Trial of Tocilizumab in Giant-Cell Arteritis Stone, John H; Tuckwell, Katie; Dimonaco, Sophie ...
New England journal of medicine/The New England journal of medicine,
07/2017, Letnik:
377, Številka:
4
Journal Article
Recenzirano
Odprti dostop
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.
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.
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.
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 .).
To develop European League Against Rheumatism (EULAR) recommendations for the management of large vessel vasculitis.
An expert group (10 rheumatologists, 3 nephrologists, 2 immunolgists, 2 internists ...representing 8 European countries and the USA, a clinical epidemiologist and a representative from a drug regulatory agency) identified 10 topics for a systematic literature search through a modified Delphi technique. In accordance with standardised EULAR operating procedures, recommendations were derived for the management of large vessel vasculitis. In the absence of evidence, recommendations were formulated on the basis of a consensus opinion.
Seven recommendations were made relating to the assessment, investigation and treatment of patients with large vessel vasculitis. The strength of recommendations was restricted by the low level of evidence and EULAR standardised operating procedures.
On the basis of evidence and expert consensus, management recommendations for large vessel vasculitis have been formulated and are commended for use in everyday clinical practice.
Imaging studies play a central role in diagnosing and monitoring giant-cell and Takayasu arteritis. Deep, large vessels can be examined by CT or MRI, while colour Doppler ultrasound and MRI have been ...used with promising results to investigate the temporal arteries. Positron emission tomography is very sensitive in detecting large-vessel inflammation, although it does not delineate the vessel wall. Imaging procedures can also be used to monitor the disease course. However, imaging signs of inflammation may sometimes persist despite clinical remission and, conversely, seemingly unaffected vessels may develop alterations later on.
To develop European League Against Rheumatism (EULAR) recommendations for the management of small and medium vessel vasculitis.
An expert group (consisting of 10 rheumatologists, 3 nephrologists, 2 ...immunologists, 2 internists representing 8 European countries and the USA, a clinical epidemiologist and a representative from a drug regulatory agency) identified 10 topics for a systematic literature search using a modified Delphi technique. In accordance with standardised EULAR operating procedures, recommendations were derived for the management of small and medium vessel vasculitis. In the absence of evidence, recommendations were formulated on the basis of a consensus opinion.
In all, 15 recommendations were made for the management of small and medium vessel vasculitis. The strength of recommendations was restricted by low quality of evidence and by EULAR standardised operating procedures.
On the basis of evidence and expert consensus, recommendations have been made for the evaluation, investigation, treatment and monitoring of patients with small and medium vessel vasculitis for use in everyday clinical practice.
Abstract Objective To report the efficacy and safety of anti-TNF agents in patients with severe and/or refractory manifestations of Behçet's disease (BD). Methods We performed a multicenter study of ...main characteristics and outcomes of anti-TNF alpha treatments mainly infliximab (62%), and adalimumab (30%) in 124 BD patients 48% of men; median age of 33.5 (28–40) years. Results Overall response (i.e. complete and partial) rate was 90.4%. Clinical responses were observed in 96.3%, 88%, 70%, 77.8%, 92.3% and 66.7% of patients with severe and/or refractory ocular, mucocutaneous, joint, gastro-intestinal manifestations, central nervous system manifestations and cardiovascular manifestations, respectively. No significant difference was found with respect to the efficacy of anti-TNF used as monotherapy or in association with an immunosuppressive agent. The incidence of BD flares/patient/year was significantly lower during anti-TNF treatment (0.2 ± 0.5 vs 1.7 ± 2.4 before the use of anti-TNF, p < 0.0001). The prednisone dose was significantly reduced at 6 and 12 months (p < 0.0001). In multivariate analysis, retinal vasculitis was negatively associated with complete response to anti-TNF (OR = 0.33 0.12–0.89; p = 0.03). The efficacy and relapse free survival were similar regardless of the type of anti-TNF agent used. After a median follow-up of 21 7–36 months, side effects were reported in 28% of patients, including infections (16.3%) and hypersensitivity reactions (4.1%). Serious adverse events were reported in 13% of cases. Conclusion Anti-TNF alpha therapy is efficient in all severe and refractory BD manifestations. Efficacy appears to be similar regardless of the anti-TNF agent used (infliximab or adalimumab).
