very similar in over 50% of the so‐called seronegative patients with generalized MG (SNMG) but without detectable autoantibodies against AChR or MuSK, consistently with other evidence that they belong to the spectrum of AChR‐seropositive MG. Together, moreover, our findings implicate both myoid cells and TEC in autoimmunization, and thus strongly support our hypothesis.

Patient-reported Outcomes in Polymyalgia Rheumatica

Objective. To prospectively evaluate the disease course and the performance of clinical, patient-reported outcome (PRO) and musculoskeletal ultrasound measures in patients with polymyalgia rheumatica (PMR). Methods. The study population included 85 patients with new-onset PMR who were initially treated with prednisone equivalent dose of 15 mg daily tapered gradually, and followed for 26 weeks. Data collection included physical examination findings, laboratory measures of acute-phase reactants, and PRO measures. Ultrasound evaluation was performed at baseline and Week 26 to assess for features previously reported to be associated with PMR. Response to corticosteroid treatment was defined as 70% improvement in PMR on visual analog scale (VAS). Results. At baseline, 77% had hip pain in addition to shoulder pain and 100% had abnormal C-reactive protein or erythrocyte sedimentation rate. On ultrasound, 84% had shoulder findings and 32% had both shoulder and hip findings. Response to corticosteroid treatment occurred in 73% of patients by Week 4 and was highly correlated with percentage improvement in other VAS measures. Presence of ultrasound findings at baseline predicted response to corticosteroids at 4 weeks. Factor analysis revealed 6 domains that sufficiently represented all the outcome measures: PMR-related pain and physical function, an elevated inflammatory marker, hip pain, global pain, mental function, and morning stiffness. Conclusion. PRO measures and inflammatory markers performed well in assessing disease activity in patients with PMR. A minimum set of outcome measures consisting of PRO measures of pain and function and an inflammatory marker should be used in practice and in clinical trials in PMR.

EULAR recommendations for the use of imaging in large vessel vasculitis in clinical practice

To develop evidence-based recommendations for the use of imaging modalities in primary large vessel vasculitis (LVV) including giant cell arteritis (GCA) and Takayasu arteritis (TAK). European League Against Rheumatism (EULAR) standardised operating procedures were followed. A systematic literature review was conducted to retrieve data on the role of imaging modalities including ultrasound, MRI, CT and [18F]-fluorodeoxyglucose positron emission tomography (PET) in LVV. Based on evidence and expert opinion, the task force consisting of 20 physicians, healthcare professionals and patients from 10 EULAR countries developed recommendations, with consensus obtained through voting. The final level of agreement was voted anonymously. A total of 12 recommendations have been formulated. The task force recommends an early imaging test in patients with suspected LVV, with ultrasound and MRI being the first choices in GCA and TAK, respectively. CT or PET may be used alternatively. In case the diagnosis is still in question after clinical examination and imaging, additional investigations including temporal artery biopsy and/or additional imaging are required. In patients with a suspected flare, imaging might help to better assess disease activity. The frequency and choice of imaging modalities for long-term monitoring of structural damage remains an individual decision; close monitoring for aortic aneurysms should be conducted in patients at risk for this complication. All imaging should be performed by a trained specialist using appropriate operational procedures and settings. These are the first EULAR recommendations providing up-to-date guidance for the role of imaging in the diagnosis and monitoring of patients with (suspected) LVV.

E-selectin, interleukin 18, serum amyloid a, and matrix metalloproteinase 9 are associated with clinical response to golimumab plus methotrexate in patients with active rheumatoid arthritis despite methotrexate therapy

Objective. To assess the effect of golimumab (human monoclonal antibody to tumor necrosis factor-α) plus methotrexate (MTX) on selected inflammatory biomarkers, and to determine if these effects predict clinical response in rheumatoid arthritis (RA). Methods. Sera from adults with active RA despite MTX therapy, who received subcutaneous injections of placebo + MTX (MTX alone, n = 34) or golimumab 50 or 100 mg every 2 or 4 weeks + MTX (n = 137), were analyzed for levels of C-reactive protein (CRP), serum amyloid A (SAA), interleukin 18 (IL-18), E-selectin, matrix metalloproteinase 9 (MMP-9), and tissue inhibitor of matrix metalloproteinase 1 (TIMP-1). Results. Golimumab + MTX treatment significantly decreased serum CRP, SAA, IL-18, E-selectin, TIMP-1, and MMP-9 levels (median percent changes of −4.1% to −74.3% across treatment groups) versus MTX alone (−5.8% to 9.7%) when first measured at Week 4; decreases were sustained through Week 16. Larger magnitudes of decrease in all biomarkers were observed for clinical responders versus nonresponders. For golimumab + MTX, regression analyses including all biomarkers and select clinical measures showed that reductions in levels of several markers (SAA, E-selectin, MMP-9) as early as Week 4 correlated significantly with improvement in swollen joint count (SJC) at Week 16, as did reductions in E-selectin with improvement in tender joint count at Week 16. After accounting for the biomarkers, however, treatment group was no longer significant for SJC. Conclusion. Significant decreases in several inflammatory biomarkers were associated with golimumab + MTX therapy. Decreases in serum levels of SAA, E-selectin, and MMP-9 at Week 4 may be useful in predicting clinical response at Week 16.

