Ignazio Olivieri

The Assessment of SpondyloArthritis international Society classification criteria for peripheral spondyloarthritis and for spondyloarthritis in general

Objective To evaluate new classification criteria for peripheral spondyloarthritis (SpA) in patients with SpA with peripheral manifestations only. Methods In this Assessment of SpondyloArthritis international Society (ASAS) study, two prespecified sets of criteria were compared against the European Spondylarthropathy Study Group (ESSG) and Amor criteria in newly referred consecutive patients with undiagnosed peripheral arthritis, and/or enthesitis, and/or dactylitis that usually began before 45 years of age. The clinical diagnosis (SpA vs no SpA) made by the ASAS rheumatologist served as reference standard. Results In all, 24 ASAS centres included 266 patients, with a final diagnosis of SpA being made in 66.2%. After adjustments a final set of criteria showed the best balance between sensitivity (77.8%) and specificity (82.9%): arthritis and/or enthesitis and/or dactylitis plus (A) one or more of the following parameters: psoriasis, inflammatory bowel disease, preceding infection, human leucocyte antigen B27, uveitis, sacroiliitis on imaging, or (B) two or more other parameters: arthritis, enthesitis, dactylitis, inflammatory back pain in the past, family history of SpA. The new criteria performed better than modified versions of the ESSG (sensitivity 62.5%, specificity 81.1%) and the Amor criteria (sensitivity 39.8%, specificity 97.8%), particularly regarding sensitivity. In the entire ASAS population of 975 patients the combined use of ASAS criteria for axial SpA and ASAS criteria for peripheral SpA also had a better balance (sensitivity 79.5%, specificity 83.3%) than the modified ESSG (sensitivity 79.1%, specificity 68.8%) and Amor criteria (sensitivity 67.5%, specificity 86.7%), respectively. Conclusions The new ASAS classification criteria for peripheral SpA performed well in patients presenting with peripheral arthritis, enthesitis and/or dactylitis.

ASAS/EULAR recommendations for the management of ankylosing spondylitis

Objective: To develop evidence based recommendations for the management of ankylosing spondylitis (AS) as a combined effort of the ‘ASsessment in AS’ international working group and the European League Against Rheumatism. Methods: Each of the 22 participants was asked to contribute up to 15 propositions describing key clinical aspects of AS management. A Delphi process was used to select 10 final propositions. A systematic literature search was then performed to obtain scientific evidence for each proposition. Outcome data for efficacy, adverse effects, and cost effectiveness were abstracted. The effect size, relative risk, number needed to treat, and incremental cost effectiveness ratio were calculated. On the basis of the search results, 10 major recommendations for the management of AS were constructed. The strength of recommendation was assessed based on the strength of the literature evidence, risk-benefit trade-off, and clinical expertise. Results: The final recommendations considered the use of non-steroidal anti-inflammatory drugs (NSAIDs) (conventional NSAIDs, coxibs, and co-prescription of gastroprotective agents), disease modifying antirheumatic drugs, treatments with biological agents, simple analgesics, local and systemic steroids, non-pharmacological treatment (including education, exercise, and physiotherapy), and surgical interventions. Three general recommendations were also included. Research evidence (categories I–IV) supported 11 interventions in the treatment of AS. Strength of recommendation varied, depending on the category of evidence and expert opinion. Conclusion: Ten key recommendations for the treatment of AS were developed and assessed using a combination of research based evidence and expert consensus. Regular updating will be carried out to keep abreast of new developments in the management of AS.

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.

The development of Assessment of SpondyloArthritis international Society classification criteria for axial spondyloarthritis (part I): classification of paper patients by expert opinion including uncertainty appraisal

Objective: Non-radiographic axial spondyloarthritis (SpA) is characterised by a lack of definitive radiographic sacroiliitis and is considered an early stage of ankylosing spondylitis. The objective of this study was to develop candidate classification criteria for axial SpA that include patients with but also without radiographic sacroiliitis. Methods: Seventy-one patients with possible axial SpA, most of whom were lacking definite radiographic sacroiliitis, were reviewed as “paper patients” by 20 experts from the Assessment of SpondyloArthritis international Society (ASAS). Unequivocally classifiable patients were identified based on the aggregate expert opinion in conjunction with the expert-reported level of certainty of their judgement. Draft criteria for axial SpA were formulated and tested using classifiable patients. Results: Active sacroiliitis on magnetic resonance imaging (MRI) (odds ratio 45, 95% CI 5.3 to 383; p<0.001) was strongly associated with the classification of axial SpA. The knowledge of MRI findings led to a change in the classification of 21.1% of patients. According to the first set of candidate criteria (sensitivity 97.1%; specificity 94.7%) a patient with chronic back pain is classified as axial SpA in the presence of sacroiliitis by MRI or x rays in conjunction with one SpA feature or, if sacroilitiis is absent, in the presence of at least three SpA features. In a second set of candidate criteria, inflammatory back pain is obligatory in the clinical arm (sensitivity 86.1%; specificity 94.7%). Conclusion: The ASAS group has developed candidate criteria for the classification of axial SpA that include patients without radiographic sacroiliitis. The candidate criteria need to be validated in an independent international study.