Objective. Treatment of large-vessel vasculitis (LVV) remains challenging. Patients usually respond to glucocorticoid (GC) therapy, but often relapse on tapering of the GC dose or after GC ...withdrawal. In addition, GCs are fraught with numerous adverse events. The aim of this study was to assess the efficacy and safety of the anti-IL-6 receptor (IL-6R) antibody tocilizumab (TCZ) in patients with LVV.
Methods. Four patients with active LVV (two with GCA and two with Takayasu arteritis) received monthly TCZ infusions (8 mg/kg bodyweight) for 6 consecutive months. Two patients were treatment naïve, while two had relapsing disease. Disease activity and drug tolerability were assessed clinically and by laboratory tests at study entry and subsequently every month for 6 months of TCZ treatment, while an 18Ffluorodeoxyglucose PET (PET/CT) scan was performed before and after treatment. In addition, a semi-quantitative clinical evaluation was performed at baseline and at 3 and 6 months using the Indian Takayasu activity score and the Kerr indices. After TCZ, MTX was used as maintenance therapy.
Results. All patients treated with TCZ therapy had a satisfactory clinical and laboratory response, while PET/CT findings significantly improved in all cases. No serious adverse events were noted. Only one patient had a transient increase in liver enzymes.
Conclusions. In this small group of patients with LVV, treatment with TCZ was effective and well tolerated. Further, larger studies are required to confirm our findings.
To develop evidence-based European League Against Rheumatism (EULAR) recommendations for the management of Behçet disease (BD) supplemented where necessary by expert opinion.
The multidisciplinary ...expert committee, a task force of the EULAR Standing Committee for Clinical Affairs (ESCCA), consisted of nine rheumatologists (one who was also a clinical epidemiologist and one also a Rehabilitation Medicine doctor), three ophthalmologists, one internist, one dermatologist and one neurologist, representing six European countries plus Tunisia and Korea. A patient representative was also present. Problem areas and related keywords for systematic literature research were identified. Systematic literature research was performed using Medline and the Cochrane Library databases from 1966 through to December 2006. A total of 40 initial statements were generated based on the systematic literature research. These yielded the final recommendations developed from two blind Delphi rounds of voting.
Nine recommendations were developed for the management of different aspects of BD. The strength of each recommendation was determined by the level of evidence and the experts' opinions. The level of agreement for each recommendation was determined using a visual analogue scale for the whole committee and for each individual aspect by the subgroups, who consider themselves experts in that field of BD. There was excellent concordance between the level of agreement of the whole group and the "experts in the field".
Recommendations related to the eye, skin-mucosa disease and arthritis are mainly evidence based, but recommendations on vascular disease, neurological and gastrointestinal involvement are based largely on expert opinion and uncontrolled evidence from open trials and observational studies. The need for further properly designed controlled clinical trials is apparent.
Inflammatory myopathies (IM) are a group of muscle diseases occurring both in children and adults. Nailfold videocapillaroscopy (NVC) alterations are described in IM, but available data are ...discordant, including differences between polymyositis (PM) and dermatomyositis (DM). The aim of this study was to describe the capillaroscopic differences between PM and DM patients and possible correlation with clinical and serological features. We analyzed 52 unselected patients with IM in a cross-sectional study in a 6-month period. NVC findings of 29 DM and 23 PM patients were compared with those of 52 patients with primary Raynaud’s phenomenon. Tortuosities, capillary loss, enlarged and giant capillaries, microhemorrhages, and ramified capillaries were scored by a semiquantitative rating; disorganization of the vascular array, avascular areas, and scleroderma pattern were scored as presence/absence. Sex, mean age, and mean disease duration were similar in both groups. Disorganization of the vascular array, enlarged and giant capillaries, capillary loss, and scleroderma-like pattern were observed almost only in IM patients. Significant differences were observed between PM and DM with higher frequency and mean score of NVC changes in DM. In DM patients with disease duration ≤6 months (14/29 patients), capillary density was significantly reduced (
P
= 0.039) and giant capillaries more frequent (
P
= 0.027), compared with patients with longer disease duration, while a scleroderma pattern tended to be more frequent in patients with a disease duration of less than 6 months. On the contrary, no differences were observed for ramified capillaries with regard to disease duration. Capillaroscopic alterations are identified only in DM patients as expression of diffuse microangiopathy; surprisingly, more severe changes were associated with shorter disease duration, while persistence of ramified capillaries with long-standing disease.