Ischaemic manifestations in giant cell arteritis are associated with area level socio-economic deprivation, but not cardiovascular risk factors

OBJECTIVESnTo determine whether ischaemic manifestations of GCA are associated with pre-existing hypertension, atherosclerosis or area-level socio-economic deprivation.nnnMETHODSnWe conducted an observational study of rheumatologist/ophthalmologist-diagnosed GCA in eight UK centres. The main outcome measure was ischaemic manifestations observed during active GCA: visual loss/blurring, aura, diplopia, jaw/tongue/limb claudication, cerebral/myocardial ischaemia or scalp necrosis.nnnRESULTSnOut of 271 patients, 222 had ischaemic manifestations. Adjusted odds ratios (ORs) for the influence of hypertension and atherosclerosis were 1.6 (95% CI 0.8, 3.1) and 1.5 (0.6, 3.5). The most striking finding was an association of ischaemic manifestations with increasing Index of Deprivation 2007 score: OR 4.2 (95% CI 1.3, 13.6) for the most-deprived quartile compared with the least-deprived quartile. Similar effect sizes were seen within each recruitment centre. Deprivation was associated with smoking and negatively associated with previous polymyalgia. However, neither of these variables, nor hypertension or atherosclerosis, appeared responsible for mediating the effect of deprivation on ischaemic complications. Smoking was not associated with ischaemic manifestations. Median symptom duration before treatment was 30 days; after adjusting for symptom duration, the OR for ischaemic complications was 3.2 (95% CI 1.0, 10.8) for the most-deprived quartile compared with the least-deprived quartile.nnnCONCLUSIONSnIn GCA, area-level socio-economic deprivation was associated with ischaemic manifestations: this was not mediated by traditional cardiovascular risk factors. These findings are novel and require replication. Delay between first symptoms and treatment may play a role. Public awareness campaigns about GCA should aim especially to engage individuals living in more deprived areas to encourage early presentation and prompt treatment.

Long-term efficacy and safety of tocilizumab in giant cell arteritis and large vessel vasculitis

Giant cell arteritis (GCA) is a chronic systemic vasculitis affecting large-sized and medium-sized vessels. Glucocorticoids are currently the mainstay of treatment for GCA and associated large vessel vasculitis (LVV) but are associated with frequent adverse events. Methotrexate has only demonstrated a modest benefit while anti-TNF biological agents (infliximab and etanercept) have been inefficacious. Elevated levels of interleukin-6 (IL-6), a proinflammatory cytokine, has been associated with GCA. Tocilizumab (TCZ), a humanised antihuman IL-6 receptor antibody, has been used successfully in several reports as a treatment for GCA and LVV. We report the potentially long-term successful use of TCZ in 8 cases of refractory LVV. All of our patients achieved a good clinical response to TCZ and C reactive protein reduced from an average of 70.3 to 2.5. In all cases, the glucocorticoid dose was reduced, from an average of 24.6u2005mg prednisolone prior to TCZ treatment to 4.7u2005mg, indicating that TCZ may enable a reduction in glucocorticoid-associated adverse events. However, regular TCZ administration was needed for disease control in most cases. TCZ was discontinued in one case due to the development of an empyema indicating the need for careful monitoring of infection when using this treatment.

Imaging in Giant Cell Arteritis

Much progress has been made in the use of imaging as a diagnostic tool in giant cell arteritis (GCA), which assists in the management of patients where the initial diagnosis is unclear. This includes patients with atypical cranial symptoms, or with predominantly systemic, constitutional or limb symptoms. Ultrasound and magnetic resonance imaging are capable of visualising both the cranial and extracranial large vessel circulation, with vessel wall thickening and stenotic lesions being visualised. Computed tomographic angiography is helpful in visualising the aorta for aneurysm complicating GCA but can also detect vessel wall thickening in established large vessel vasculitis. PET-CT is a very sensitive test for early vascular inflammation in extracranial large vessel vasculitis, before aneurysmal or stenotic lesions have developed, of use in the patient with unexplained constitutional symptoms. The place of imaging in the follow-up of GCA is being investigated, and repeated imaging may be useful in select cases. Generally, vascular abnormalities become less defined once glucocorticoid treatment has been started, and therefore, imaging studies must be conducted early as part of a GCA fast-track assessment.