Laura Niccoli

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

Successful treatment of SAPHO syndrome with infliximab: report of two cases

The treatment of SAPHO syndrome is empirical and has recently been reviewed.1–3 Non-steroidal anti-inflammatory drugs (NSAIDs) are the first choice but have limited efficacy. Second line drugs have been tried with mixed results. Positive effects with pamidronate, which partly works by blocking tumour necrosis factor α, have been reported.3,4 Recently, Maksymowych et al suggested that pamidronate is also effective in spondarthritis, which shares manifestations and clinical associations with the SAPHO syndrome.5,6 Infliximab, a chimeric anti-tumour necrosis factor α monoclonal IgG1 antibody, has recently been proved to be effective in the treatment of ankylosing spondylitis7,8 and psoriatic arthritis.7,9 In view of this information we treated two patients affected by refractory SAPHO syndrome with infliximab. Both patients had chest pain limiting normal activity despite adequate treatment with NSAIDs and second line treatment was unsuccessful. Both patients received three intravenous infusions of infliximab (5 mg/kg) at …

Remitting seronegative symmetrical synovitis with pitting oedema (RS3PE) syndrome: a prospective follow up and magnetic resonance imaging study

OBJECTIVE To determine the clinical characteristics of patients with “pure” remitting seronegative symmetrical synovitis with pitting oedema (RS3PE) syndrome, and to investigate its relation with polymyalgia rheumatica (PMR). Magnetic resonance imaging (MRI) was used to describe the anatomical structures affected by inflammation in pure RS3PE syndrome. METHODS A prospective follow up study of 23 consecutive patients with pure RS3PE syndrome and 177 consecutive patients with PMR diagnosed over a five year period in two Italian secondary referral centres of rheumatology. Hands or feet MRI, or both, was performed at diagnosis in 7 of 23 patients. RESULTS At inspection evidence of hand and/or foot tenosynovitis was present in all the 23 patients with pure RS3PE syndrome. Twenty one (12%) patients with PMR associated distal extremity swelling with pitting oedema. No significant differences in the sex, age at onset of disease, acute phase reactant values at diagnosis, frequency of peripheral synovitis and carpal tunnel syndrome and frequency of HLA-B7 antigen were present between patients with pure RS3PE and PMR. In both conditions no patient under 50 was observed, the disease frequency increased significantly with age and the highest frequency was present in the age group 70–79 years. Clinical symptoms for both conditions responded promptly to corticosteroids and no patient developed rheumatoid arthritis during the follow up. However, the patients with pure RS3PE syndrome were characterised by shorter duration of treatment, lower cumulative corticosteroid dose and lower frequency of systemic signs/symptoms and relapse/recurrence. Hands and feet MRI showed evidence of tenosynovitis in five patients and joint synovitis in three patients. CONCLUSION The similarities of demographic, clinical, and MRI findings between RS3PE syndrome and PMR and the concurrence of the two syndromes suggest that these conditions may be part of the same disease and that the diagnostic labels of PMR and RS3PE syndrome may not indicate a real difference. The presence of distal oedema seems to indicate a better prognosis.

Distal musculoskeletal manifestations in polymyalgia rheumatica : A prospective followup study

OBJECTIVE To determine the frequency and the characteristics of distal musculoskeletal manifestations in polymyalgia rheumatica (PMR). METHODS Prospective followup study of 177 consecutive patients meeting clinical criteria for PMR, diagnosed over a 5-year period in 2 rheumatology secondary referral centers in Italy. RESULTS Seventy-nine of the 177 patients (45%) had distal musculoskeletal manifestations. Peripheral arthritis occurred in 45 patients (25%), carpal tunnel syndrome in 24 (14%), distal extremity swelling with pitting edema in 21 (12%), and distal tenosynovitis in 5 (3%). These manifestations were usually associated with PMR proximal symptoms (69%); however, 31% of the episodes represented isolated relapse/recurrence at distal sites. Distal symptoms responded promptly to corticosteroids. No evidence of joint deformities, erosions, or development of rheumatoid arthritis was observed during the followup. The group of patients with peripheral arthritis included a higher proportion of females, had a longer duration of therapy, and had more relapses/ recurrences. Patients who had distal extremity swelling with pitting edema had a higher age at disease onset, a shorter duration of therapy, and lower initial and cumulative prednisone doses. CONCLUSION Inflammatory involvement of distal articular and/or tenosynovial structures occurs in approximately half of the cases of PMR. Peripheral arthritis is associated with more severe disease, while distal extremity swelling with pitting edema appears to identify a more benign disease subset.