New criteria for inflammatory back pain in patients with chronic back pain: a real patient exercise by experts from the Assessment of SpondyloArthritis international Society (ASAS)

Objective: Inflammatory back pain (IBP) is an important clinical symptom in patients with axial spondyloarthritis (SpA), and relevant for classification and diagnosis. In the present report, a new approach for the development of IBP classification criteria is discussed. Methods: Rheumatologists (n = 13) who are experts in SpA took part in a 2-day international workshop to investigate 20 patients with back pain and possible SpA. Each expert documented the presence/absence of clinical parameters typical for IBP, and judged whether IBP was considered present or absent based on the received information. This expert judgement was used as the dependent variable in a logistic regression analysis in order to identify those individual IBP parameters that contributed best to a diagnosis of IBP. The new set of IBP criteria was validated in a separate cohort of patients (n = 648). Results: Five parameters best explained IBP according to the experts. These were: (1) improvement with exercise (odds ratio (OR) 23.1); (2) pain at night (OR 20.4); (3) insidious onset (OR 12.7); (4) age at onset <40 years (OR 9.9); and (5) no improvement with rest (OR 7.7). If at least four out of these five parameters were fulfilled, the criteria had a sensitivity of 77.0% and specificity of 91.7% in the patients participating in the workshop, and 79.6% and 72.4%, respectively, in the validation cohort. Conclusion: This new approach with real patients defines a set of IBP definition criteria using overall expert judgement on IBP as the gold standard. The IBP experts’ criteria are robust, easy to apply and have good face validity.

Treating spondyloarthritis, including ankylosing spondylitis and psoriatic arthritis, to target: recommendations of an international task force

Background Therapeutic targets have been defined for diseases like diabetes, hypertension or rheumatoid arthritis and adhering to them has improved outcomes. Such targets are just emerging for spondyloarthritis (SpA). Objective To define the treatment target for SpA including ankylosing spondylitis and psoriatic arthritis (PsA) and develop recommendations for achieving the target, including a treat-to-target management strategy. Methods Based on results of a systematic literature review and expert opinion, a task force of expert physicians and patients developed recommendations which were broadly discussed and voted upon in a Delphi-like process. Level of evidence, grade and strength of the recommendations were derived by respective means. The commonalities between axial SpA, peripheral SpA and PsA were discussed in detail. Results Although the literature review did not reveal trials comparing a treat-to-target approach with another or no strategy, it provided indirect evidence regarding an optimised approach to therapy that facilitated the development of recommendations. The group agreed on 5 overarching principles and 11 recommendations; 9 of these recommendations related commonly to the whole spectrum of SpA and PsA, and only 2 were designed separately for axial SpA, peripheral SpA and PsA. The main treatment target, which should be based on a shared decision with the patient, was defined as remission, with the alternative target of low disease activity. Follow-up examinations at regular intervals that depend on the patients status should safeguard the evolution of disease activity towards the targeted goal. Additional recommendations relate to extra-articular and extramusculoskeletal aspects and other important factors, such as comorbidity. While the level of evidence was generally quite low, the mean strength of recommendation was 9–10 (10: maximum agreement) for all recommendations. A research agenda was formulated. Conclusions The task force defined the treatment target as remission or, alternatively, low disease activity, being aware that the evidence base is not strong and needs to be expanded by future research. These recommendations can inform the various stakeholders about expert opinion that aims for reaching optimal outcomes of SpA.

