Maria C. Cid

2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides

2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides J. Jennette;R. Falk;P. Bacon;N. Basu;M. Cid;F. Ferrario;L. Flores-Suarez;W. Gross;L. Guillevin;E. Hagen;G. Hoffman;D. Jayne;C. Kallenberg;P. Lamprecht;C. Langford;R. Luqmani;A. Mahr;E. Matteson;P. Merkel;S. Ozen;C. Pusey;N. Rasmussen;A. Rees;D. Scott;U. Specks;J. Stone;K. Takahashi;R. Watts; Arthritis & Rheumatism

EULAR recommendations for the management of primary small and medium vessel vasculitis

Objectives: To develop European League Against Rheumatism (EULAR) recommendations for the management of small and medium vessel vasculitis. Methods: 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. Results: 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. Conclusions: 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.

Infliximab for Maintenance of Glucocorticosteroid-Induced Remission of Giant Cell Arteritis: A Randomized Trial

Context Up to 80% of patients with giant cell arteritis (GCA) experience complications related to glucocorticoid therapy. Case reports suggest that patients with GCA who received infliximab achieved sustained disease remission and independence from glucocorticoids. Contribution Patients with glucocorticoid-induced GCA remission were randomly assigned to infusions of infliximab, 5 mg/kg, or placebo at 0, 2, and 6 weeks and every 8 weeks thereafter. The investigators found that infliximab did not reduce rates of relapse or any secondary end point. Caution The study was small and stopped early (after week 22 of the planned 54 weeks), so it could not definitively identify harms or small benefits. Implication Infliximab is unlikely to cause large reductions in rates of relapse of GCA. The Editors In northern Europe and North America, the estimated annual incidence of giant cell arteritis is 19 to 32 cases per 100000 persons older than 50 years of age. In Mediterranean countries, the annual incidence appears to be lower: 6 to 10 cases per 100000 persons (15). Treatment with glucocorticosteroids dramatically alters the symptoms and course of giant cell arteritis, reducing the likelihood that the patient will develop blindness (6, 7). However, relapses usually occur when glucocorticosteroid dosages are tapered, resulting in frequent re-treatment and glucocorticosteroid dependence and toxicity (810). Approximately 80% of patients with giant cell arteritis will eventually experience at least 1 adverse event attributable to glucocorticosteroids, and about 60% will have 2 or more adverse events. Compared with age- and sex-matched controls, patients with giant cell arteritis have an increased risk for fractures and corticosteroid-related cataracts (9). Adjunctive treatments are needed that would effectively reduce the dose and duration of glucocorticosteroid therapy and provide more durable remissions of giant cell arteritis. Other investigators have evaluated the utility of cytotoxic and anti-inflammatory agents in giant cell arteritis. However, the reports have been anecdotal, of uncontrolled studies, or of controlled studies with conflicting results in terms of efficacy (11, 12). Increased knowledge of cell types and mediators within vessels damaged by giant cell arteritis has led to speculation about the potential therapeutic role of several cytokine antagonists. Interleukin-1, interleukin-6, tumor necrosis factor (TNF), and interferon- have been implicated in contributing to vascular injury in patients with giant cell arteritis (1316). Published case studies reported that some patients with giant cell arteritis or polymyalgia rheumatica who received the antiTNF- agent infliximab had sustained remission and became glucocorticosteroid-independent (17, 18). However, the investigators cautioned that randomized, controlled studies were needed to validate these results. We report the results of the first randomized, placebo-controlled, double-blind, multicenter trial of standardized treatment with glucocorticosteroids and adjunctive treatment with placebo or infliximab in patients with newly diagnosed giant cell arteritis. Methods Design We designed a multicenter, randomized, double-blind, placebo-controlled study to determine whether infliximab added to a standardized program of glucocorticosteroid therapy (equivalent daily doses of prednisone or prednisolone) in patients with newly diagnosed giant cell arteritis would decrease the frequency of relapse, cumulative glucocorticosteroid requirement, and glucocorticosteroid-associated toxicity. The study protocol was approved by the institutional review boards or ethics committees of the individual study sites. The study was conducted according to the current regulations of the U.S. Food and Drug Administration, the International Conference on Harmonization guidelines, and the principles of the Declaration of Helsinki. All patients provided written informed consent before participating in any protocol-specific procedures. An independent safety monitoring committee reviewed safety information during the trial. The first patient was enrolled on 22 October 2003, and the last patient completed the study on 29 July 2005. The primary objective was to obtain preliminary evidence on the safety and efficacy of infliximab therapy in patients with glucocorticoid-induced remission of newly diagnosed giant cell arteritis, as measured by the proportion of patients who were relapse-free through week 22 and the incidence of adverse events. The secondary objective was to further evaluate the preliminary evidence of the efficacy of infliximab therapy, as measured by the proportion of patients who