Trial of Tocilizumab in Giant-Cell Arteritis Stone, John H; Tuckwell, Katie; Dimonaco, Sophie ...
The New England journal of medicine,
07/2017, Letnik:
377, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Treatment of giant-cell arteritis with tocilizumab, an interleukin-6 receptor alpha inhibitor, while prednisone was tapered over a 26-week period resulted in higher rates of sustained remission than ...prednisone tapering plus placebo and reduced the total prednisone dose.
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
F-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.
Since the publication of the EULAR recommendations for the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in 2016, several randomised clinical trials have been ...published that have the potential to change clinical care and support the need for an update.
Using EULAR standardised operating procedures, the EULAR task force undertook a systematic literature review and sought opinion from 20 experts from 16 countries. We modified existing recommendations and created new recommendations.
Four overarching principles and 17 recommendations were formulated. We recommend biopsies and ANCA testing to assist in establishing a diagnosis of AAV. For remission induction in life-threatening or organ-threatening AAV, we recommend a combination of high-dose glucocorticoids (GCs) in combination with either rituximab or cyclophosphamide. We recommend tapering of the GC dose to a target of 5 mg prednisolone equivalent/day within 4-5 months. Avacopan may be considered as part of a strategy to reduce exposure to GC in granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA). Plasma exchange may be considered in patients with rapidly progressive glomerulonephritis. For remission maintenance of GPA/MPA, we recommend rituximab. In patients with relapsing or refractory eosinophilic GPA, we recommend the use of mepolizumab. Azathioprine and methotrexate are alternatives to biologics for remission maintenance in AAV.
In the light of recent advancements, these recommendations provide updated guidance on AAV management. As substantial data gaps still exist, informed decision-making between physicians and patients remains of key relevance.
This multicentre study was performed to evaluate the diagnostic accuracy of a wide spectrum of novel technologies nowadays available for detection of myeloperoxidase (MPO) and proteinase 3 ...(PR3)-antineutrophil cytoplasmic antibodies (ANCAs).
Sera (obtained at the time of diagnosis) from 251 patients with ANCA-associated vasculitis (AAV), including granulomatosis with polyangiitis and microscopic polyangiitis, and from 924 disease controls were tested for the presence of cytoplasmic pattern/perinuclear pattern and atypical ANCA (A-ANCA) by indirect immunofluorescence (IIF) (at two sites) and for the presence of PR3-ANCA and MPO-ANCA by eight different immunoassays.
The area under the curve (AUC) of the receiver operating characteristic curve to discriminate AAV from controls was 0.923 (95% CI 0.902 to 0.944) and 0.843 (95% CI 0.814 to 0.871) for the two IIF methods. For the antigen-specific immunoassays, the AUC varied between 0.936 (95% CI 0.912 to 0.960) and 0.959 (95% CI 0.941 to 0.976), except for one immunoassay for which the AUC was 0.919 (95% CI 0.892 to 0.945).
Our comparison of various ANCA detection methods showed (i) large variability between the two IIF methods tested and (ii) a high diagnostic performance of PR3-ANCA and MPO-ANCA by immunoassay to discriminate AAV from disease controls. Consequently, dual IIF/antigen-specific immunoassay testing of each sample is not necessary for maximal diagnostic accuracy. These results indicate that the current international consensus on ANCA testing for AAV needs revision.
The previously reported randomised controlled trial of a consensus regimen of pulse cyclophosphamide suggested that it was as effective as a daily oral (DO) cyclophosphamide for remission induction ...of antineutrophil cytoplasm autoantibodies-associated systemic vasculitis when both were combined with the same glucocorticoid protocol (CYCLOPS study (Randomised trial of daily oral versus pulse Cyclophosphamide as therapy for ANCA-associated Systemic Vasculitis published de groot K, harper L et al Ann Int Med 2009)). The study had limited power to detect a difference in relapse. This study describes the long-term outcomes of patients in the CYCLOPS study.
Long-term outcomes were ascertained retrospectively from 148 patients previously recruited to the CYCLOPS Trial. Data on survival, relapse, immunosuppressive treatment, cancer incidence, bone fractures, thromboembolic disease and cardiovascular morbidity were collected from physician records retrospectively. All patients were analysed according to the group to which they were randomised.
Median duration of follow-up was 4.3 years (IQR, 2.95-5.44 years). There was no difference in survival between the two limbs (p=0.92). Fifteen (20.8%) DO and 30 (39.5%) pulse patients had at least one relapse. The risk of relapse was significantly lower in the DO limb than the pulse limb (HR=0.50, 95% CI 0.26 to 0.93; p=0.029). Despite the increased risk of relapse in pulse-treated patients, there was no difference in renal function at study end (p=0.82). There were no differences in adverse events between the treatment limbs.
Pulse cyclophosphamide is associated with a higher relapse risk than DO cyclophosphamide. However, this is not associated with increased mortality or long-term morbidity. Although the study was retrospective, data was returned in 90% of patients from the original trial.
Objective
To evaluate the safety and efficacy of belimumab as adjunctive therapy to maintain remission in antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV).