European League Against Rheumatism (EULAR) recommendations for the management of psoriatic arthritis with pharmacological therapies: 2015 update

Background Since the publication of the European League Against Rheumatism recommendations for the pharmacological treatment of psoriatic arthritis (PsA) in 2012, new evidence and new therapeutic agents have emerged. The objective was to update these recommendations. Methods A systematic literature review was performed regarding pharmacological treatment in PsA. Subsequently, recommendations were formulated based on the evidence and the expert opinion of the 34 Task Force members. Levels of evidence and strengths of recommendations were allocated. Results The updated recommendations comprise 5 overarching principles and 10 recommendations, covering pharmacological therapies for PsA from non-steroidal anti-inflammatory drugs (NSAIDs), to conventional synthetic (csDMARD) and biological (bDMARD) disease-modifying antirheumatic drugs, whatever their mode of action, taking articular and extra-articular manifestations of PsA into account, but focusing on musculoskeletal involvement. The overarching principles address the need for shared decision-making and treatment objectives. The recommendations address csDMARDs as an initial therapy after failure of NSAIDs and local therapy for active disease, followed, if necessary, by a bDMARD or a targeted synthetic DMARD (tsDMARD). The first bDMARD would usually be a tumour necrosis factor (TNF) inhibitor. bDMARDs targeting interleukin (IL)12/23 (ustekinumab) or IL-17 pathways (secukinumab) may be used in patients for whom TNF inhibitors are inappropriate and a tsDMARD such as a phosphodiesterase 4-inhibitor (apremilast) if bDMARDs are inappropriate. If the first bDMARD strategy fails, any other bDMARD or tsDMARD may be used. Conclusions These recommendations provide stakeholders with an updated consensus on the pharmacological treatment of PsA and strategies to reach optimal outcomes in PsA, based on a combination of evidence and expert opinion.

Efficacy of celecoxib, a cyclooxygenase 2–specific inhibitor, in the treatment of ankylosing spondylitis: A six-week controlled study with comparison against placebo and against a conventional nonsteroidal antiinflammatory drug

OBJECTIVE To evaluate the short-term efficacy of celecoxib, a cyclooxygenase 2-specific inhibitor, in the treatment of ankylosing spondylitis (AS). METHODS The study was a 6-week randomized, double-blind, placebo-controlled trial with 3 treatment arms: placebo, ketoprofen 100 mg twice daily, and celecoxib 100 mg twice daily. Patients who had AS according to the modified New York criteria, without peripheral synovitis and with active disease (pain > or =40 mm on a 100-mm visual analog scale [VAS] and an increase in pain of at least 30% after nonsteroidal antiinflammatory drug withdrawal) were eligible for study. Primary outcome measures were change in pain intensity (VAS) and change in functional impairment (Bath Ankylosing Spondylitis Functional Index [BASFI]). RESULTS Of the 246 randomized patients, 76 were allocated to receive placebo, 90 ketoprofen, and 80 celecoxib. There were no statistically significant differences between treatment groups at study entry. During the 6 weeks of the study, the decrease in pain and functional impairment was greater in the active treatment groups than in the placebo group, with a trend in favor of celecoxib when the 2 active treatments were compared. The mean changes were -13 mm, -21 mm, and -27 mm (P = 0.006) for pain and 1, -6, and -12 (P = 0.0008) for BASFI score in the placebo, ketoprofen, and celecoxib groups, respectively. During treatment, the number of patients reporting epigastric pain was 6 (8%), 13 (14%), and 10 (13%) in the placebo, ketoprofen, and celecoxib groups, respectively. CONCLUSION The results of this study confirm the clinically relevant antiinflammatory effect of celecoxib at a 200-mg daily dosage, with significant improvement of both pain and function in patients with AS.

Management of Behçet disease: a systematic literature review for the European League Against Rheumatism evidence-based recommendations for the management of Behçet disease

Objectives: To present and analyse the literature sources regarding the management of Behçet disease (BD) identified during the systematic literature research, which formed the basis for the European League Against Rheumatism (EULAR) evidence-based recommendations for the management of BD. Methods: Problem areas and related keywords regarding the management of BD were determined by the multidisciplinary expert committee commissioned by EULAR for developing the recommendations. A systematic literature research was performed using MedLine and Cochrane Library resources through to December 2006. Meta-analyses, systematic reviews, randomised controlled trials (RCTs), open studies, observational studies, case control studies and case series’ involving ⩾5 patients were included. For each intervention the effect size and number needed to treat were calculated for efficacy. Odds ratios and numbers needed to harm were calculated for safety issues of different treatment modalities where possible. Results: The literature research yielded 137 articles that met the inclusion criteria; 20 of these were RCTs. There was good evidence supporting the use of azathioprine and ciclosporin A in eye involvement and interferon (IFN)α in mucocutaneous involvement. There were no RCTs with IFNα or tumour necrosis factor (TNF)α antagonists in eye involvement. Similarly controlled data for the management of vascular, gastrointestinal and neurological involvement is lacking. Conclusion: Properly designed, controlled studies (new and confirmatory) are still needed to guide us in managing BD.

