Carlo Salvarani

Polymyalgia rheumatica and giant-cell arteritis.

Polymyalgia rheumatica and giant-cell arteritis are closely related disorders that aff ect people of middle age and older. They frequently occur together. Both are syndromes of unknown cause, but genetic and environmental factors might have a role in their pathogenesis. The symptoms of polymyalgia rheumatica seem to be related to synovitis of proximal joints and extra-articular synovial structures. Giant-cell arteritis primarily aff ects the aorta and its extracranial branches. The clinical fi ndings in giant-cell arteritis are broad, but commonly include visual loss, headache, scalp tenderness, jaw claudication, cerebrovascular accidents, aortic arch syndrome, thoracic aorta aneurysm, and dissection. Glucocorticosteroids are the cornerstone of treatment of both polymyalgia rheumatica and giant-cell arteritis. Some patients have a chronic course and might need glucocorticosteroids for several years. Adverse events of glucocorticosteroids aff ect more than 50% of patients. Trials of steroid-sparing drugs have yielded confl icting results. A greater understanding of the molecular mechanisms involved in the pathogenesis should provide new targets for therapy.

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.

EULAR recommendations for the management of Behçet disease

Objectives: To develop evidence-based European League Against Rheumatism (EULAR) recommendations for the management of Behçet disease (BD) supplemented where necessary by expert opinion. Methods: 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. Results: 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”. Conclusion: 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.

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.

Primary central nervous system vasculitis: analysis of 101 patients

To analyze the clinical findings, response to therapy, outcome, and incidence of primary central nervous system vasculitis (PCNSV) in a large cohort from a single center

The International Criteria for Behcet's Disease (ICBD): a collaborative study of 27 countries on the sensitivity and specificity of the new criteria

Behçets disease (BD) is a chronic, relapsing, inflammatory vascular disease with no pathognomonic test. Low sensitivity of the currently applied International Study Group (ISG) clinical diagnostic criteria led to their reassessment.

The Incidence of Giant Cell Arteritis in Olmsted County, Minnesota: Apparent Fluctuations in a Cyclic Pattern