Cervical interspinous bursitis in active polymyalgia rheumatica

Objective: To evaluate the inflammatory involvement of cervical interspinous bursae in patients with polymyalgia rheumatica (PMR) using MRI. Methods: In all, 12 consecutive, untreated new patients with PMR were investigated. Five patients with fibromyalgia, two patients with cervical osteoarthritis and six patients with spondyloarthritis with neck pain served as controls. MRI of the cervical spine was performed in all 12 PMR case patients and in 13 control patients. Two of the four patients with PMR with pelvic girdle pain also had MRI of the lumbar spine. Results: MRI evidence of interspinous cervical bursitis was found in all patients with PMR, and in three patients with fibromyalgia, in two with psoriatic spondylitis and one with cervical osteoarthritis. A moderate to marked (grade ⩾2 on a semiquantitative 0–3 scale) cervical bursitis occurred significantly more frequently in patients with PMR than in control patients (83.3% compared with 30.7%, p = 0.015). In all patients and controls with cervical bursitis the involvement was found at the C5–C7 cervical interspaces. MRI of the lumbar spine showed lumbar interspinous bursitis at the L3–L5 lumbar interspaces in the two patients with PMR and pelvic girdle pain examined. Conclusions: Cervical interspinous bursitis is a likely basis for discomfort in the neck of patients with PMR. The prominent inflammatory involvement of cervical bursae supports the hypothesis that PMR is a disorder of prominent involvement of extra-articular synovial structures.

Psoriatic arthritis: a systematic review.

Psoriatic arthritis is an inflammatory rheumatic disorder of unknown etiology occurring in patients with psoriasis. The Classification Criteria for Psoriatic Arthritis study group has recently developed a validated set of classification criteria for psoriatic arthritis with a sensitivity of 91.4% and a specificity of 98.7%. Three main clinical patterns have been identified: oligoarticular (≤ 4 involved joints) or polyarticular (≥ 5 involved joints) peripheral disease and axial disease with or without associated peripheral arthritis. In this context distal interphalangeal arthritis and arthritis mutilans may occur. According to other reports, also in our centre, asymmetric oligoarthritis is the most frequent pattern at onset. Axial disease has been estimated between 5% and 36% of patients. It is characterized by an irregular involvement of the axial skeleton with a predilection for the cervical spine. Recurrent episodes of enthesitis and dactylitis represent a hallmark of psoriatic arthritis. In around 20% of cases distal extremity swelling with pitting edema of the hands or feet is observed. Unilateral acute iridocyclitis, usually recurrent in alternate fashion, is the most frequent extra‐articular manifestation, and accelerated atherosclerosis is the prominent comorbidity. The clinical course of peripheral and axial psoriatic arthritis is usually less severe than rheumatoid arthritis and ankylosing spondylitis, respectively. Local corticosteroid injections and non‐steroidal anti‐inflammatory drugs are recommended in milder forms. Sulphasalazine and methotrexate are effective in peripheral psoriatic arthritis. Recent studies have provided evidence on the efficacy of anti‐tumor necrosis factor‐α drugs to control symptoms and to slow or arrest radiological disease progression.