Proximal Bursitis in Active Polymyalgia Rheumatica

Polymyalgia rheumatica, a common disorder in elderly persons, is characterized by aches and morning stiffness in the neck, shoulders, and pelvic girdle [1-4]. A systemic inflammatory reaction (including fever, anorexia, weight loss, and high erythrocyte sedimentation rate) is usually associated with the condition. The cause of musculoskeletal symptoms in the proximal extremities is not completely understood. Evidence of joint synovitis has been revealed through scanning, arthroscopy, and synovial biopsy [5-8]. In a recent immunohistochemical study [8], researchers observed mild synovitis characterized by infiltration of macrophages and CD4 T cells. Diffuse and severe musculoskeletal discomfort of the proximal extremities can only be partially explained by this mild joint synovitis. In addition to involvement of the pelvic girdle, some patients have symptoms in the distal extremities that are caused by inflammation of the joints, inflammation of the tenosynovial membrane, or inflammation of both. Clinical evidence of peripheral synovitis was observed in 31% to 38% of patients who had polymyalgia rheumatica [2, 9]. In a recent study [10] conducted by the Mayo Clinic in 245 patients who had polymyalgia rheumatica, 19 patients (8%) had diffuse swelling and pitting edema in the distal extremities. The swelling and edema were similar to those observed in patients who had the remitting, seronegative, symmetrical synovitis with pitting edema syndrome (described by McCarty and colleagues in 1985 [11]). The authors of the study concluded that these clinical findings were most likely the result of vigorous tenosynovitis in the distal extremities and represent a symptom of polymyalgia rheumatica that had previously been poorly recognized. We recently observed a patient who satisfied diagnostic criteria of polymyalgia rheumatica and had bilateral diffuse swelling with pitting edema on the dorsum of the hand [12]. Magnetic resonance imaging (MRI) showed extensor tenosynovitis of the hand and synovitis of the glenohumeral joints together with marked inflammation of subacromial and subdeltoid bursae and tenosynovitis of the biceps in both shoulders. Impressed by the severe involvement of proximal periarticular synovial structures, we decided to use MRI to study the involvement of the shoulders and pelvic girdle in a series of consecutive patients who had symptoms of active polymyalgia rheumatica. Methods Consecutive patients who were seen at the Prato and Reggio Emilia rheumatology centers during a 6-month period and satisfied the Healey criteria for polymyalgia rheumatica [2] were considered suitable candidates for the study. Table 1 shows the demographic characteristics, clinical findings, and MRI results in the 13 case-patients. None of the case-patients had clinical or histologic evidence of giant cell arteritis. Bilateral MRI of the shoulders of the first three case-patients who entered the study revealed that the lesions were symmetrical and their severity was identical. We therefore decided to perform only monolateral MRI in the subsequent 10 case-patients. Three of the 8 case-patients in whom the hip girdle was involved also had pelvic scanning. Table 1. Demographic and Clinical Findings and Results of Magnetic Resonance Imaging of 13 Patients with Polymyalgia Rheumatica* Two control groups were considered. The first group consisted of nine control-patients who had elderly-onset rheumatoid arthritis (median age at onset, 71 years [range, 66 to 76 years]) and met the American Rheumatism Association 1987 modified criteria for rheumatoid arthritis [13]. The control-patients were seen at the Prato and Reggio Emilia rheumatology centers during the same 6-month period as the case-patients. The control-patients had early active disease (median disease duration, 3 months [range, 3 to 6 months]) and clinical evidence of shoulder involvement. The results of serologic examination were positive in three control-patients and negative in six control-patients. The median erythrocyte sedimentation rate at diagnosis was 65 mm/h (range, 56 to 88 mm/h). Bilateral MRI was done on two control-patients who had clinical involvement of both shoulders. Because only one shoulder was clinically involved in the other seven control-patients, monolateral MRI of only the affected shoulder was done. Second-line drug and corticosteroid therapies were not started until MRI had been completed. The second control group consisted of 10 age-matched healthy controls who did not have any clinical problems with their shoulders. The healthy controls were relatives of medical staff at both rheumatology centers. Monolateral MRI of the shoulder was done in all 10 healthy controls. Scanning of the shoulders of three case-patients was repeated after they began corticosteroid therapy (median, 2 months [range, 2 to 3 months]) and were in clinical remission. Scanning was done with a 0.5-T superconductive magnet system (MR Max Plus, GE