remained relapse-free through week 54, time to first relapse, levels of biochemical markers of inflammation and disease activity, and cumulative dose of glucocorticosteroids. Setting The study was conducted at 22 sites in the United States, United Kingdom, Belgium, Italy, and Spain. Participants To be eligible for the study, patients must have had a diagnosis of giant cell arteritis within 4 weeks of enrollment, satisfied the American College of Rheumatology criteria for giant cell arteritis (19), had an erythrocyte sedimentation rate 40 mm or greater in the first hour at the time of diagnosis, and achieved clinical remission before randomization. For at least 1 week before randomization, patients were required to be receiving prednisone or prednisolone at a stable dosage of 40 to 60 mg/d, have a normal erythrocyte sedimentation rate (<40 mm in the first hour, as determined by using the Westergren method), and have no symptoms or signs of active giant cell arteritis. Patients were excluded if they had received a diagnosis of giant cell arteritis or polymyalgia rheumatica more than 4 weeks before screening, did not respond to glucocorticosteroid therapy within 5 days of initiation of therapy, received intravenous glucocorticosteroid therapy with an equivalent dose of methylprednisolone (>1000 mg/d for >3 days), or received other forms of immunosuppressive therapy (such as methotrexate, azathioprine, or other cytotoxic agents) or any investigational or biological agents within the 3 months before screening. Patients with screening blood test results within the following ranges were also excluded: leukocyte count less than 3.5109 cells/L, neutrophil count less than 1.5109 cells/L, hemoglobin level less than 85 g/L, platelet count less than 100109 cells/L, or hepatic aminotransferase or alkaline phosphatase levels greater than 3 times the upper limit of normal. We excluded patients with serious or chronic infections in the previous 3 months; opportunistic infections within the 6 months before screening; cancer within the 5 years before screening (with the exception of treated and cured squamous or basal cell carcinoma of the skin); a history of severe congestive heart failure or demyelinating disease; current signs or symptoms of severe, progressive, or uncontrolled renal, hepatic, hematologic, gastrointestinal, endocrine, pulmonary, cardiac, neurologic, or cerebral disease; a transplanted organ (with the exception of corneal transplantation done more than 3 months before screening); or evidence of active or previous tuberculosis. Randomization and Intervention Patients were randomly assigned in a 2:1 ratio to receive infliximab, 5 mg/kg, or placebo by using adaptive treatment allocation (20, 21) stratified by baseline glucocorticosteroid dosage (40 to 50 mg/d or 51 to 60 mg/d prednisone equivalent). Patients received infusions at weeks 0, 2, and 6 and every 8 weeks thereafter. Allocation to treatment group was performed by using a central randomization procedure through an interactive voice response system. Patients, investigators, and study personnel were blinded to treatment assignments during the study; the site pharmacists, who prepared study medication, were not blinded to this information. Infliximab and placebo were supplied as sterile, white, lyophilized powders that were reconstituted with sterile water for injection. The reconstituted placebo solution contained the same excipients as the infliximab solution but did not contain infliximab. Glucocorticosteroid dosages were tapered according to a predefined schedule (Table 1). Each week, the daily dose of prednisone or prednisolone was decreased by 10 mg until the dosage reached 20 mg/d. It was then tapered by 2.5 mg until it reached 10 mg/d and then by 1 mg until the dosage was 0 mg/d. In the absence of a relapse, this schedule results in a glucocorticosteroid dosage of 10 mg/d after 4 months and no glucocorticosteroid use after 6 months. If a relapse occurred, the patient was to resume treatment with the previous higher dose of prednisone or prednisolone that provided disease remission, plus 10 mg/d. If the relapse resolved within 72 hours, the patient was to continue receiving that dosage for 2 weeks and then resume tapering according to the protocol. If relapse did not resolve within 72 hours, the patient was to receive another increase of 10 mg and resume treatment according to the protocol. Table 1. Schedule of Dosage Tapering for Glucocorticosteroid Therapy* If relapse included visual symptoms, the patient was to receive at least 40 mg/d or the previous higher dosage of prednisone or prednisolone, plus 10 mg (whichever was higher). If the visual symptoms improved within 48 hours, the patient was to resume tapering according to the protocol above. If the visual symptoms did not resolve within 48 hours, the patients vision was threatened, or there was concern about any other catastrophic event, the investigator was to take any measures necessary according to clinical judgment to treat the patient, including but not limited to increasing the glucocorticosteroid dosage to more than 60 mg/d. If a patient received more than 60 mg of oral prednisone or prednisolone daily or more than 1000 mg of intravenous glucocorticosteroid daily for more than

EULAR Recommendations for the management of large vessel vasculitis

Objectives: To develop European League Against Rheumatism (EULAR) recommendations for the management of large vessel vasculitis. Methods: 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. Results: 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. Conclusions: 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.