Objective. To evaluate the impact of traditional cardiovascular risk factors, carotid atherosclerosis and the effect of anti-platelet/anti-coagulant therapy on the occurrence of severe cranial ...ischaemic events (CIEs) in GCA. Methods. We identified 180 Reggio Emilia (Italy) residents with biopsy-proven GCA diagnosed between 1986 and 2005. We evaluated data on demographics, clinical features, laboratory investigations, cardiovascular risk factors, anti-platelet/anti-coagulant use and carotid atherosclerosis. Results. Systemic signs/symptoms were significantly less frequent (P = 0.004) and ESR and C-reactive protein (CRP) values at diagnosis were significantly lower (P = 0.03 and P = 0.04, respectively) in patients with CIEs. The prevalence of hypertension and ischaemic heart disease was significantly higher in patients with CIEs than in those without (P = 0.01 and P = 0.006, respectively). Patients treated with anti-platelet/anti-coagulant therapy were significantly more likely to suffer CIEs than those without (P = 0.03), while CIEs were significantly associated with ischaemic heart disease in this subset of patients (P = 0.02). By multivariate logistic regression, we found that the best predictors for the development of severe CIEs included the absence of high (>5.38 mg/dl) CRP levels at diagnosis (OR = 0.31, 95% CI 0.08, 1.20), the absence of systemic manifestations (OR = 0.30, 95% CI 0.08, 1.08), the presence of hypertension (OR = 7.77, 95% CI 0.83, 72.76), and a past history of ischaemic heart disease (OR = 8.65, 95% CI 0.92, 80.95). Conclusions. In GCA, hypertension, a past history of ischaemic heart disease and a low inflammatory response are associated with a higher risk of developing severe CIEs.
Interstitial lung disease (ILD) is a severe systemic manifestation of rheumatoid arthritis (RA). High-resolution computed tomography (HRCT) represents the gold standard for the diagnosis of ILD, but ...its routine use for screening programs is not advisable because of both high cost and X-ray exposure. Velcro crackles at lung auscultation occur very early in the course of interstitial pneumonia, and their detection is an indication for HRCT. Recently, we developed an algorithm (VECTOR) to detect the presence of Velcro crackles in pulmonary sounds and showed good results in a small sample of RA patients. The aim of the present investigation was to validate the diagnostic accuracy of VECTOR in a larger population of RA patients, compared with that of the reference standard of HRCT, from a multicentre study.
To avoid X-ray exposure, we enrolled 137 consecutive RA patients who had recently undergone HRCT. Lung sounds of all patients were recorded in 4 pulmonary fields bilaterally with a commercial electronic stethoscope (ES); subsequently, all HRCT images were blindly evaluated by a radiologist, and audio data were analysed by means of VECTOR.
Fifty-nine of 137 patients showed ILD (43.1%). VECTOR correctly classified 115/137 patients, showing a diagnostic accuracy of 83.9% and a sensitivity and specificity of 93.2 and 76.9%, respectively.
VECTOR may represent the first validated tool for the screening of RA patients who are suspected for ILD and who should be directed to HRCT for the diagnosis. Moreover, early identification of RA-ILD could contribute to the design of prospective studies aimed at elucidating unclear aspects of the disease.
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