The cause of giant cell arteritis is unknown. Many investigators have suggested that environmental factors, such as infectious agents, exposure to sunlight, and contact with birds may be involved in the pathogenesis of this condition [1, 2]. Population-based studies that provide the incidence rate of a disease over time can provide clues about etiologic or environmental factors that influence the risk for the disease. The incidence of giant cell arteritis has already been determined for the population of Olmsted County, Minnesota, from 1950 to 1985 [3]. We determined the incidence from 1986 to 1991 and analyzed the trends in incidence rates over 42 years to generate hypotheses about factors that may be related to the pathogenesis of giant cell arteritis. Methods The details of our epidemiologic methods have been described previously [4]. Our unique medical records linkage system allows ready access to the medical records of all health care providers for the population of Olmsted County, Minnesota, including the Mayo Clinic and its affiliated hospitals; the Olmsted Medical Group and Olmsted Community Hospital; local nursing homes; and the few private practitioners. All medical records (inpatient and outpatient) of Olmsted County residents that showed a surgical index entry of temporal or occipital artery biopsy or a medical diagnosis of giant cell arteritis between 1986 and 1991 were reviewed, and information about clinical manifestations, laboratory findings, and disease course was collected. In cases where the diagnosis was questionable, three rheumatologists reviewed all of the medical information and reached a consensus. The medical records of all patients from the previous study (1950 to 1985) were also reviewed [3], and the two data sets were collated. The diagnoses of giant cell arteritis and polymyalgia rheumatica were made according to the 1990 American College of Rheumatology criteria [5] and the criteria of Chuang and colleagues [6], respectively. Only persons who had been residents of Olmsted County for at least 12 months before the diagnosis of giant cell arteritis were included as incidence cases. Age- and sex-specific incidence rates were calculated using the number of incidence cases as the numerator and population estimates based on decennial census counts as the denominator; linear interpolation was used to estimate population counts for years between censuses. Overall rates were age- and sex-adjusted to the 1980 United States white population. Ninety-five percent CIs were computed for incidence rates. The annual incidence rates were graphically illustrated using a 3-year centered moving average to eliminate some of the random fluctuation over time. The month of onset of the first symptoms related to giant cell arteritis was used to calculate the season-specific incidence rates. A generalized linear model [7] with log-link function and Poisson error structure was used to evaluate the relation between log incidence (the dependent variable) and age, sex, and chronologic time (in 5-year intervals), two-way interaction terms, and higher-order polynomial terms for age and time. The models were fit using GLIM (Generalized Linear Interactive Modelling). The observations used for the regression analysis were the crude incidence rates for both sexes in the following age groups: 50 to 59 years, 60 to 69 years, 70 to 79 years, and 80 or more years; and in the following calendar time periods: 1950-1954, 1955-1959, 1960-1964, 1965-1969, 1970-1974, 1975-1979, 1980-1984, and 1985-1991. The midpoints of the age groups and the calendar time periods were used in the trend analysis. Results Between 1950 and 1991, 125 Olmsted County residents (103 women and 22 men) were diagnosed with giant cell arteritis. Of these, 81 (64.8%) had giant cell arteritis alone and 44 (35.2%) also had polymyalgia rheumatica. One hundred and fifteen (92%) had positive temporal artery biopsies, and all fulfilled the 1990 American College of Rheumatology criteria for giant cell arteritis [5]. Table 1 shows the age- and sex-specific incidence rates, the overall age-adjusted rates for each sex, and these same age-adjusted rates according to time periods. The best generalized linear model analysis of predictors of incidence showed a significant elevation of incidence in women compared with men (P < 0.0001), a significant increase with age (P < 0.0001), and a significant linear effect of calendar time (P = 0.002). This calendar-time effect predicted a 2.6% increase in incidence every 5 years (CI, 0.9% to 4.3%). Table 1. Incidence of Giant Cell Arteritis in Residents of Olmsted County, Minnesota, 1950-1991 Figure 1 shows the annual incidence rates per 100 000 persons 50 years of age or more between 1950 and 1991. Cases appear to have clustered in five peak periods (1953-1955, 1959-1961, 1967-1969, 1974-1976, and 1982-1984), each of which lasted about 3 years. The peaks in this cyclic pattern occurred approximately every 7 years. At every peak, the incidence rate was more than twice the previous level. Plots of the deviance residuals, taken from the generalized linear model, over time did not show a deviation from the linear trend. However, the relatively small number of incidence cases provided us with limited statistical power to detect important nonlinear trends. The trends in incidence among men and women were similar except during the earlier time periods, 1950-1970. The irregular fluctuations seen in men between 1950 and 1970 cannot be interpreted due to the small number of cases (n = 4) diagnosed among men during this time. Figure 1. Annual incidence rates of giant cell arteritis in Olmsted County, Minnesota, per 100 000 persons 50 years of age or older. Plots of the annual incidence rates per 100 000 persons 50 years of age or more showed that, among patients with giant cell arteritis but not polymyalgia rheumatica (n = 81), the five peaks remain clearly delineated. In fact, these peaks were somewhat less evident among patients with giant cell arteritis and polymyalgia rheumatica. Differences in season-specific incidence rates were not statistically significant. Discussion Our results, which show that giant cell arteritis is more common in women and in persons more than 70 years of age (Table 1), confirm the results of earlier studies [8, 9]. We show a statistically significant increase in the incidence of giant cell arteritis over the study period (Table 1), but heightened physician awareness and surveillance may account for this. However, our most remarkable finding was the apparent cyclic fluctuation in the incidence rate over the 42-year study period. This observation has not been previously reported. A regular repeating cyclic pattern in the development of giant cell arteritis over the 42-year period was apparent, with peaks appearing at intervals of about 7 years and lasting about 3 years. Although it seems unlikely that this regular cyclic pattern of incidence rates is random, we could not detect a statistically significant cyclic pattern. To suggest that this pattern is due to differences in disease ascertainment would imply alternating periods of high and low ascertainment; this is not plausible. The diagnosis in most cases (92%) was confirmed by temporal artery biopsy, making overascertainment unlikely. Furthermore, most physicians at our institution are very familiar with the presenting manifestations of giant cell arteritis, and rheumatologic consultation is readily available. Finally, the patients were identified using the medical records linkage system of the Mayo Clinic, which ensures almost complete ascertainment of all cases of any disease diagnosed in Olmsted County dating back 75 years [4]. The cyclic pattern is somewhat less evident in men than in women; this is probably due to the much smaller number of cases occurring among men. The cyclic pattern is also less evident among patients with giant cell arteritis and coexistent polymyalgia rheumatica than among those with giant cell arteritis alone. The exact nature of the relation between giant cell arteritis and polymyalgia rheumatica is uncertain. The differences we observed may reflect an unknown additional factor or factors that influence the development of polymyalgia rheumatica in patients with giant cell arteritis. Illnesses with cyclic frequencies are most often infectious. An infectious cause has been previously postulated for giant cell arteritis and polymyalgia rheumatica [1, 10, 11]. Several reports of conjugal cases have been described and interpreted as evidence of a possible infectious cause [12-14]. Also, the presence of antibodies to intermediate filaments in patients with polymyalgia rheumatica or giant cell arteritis may indicate a viral cause [15] because these antibodies have also been found in serum specimens from patients with viral diseases [16]. Like giant cell arteritis [3, 17-23], other conditions (such as multiple sclerosis) that are suspected of having a viral cause have been noted to have an increased incidence at higher latitudes [24]. This implicates an environmental cause, in particular an infectious agent, that operates with increasing effectiveness or is more common at northern latitudes. We have shown a statistically significant increase in the incidence of giant cell arteritis over the past four decades. Moreover, ours is the first study to report a regular cyclic pattern in giant cell arteritis incidence rates over time. We wish to emphasize, however, that although these results are intriguing, they are hypothesis-generating, and similar studies in other populations are needed to confirm our observations. Nonetheless, our findings support the hypothesis of an infectious cause for giant cell arteritis, perhaps in a genetically predisposed host. We hope that our data will serve as a stimulus for further research into the cause of this condition.