Medical System, Milwaukee, Wisconsin) and a 17-cm extremity bore transmit-receive coil. A body coil was used to evaluate hip regions. Pulse sequences included coronal T1-weighted sequences (240-ms repetition time, 25-ms echo time, and four excitations), axial proton density sequences (2000-ms repetition time, 25-ms echo time, and two excitations), and T2-weighted sequences (2000-ms repetition time, 90-ms echo time, and two excitations). The coronal section was 5 mm thick, and the axial section was 7 mm thick; both had an intersection gap of 1 mm. The field of view was 20 cm; the matrix size was 160 cm 224 cm or 128 cm 192 cm. Scans were examined by a radiologist who was blinded to clinical findings and the diagnosis. The joint space, subacromial and subdeltoid bursae, and synovial sheaths of the long head of the biceps of the shoulder were evaluated for fluid collection. In addition, the joint space and the ileopectineal bursa in the hip region were evaluated. As shown in Figure 1, measurement of fluid accumulation was graded by using a semiquantitative scale (0 = no accumulation; 1 = sufficient accumulation to allow visualization of the articular shoulder structure, periarticular shoulder structure, or both; 2 = moderate accumulation; and 3 = sufficient quantity to stretch the walls of structures). Figure 1. Magnetic resonance images of patients with polymyalgia rheumatica. arrows arrows Statistical analysis was done by using the SPS program (SPS Inc., Chicago, Illinois). The Fisher exact test was used to compare the frequencies. Results All 13 case-patients (who had active polymyalgia rheumatica) showed bilateral fluid accumulation in the subacromial and subdeltoid bursae, thereby suggesting bursitis (Figure 1 and Table 1). Ten of the 13 case-patients had synovitis of the shoulder joint. Tenosynovitis of the long head of the biceps was found in 7 case-patients. No erosions were observed. Mild (grade 1) synovitis of the hip was seen in all three case-patients who had scans of the hip girdle. One of the three case-patients also had mild (grade 1) ileopectineal bursitis. Fluid accumulated in the subacromial and subdeltoid bursae of only two of the nine control-patients (that is, patients who had early symptoms of elderly-onset rheumatoid arthritis). Fluid accumulated in the joint space of five control-patients, and tenosynovitis of the long head of the biceps was observed in three control-patients. Joints were eroded in two control-patients. None of the 10 age-matched healthy controls showed evidence of fluid collection in joints, bursae, or sheaths of the long head of the biceps. Inflammation in the subacromial and subdeltoid bursae occurred significantly more frequently in case-patients than in control-patients (100% compared with 22%; P < 0.001). The frequencies of joint synovitis and tenosynovitis of the biceps did not significantly differ between case-patients and control-patients (77% compared with 55% and 54% compared with 33%, respectively). However, the frequency of both disorders was higher in the case-patients. Two of the three case-patients who had repeated MRI of the shoulder during treatment showed complete resolution of bursitis, tenosynovitis, and joint synovitis. The third case-patient showed only an improvement (from grade 3 to grade 2) of bursitis and joint synovitis. All three of these case-patients received a starting dosage of 12.5 mg of prednisone per day. When the second scan was obtained, the patients were asymptomatic, the erythrocyte sedimentation rate was normal (median, 18 mm/h [range, 15 to 20 mm/h]), and the median daily dosage of prednisone was 10 mg/d. Discussion All 13 case-patients showed evidence of subacromial and subdeltoid bursitis. This finding occurred significantly more frequently in the 13 case-patients than in the nine control-patients. The frequency of joint synovitis and bicipital tenosynovitis did not differ significantly between case-patients and control-patients. Joint erosions have never been observed in patients with polymyalgia rheumatica; in our study, however, erosions were seen in two control-patients (who had elderly-onset rheumatoid arthritis). According to MRI of normal shoulders [14], no pathologic findings were observed in the age-matched healthy controls. Our MRI study of pelvic girdles was limited because of the small number of study participants. However, one of the three patients had evidence of ileopectineal bursitis in addition to mild joint synovitis. No published studies have examined the results of MRI of the shoulders of patients with polymyalgia rheumatica. One ultrasonographic study [15] that examined hip and glenohumeral joints focused on an effusion of the two joints, which was found in 68% of the patients examined. A study [16] of MRI of the shoulder of patients who had rheumatoid arthritis did not report evidence of prominent bursitis or tenosynovitis. However, this study was not designed to investigate periarticular synovial structures. Possible limitations of