Methods
In this ...multicenter, double‐blind, placebo‐controlled study, patients with AAV (ages ≥18 years) were randomized 1:1 to receive azathioprine (2 mg/kg/day), low‐dose oral glucocorticoids (≤10 mg/day), and either intravenous belimumab (10 mg/kg) or placebo, following remission induction with rituximab or cyclophosphamide along with glucocorticoids. The primary end point was time to first protocol‐specified event (PSE), with first PSE defined as a Birmingham Vasculitis Activity Score (BVAS) of ≥6, presence of ≥1 major BVAS item, or receipt of prohibited medications for any reason, resulting in treatment failure (adjusted for ANCA type proteinase 3 (PR3) or myeloperoxidase (MPO), disease stage at induction, and induction regimen). Vasculitis relapse was defined as the PSE of either a BVAS activity score of ≥6 or receipt of prohibited medications for vasculitis. Changes in treatment practice led to truncation of the study population from ~300 patients to ~100 patients.
Results
The intent‐to‐treat population totaled 105 patients with AAV, of whom 52 (40 with PR3‐ANCAs, 12 with MPO‐ANCAs) received placebo and 53 (41 with PR3‐ANCAs, 12 with MPO‐ANCAs) received belimumab; 27 of the patients were in rituximab‐induced disease remission, while 78 were in cyclophosphamide‐induced disease remission at baseline. Compared with placebo, treatment with belimumab did not reduce the risk of a PSE (adjusted hazard ratio HR 1.07, 95% confidence interval 95% CI 0.44–2.59; P = 0.884) or vasculitis relapse (adjusted HR 0.88, 95% CI 0.29–2.65; P = 0.821). The overall rate of PSEs was low (11 21.2% of 52 patients receiving placebo, 10 18.9% of 53 patients receiving belimumab). Vasculitis relapse in the placebo group (n = 8) occurred independent of the induction regimen, disease stage, or ANCA type. All vasculitis relapses in the belimumab group (n = 6) occurred in patients who had PR3‐ANCA–associated vasculitis with cyclophosphamide‐induced disease remission. Adverse events occurred in 49 (92.5%) of 53 patients receiving belimumab and 43 (82.7%) of 52 patients receiving placebo, with no new safety concerns.
Conclusion
Belimumab plus azathioprine and glucocorticoids for the maintenance of remission in AAV did not reduce the risk of relapse.
Performing a temporal artery biopsy is still the easiest way to diagnose giant cell arteritis.
However, this biopsy is not always positive, even not in patients with prominent cranial symptoms. In ...these cases, positron emission tomography with 18-fluorodeoxyglucose as a tracer is a valid alternative.
This nuclear technique has demonstrated that involvement of large arteries such as the aorta or the subclavian arteries occurs in 50 to 80% of patients.
Ultrasonographic examination of an inflamed temporal artery can demonstrate a “halo”, corresponding to edema of the intimal layer of the artery. Only in very experienced hands, this non-invasive technique can replace a surgical biopsy.
Magnetic resonance imaging and computerized tomographic scanning are not used in the diagnosis of giant cell arteritis, but these techniques can visualize the extent of the disease, e.g. to the aorta with possible aortitis or to a partical artery.
La biopsie chirurgicale de l’artère temporale reste la façon la plus directe de diagnostiquer une maladie de Horton. Pourtant, la biopsie n’est pas positive dans 100 % des cas, même pas chez les patients atteints de symptômes purement crâniaux.
Ici, la tomographieparémission de positons peut venir en aide. Cette technique nucléaire a démontré que la maladie de Horton touche les grands vaisseaux comme l’aorte ou les artères subclavières dans 50 à 80 % des cas.
L’ultrasonographie de l’artère temporale touchée par l’inflammation peut révéler un halo, correspondant à un œdème intimal. Confiée à des praticiens très expérimentés, l’ultrasonographie peut remplacer la biopsie chirurgicale.
Imagerie par résonance magnétique et la tomodensitométrie ne sont pas employés pour diagnostiquer la maladie de Horton, mais ces techniques peuvent visualiser une atteinte de l’aorte avec une aortite ou une inflammation d’une artère particulière.
Objective
This study was undertaken to evaluate glucocorticoid dosages and serologic findings in patients with giant cell arteritis (GCA) flares.
Methods
Patients with GCA were randomly assigned to ...receive double‐blind dosing with either subcutaneous tocilizumab (TCZ) 162 mg weekly plus 26‐week prednisone taper (TCZ‐QW + Pred‐26), every‐other‐week TCZ plus 26‐week prednisone taper (TCZ‐Q2W + Pred‐26), placebo plus 26‐week prednisone taper (PBO + Pred‐26), or placebo plus 52‐week prednisone taper (PBO + Pred‐52). Outcome measures were prednisone dosage, C‐reactive protein (CRP) level, and erythrocyte sedimentation rate (ESR) at the time of flare.