2012 provisional classification criteria for polymyalgia rheumatica: a European League Against Rheumatism/American College of Rheumatology collaborative initiative

The objective of this study was to develop EULAR/ACR classification criteria for polymyalgia rheumatica (PMR). Candidate criteria were evaluated in a 6-month prospective cohort study of 125 patients with new onset PMR and 169 non-PMR comparison subjects with conditions mimicking PMR. A scoring algorithm was developed based on morning stiffness >45 minutes (2 points), hip pain/limited range of motion (1 point), absence of RF and/or ACPA (2 points), and absence of peripheral joint pain (1 point). A score ≥4 had 68% sensitivity and 78% specificity for discriminating all comparison subjects from PMR. The specificity was higher (88%) for discriminating shoulder conditions from PMR and lower (65%) for discriminating RA from PMR. Adding ultrasound, a score ≥5 had increased sensitivity to 66% and specificity to 81%. According to these provisional classification criteria, patients ≥50 years old presenting with bilateral shoulder pain, not better explained by an alternative pathology, can be classified as having PMR in the presence of morning stiffness>45 minutes, elevated CRP and/or ESR and new hip pain. These criteria are not meant for diagnostic purposes.

Outcomes from studies of antineutrophil cytoplasm antibody associated vasculitis: a systematic review by the European League Against Rheumatism Systemic Vasculitis Task Force

Objectives: We undertook a systematic literature review as a background to the European League Against Rheumatism (EULAR) recommendations for conducting clinical trials in anti-neutrophil cytoplasm antibody associated vasculitis (AAV), and to assess the quality of evidence for outcome measures in AAV. Methods: Using a systematic Medline search, we categorised the identified studies according to diagnoses. Factors affecting remission, relapse, renal function and overall survival were identified. Results: A total of 44 papers were reviewed from 502 identified by our search criteria. There was considerable inconsistency in definitions of end points. Remission rates varied from 30% to 93% in Wegener granulomatosis (WG), 75% to 89% in microscopic polyangiitis (MPA) and 81% to 91% in Churg–Strauss syndrome (CSS). The 5-year survival for WG, MPA and CSS was 74–91%, 45–76% and 60–97%. Relapse (variably defined) was common in the first 2 years but the frequency varied: 18% to 60% in WG, 8% in MPA, and 35% in CSS. The rate of renal survival in WG varied from 23% at 15 months to 23% at 120 months. Methods used to assess morbidity varied between studies. Ignoring the variations in definitions of the stage of disease, factors influencing remission, relapse, renal and overall survival included immunosuppressive therapy used, type of organ involvement, presence of ANCA, older age and male gender. Conclusions: Factors influencing remission, relapse, renal and overall survival include the type of immunosuppressive therapy used, pattern of organ involvement, presence of ANCA, older age and male gender. Methodological variations between studies highlight the need for a consensus on terminology and definitions for future conduct of clinical studies in AAV.

Estradiol enhances leukocyte binding to tumor necrosis factor (TNF)-stimulated endothelial cells via an increase in TNF-induced adhesion molecules E-selectin, intercellular adhesion molecule type 1, and vascular cell adhesion molecule type 1.

Adhesion of leukocytes to endothelial cells is a critical step in the development of acute and chronic inflammatory lesions. We report here that estradiol treatment of cultured human umbilical vein endothelial cells stimulated up to a twofold increase in TNF-induced adhesion of both polymorphonuclear leukocytes and PMA-activated peripheral blood mononuclear cells. This effect was more evident (threefold increase) when endothelial cells were cultured on the basement membrane glycoprotein laminin. Progesterone, but not testosterone, had a similar stimulatory effect. Estradiol also promoted a slight increase in interferon gamma-stimulated endothelial cell adherence for peripheral blood mononuclear cells, but no effect of estradiol was observed when adhesion of leukocytes to endothelial cells was stimulated with IL-1 or IL-4. The estradiol-induced increase in leukocyte binding to human umbilical vein endothelial cells was partially blocked by antibodies to the adhesion molecules E-selectin, intercellular adhesion molecule type 1 (ICAM-1), and vascular cell adhesion molecule type 1 (VCAM-1). Indirect immunofluorescence techniques showed that estradiol produces an increase in TNF-induced cell surface expression of these molecules. Northern blot analysis demonstrated a transient increase in TNF-induced expression of mRNA for E-selectin, ICAM-1, and VCAM-1 in endothelial cells treated with estradiol. Our data demonstrate that estradiol has important regulatory functions in promoting leukocyte-endothelial cell interactions that might contribute to the observed predominance in females of some autoimmune inflammatory diseases.