Outcomes of a multicentre randomised clinical trial of etanercept to treat ankylosing spondylitis

Objective: A double blind, randomised, placebo controlled study to evaluate the safety and efficacy of etanercept to treat adult patients with ankylosing spondylitis (AS). Methods: Adult patients with AS at 14 European sites were randomly assigned to 25 mg injections of etanercept or placebo twice weekly for 12 weeks. The primary efficacy end point was an improvement of at least 20% in patient reported symptoms, based on the multicomponent Assessments in Ankylosing Spondylitis (ASAS) response criteria (ASAS 20). Secondary end points included ASAS 50 and ASAS 70 responses and improved scores on individual components of ASAS, the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), acute phase reactants, and spinal mobility tests. Safety was evaluated during scheduled visits. Results: Of 84 patients enrolled, 45 received etanercept and 39 received placebo. Significantly more etanercept patients than placebo patients responded at the ASAS 20 level as early as week 2, and sustained differences were evident up to week 12. Significantly more etanercept patients reported ASAS 50 responses at all times and ASAS 70 responses at weeks 2, 4, and 8; reported lower composite and fatigue BASDAI scores; had lower acute phase reactant levels; and had improved spinal flexion. Etanercept was well tolerated. Most adverse events were mild to moderate; the only between-group difference was injection site reactions, which occurred significantly more often in etanercept patients. Conclusions: Etanercept is a well tolerated and effective treatment for reducing clinical symptoms and signs of AS.

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.