Results
One hundred patients received TCZ‐QW + Pred‐26, 49 received TCZ‐Q2W + Pred‐26, 50 received PBO + Pred‐26, and 51 received PBO + Pred‐52. Of the 149 TCZ‐treated patients, 36 (24%) experienced flare, 23 (64%) of whom were still receiving prednisone (median dosage 2.0 mg/day). Among 101 PBO + Pred–treated patients, 59 (58%) experienced flare, 45 (76%) of whom were receiving prednisone (median dosage 5.0 mg/day). Many flares occurred while patients were taking >10 mg/day prednisone: 9 (25%) in the TCZ groups and 13 (22%) in the placebo groups. Thirty‐three flares (92%) in TCZ‐treated groups and 20 (34%) in PBO + Pred–treated groups occurred with normal CRP levels. More than half of the PBO + Pred–treated patients had elevated CRP levels without flares. Benefits of the TCZ and prednisone combination over prednisone alone for remission induction were apparent by 8 weeks.
Conclusion
Most GCA flares occurred while patients were still receiving prednisone. Acute‐phase reactant levels were not reliable indicators of flare in patients treated with TCZ plus prednisone or with prednisone alone. The addition of TCZ to prednisone facilitates earlier GCA control.
Atypical manifestations have been described in patients with ANCA-associated vasculitides (AAV), such as pachymeningitis, orbital mass or chronic periaortitis. Because these manifestations have been ...associated to the spectrum of IgG4-related disease (IgG4-RD), we hypothesized that both diseases could overlap.
We conducted a European retrospective multicenter observational study including patients fulfilling ACR and Chapel Hill criteria for AAV and IgG4-RD Comprehensive Diagnostic Criteria.
Eighteen patients were included (median age 55.5years, 13 men). AAV and IgG4-RD were diagnosed concomitantly in 13/18 (72%) patients; AAV preceded IgG4-RD in 3/18 (17%) while IgG4-RD preceded AAV in 2/18 (11%). AAV diagnoses included granulomatosis with polyangiitis in 14 (78%), microscopic polyangiitis in 3 (17%), and eosinophilic granulomatosis with polyangiitis in one case. IgG4-RD diagnosis included definite IgG4-RD in 5 (28%) cases, probable IgG4-RD in 5 (28%) and possible IgG4-RD in 8 (44%). IgG4-RD manifestations were chronic periaortitis in 9/18 (50%) patients, orbital mass and tubulointerstitial nephritis in 4 (22%) cases, prevertebral fibrosis in 3 (17%), pachymeningitis and autoimmune pancreatitis in 2 (11%) cases. Patients required median number of 2 (range 0–4) lines of immunosuppressants in combination with glucocorticoids. During the follow-up (median 49,8months, range 17,25–108months), AAV manifestations relapsed in 10/18 (56%) cases and IgG4-RD lesions in 5/18 (28%). When used, mainly for relapses, rituximab showed response in all cases.
AAV and IgG4-RD may overlap. Clinicians should consider that atypical manifestations during AAV could be related to IgG4-RD rather than to refractory granulomatous or vasculitic lesions.
•ANCA-associated vasculitis and IgG4-related diseases may overlap, mainly in patients with granulomatosis with polyangiitis.•IgG4-related diseases manifestations were mainly chronic periaortitis, orbital mass and tubulointerstitial nephritis.•Rituximab could be preferentially used in these overlap syndromes to treat both diseases.
Abstract Objective To report entry criteria and clinical features of patients with newly diagnosed and relapsing giant cell arteritis (GCA) enrolled in a randomized trial of tocilizumab, an ...interleukin-6 receptor-alpha inhibitor. Methods Newly diagnosed GCA was defined as diagnosis ≤6 weeks before baseline. Relapsing GCA was defined as diagnosis >6 weeks before baseline with ≥2 consecutive weeks of prednisone ≥40 mg/day. All patients had active GCA within 6 weeks of baseline. All statistical results are exploratory. Results Of 251 patients, 119 (47%) had newly diagnosed and 132 (53%) had relapsing GCA. Mean age was 69 years in both subsets; 75% were women. Relapsing patients were heavier difference in means (95% CI): women, 4.18 kg (0.49–7.87, P = 0.027); men, 8.25 kg (1.42–15.09, P = 0.019) and had higher mean body mass index difference in means (95% CI): women, 1.72 kg/m2 (0.44–2.99, P = 0.009); men, 2.85 kg/m2 (0.32 –5.37, P = 0.028). Relapsers had higher baseline prevalence of depression (16% vs. 4%) and osteopenia/osteoporosis (33% vs. 23%, P = 0.002 and P = 0.062, respectively). At diagnosis, 67% had new-onset headaches; 34% had mouth pain/jaw claudication. One-fifth had polymyalgia rheumatica symptoms but no cranial manifestations; 62% had positive temporal artery biopsy findings; 37% were enrolled on the basis of cross-sectional imaging study findings. Conclusions Demographics of the GiACTA population reflect the epidemiologic profile of GCA. Baseline comorbidities associated with glucocorticoids were more prevalent among relapsing patients than among those with newly diagnosed disease, highlighting the need for new GCA treatment options. More than one-third of patients were enrolled based on large-vessel imaging.
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