Expression of an Estrogen Receptor by Human Coronary Artery and Umbilical Vein Endothelial Cells

BACKGROUND Premenopausal women have much lower susceptibility to coronary artery disease than do men or postmenopausal women. It has been proposed that estrogen plays a role in cardioprotection, but little information is available regarding the mechanism by which estrogen may help to protect the vasculature. Here, we describe an estrogen receptor (ER) in human coronary artery and umbilical vein endothelial cells. METHODS AND RESULTS Human umbilical vein endothelial cells and human coronary artery endothelial cells were cultured in hormone-free medium for 48 hours before experiments. Estradiol (3.7 nmol/L) added to cultures promoted proliferation by a mechanism that is inhibited by the specific ER antagonist ICI182,780. Estradiol-treated cells incorporated twice the [3H]thymidine of hormone-free cells; this increase was prevented by ICI182,780. Endothelial cells from both sources stained in a nuclear pattern with an ER-specific antibody. Ribonuclease protection assay detected mRNA for the ER. Ligand-binding studies estimated 2 x 10(4) to 8 x 10(4) receptors per cell and a Kd of approximately 5 nmol/L. Interaction of ERs with a consensus estrogen response element was shown by an electrophoretic mobility shift assay. In addition, an antibody against the ER supershifted the protein-DNA complex. CONCLUSIONS These studies define the presence of an ER in human coronary artery and umbilical vein endothelial cells. They support the hypothesis that cardioprotective effects of estrogen are mediated, at least in part, through a classic steroid hormone receptor mechanism.

Association between strong inflammatory response and low risk of developing visual loss and other cranial ischemic complications in giant cell (temporal) arteritis

OBJECTIVE To identify clinical and biochemical parameters that have good predictive value for identifying giant cell (temporal) arteritis (GCA) patients who are at high or low risk of developing cranial ischemic events. METHODS In this multicenter study, records of patients at 3 university hospitals in Barcelona were reviewed retrospectively. Two hundred consecutive patients with biopsy-proven GCA were studied. RESULTS Thirty-two patients developed irreversible cranial ischemic complications. The duration of clinical symptoms before diagnosis was similar in patients with and those without ischemic events. Patients with ischemic complications less frequently had fever (18.8% versus 56.9%) and weight loss (21.9% versus 62%) and more frequently had amaurosis fugax (32.3% versus 6%) and transient diplopia (15.6% versus 3.6%). Patients with ischemic events had lower erythrocyte sedimentation rates (ESR) (82.7 mm/hour versus 104.4 mm/hour) and higher concentrations of hemoglobin (12.2 gm/dl versus 10.9 gm/dl) and albumin (37.4 gm/liter versus 32.7 gm/liter). Clinical inflammatory status and biologic inflammatory status were defined empirically (clinical: fever and weight loss; biologic: ESR > or =85 mm/hour and hemoglobin < 11.0 gm/dl). Patients not showing a clinical and biologic inflammatory response were at high risk of developing ischemic events (odds ratio [OR] 5, 95% confidence interval [95% CI] 2.05-12.2). The risk was greatly reduced among patients with either a clinical (OR 0.177, 95% CI 0.052-0.605) or a biologic (OR 0.226, 95% CI 0.076-0.675) inflammatory reaction. No patient with both a clinical and a biologic response developed ischemic events. CONCLUSION The presence of a strong acute-phase response defines a subgroup of patients at very low risk of developing cranial ischemic complications. Our findings provide a rationale for testing less aggressive treatment schedules in these individuals. Conversely, a low inflammatory response and the presence of transient cranial ischemic events provide a high risk of developing irreversible ischemic complications and require a prompt therapeutic intervention.

EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis

In this article, the 2009 European League Against Rheumatism (EULAR) recommendations for the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) have been updated. The 2009 recommendations were on the management of primary small and medium vessel vasculitis. The 2015 update has been developed by an international task force representing EULAR, the European Renal Association and the European Vasculitis Society (EUVAS). The recommendations are based upon evidence from systematic literature reviews, as well as expert opinion where appropriate. The evidence presented was discussed and summarised by the experts in the course of a consensus-finding and voting process. Levels of evidence and grades of recommendations were derived and levels of agreement (strengths of recommendations) determined. In addition to the voting by the task force members, the relevance of the recommendations was assessed by an online voting survey among members of EUVAS. Fifteen recommendations were developed, covering general aspects, such as attaining remission and the need for shared decision making between clinicians and patients. More specific items relate to starting immunosuppressive therapy in combination with glucocorticoids to induce remission, followed by a period of remission maintenance; for remission induction in life-threatening or organ-threatening AAV, cyclophosphamide and rituximab are considered to have similar efficacy; plasma exchange which is recommended, where licensed, in the setting of rapidly progressive renal failure or severe diffuse pulmonary haemorrhage. These recommendations are intended for use by healthcare professionals, doctors in specialist training, medical students, pharmaceutical industries and drug regulatory organisations.