Frequency and duration of clinical remission in patients with peripheral psoriatic arthritis requiring second-line drugs

OBJECTIVE To evaluate the frequency and duration of clinical remission in patients with PsA. METHODS All consecutive new outpatients with peripheral PsA requiring second-line drugs and RA observed between January 2000 and December 2005 were included in a prospective, case-control study. Primary end point was to assess the frequency of remission in peripheral PsA compared with RA. Secondary end points were to compare the duration of clinical remission during treatment and after therapy interruption, ACR 20, 50, 70 response rates and to detect any remission predictor at diagnosis. Treatment regimen was standardized in both groups. From January 2003 to December 2005, therapy was suspended in PsA patients and controls if achieving remission. RESULTS One or more episodes of remission occurred in 57/236 (24.1%) PsA patients and in 20/268 (7.5%) controls (P < 0.001). The mean duration of remission was of 13 +/- 9.4 months in PsA patients and 4 +/- 3.7 in controls (P > 0.001). Remission episodes were more frequent in PsA patients treated with anti-TNF compared with those receiving traditional DMARDs (P > 0.001), with no differences regarding the duration. After therapy interruption, the remission duration was 12 +/- 2.4 months in PsA and 3 +/- 1.5 in RA (P < 0.001). No remission predictor at diagnosis resulted by multivariate analysis. CONCLUSION Remission is possible in up to 24% of patients with peripheral PsA. It is significantly more frequent, but not longer, in patients receiving anti-TNF drugs compared with those treated with traditional DMARDs. Patients remain in remission for a long period after therapy interruption, thus suggesting an intermittent therapeutic strategy.

Adalimumab, Etanercept, Infliximab, and the Risk of Tuberculosis: Data from Clinical Trials, National Registries, and Postmarketing Surveillance

This review evaluates the risk of tuberculosis (TB), adherence with recommendations for TB prevention, and host-related risk in patients with rheumatoid arthritis (RA), psoriatic arthritis, and ankylosing spondylitis receiving infliximab (IFX), adalimumab (ADA), and etanercept (ETN) through an analysis of phase III randomized controlled trials (RCT), postmarketing surveillance, and national registries. Ten (0.21%) TB cases occurred among 4590 patients in 16 RCT of IFX, 9 (0.12%) among 7009 patients in 21 RCT of ADA, and 4 (0.05%) among 7741 patients in 26 RCT of ETN. Overall, 19/23 (83%) TB cases occurred in patients with RA. Data from national registries and postmarketing surveillance showed an increased risk of TB in patients receiving any of the 3 anti-tumor necrosis factor (TNF) drugs, with a 3–4 times higher risk associated with IFX and ADA than with ETN. Deviations from recommended TB prevention procedures were observed in up to 80% of patients, and most registries did not include data on host-related risk factors for TB. TB occurrence was reduced in recent RCT but not in real-life practice. TB risk was lower for ETN than for monoclonal antibody anti-TNF agents. More complete data collection, including host-related TB risk factors, is advisable to avoid biased results.

Inflamed shoulder structures in polymyalgia rheumatica with normal erythrocyte sedimentation rate.

OBJECTIVE To investigate the inflammatory involvement of shoulder articular and extraarticular structures in polymyalgia rheumatica (PMR) patients with a normal erythrocyte sedimentation rate (ESR) at diagnosis. METHODS This was a case-control study. All consecutive, untreated new outpatients diagnosed as having PMR with a normal ESR (<40 mm/hour) during a 6-month period were included in the study (case patients). Controls were 12 consecutive, untreated PMR outpatients with an ESR of >40 mm/hour who were observed after the case patients. Before starting corticosteroid therapy, all case patients and controls underwent bilateral shoulder ultrasonography (US) and magnetic resonance imaging (MRI). US and MRI scans were evaluated independently by two radiologists who were blinded to the reciprocal results. RESULTS Six case patients (4 men and 2 women) and 12 controls (4 men and 8 women) were studied. Both US and MRI demonstrated bilateral subacromial/subdeltoid bursitis in all 6 case patients and in 11 of the 12 (92%) controls (P not significant [NS]). One control had unilateral bursitis. Glenohumeral joint synovitis was found in 4 of 6 case patients (67%) by MRI and in 3 of 6 case patients (50%) by US (P NS), as well as in 8 of 12 controls (67%) by MRI and in 7 of 12 controls (58%) by US (P NS). Both MRI and US detected biceps tenosynovitis in 5 of 6 case patients (83%) and in 8 of 12 controls (67%) (P NS). The severity of bursitis did not differ significantly between the groups. US was as effective as MRI in detecting inflammatory changes of the shoulder. CONCLUSION MRI and US studies showed that PMR patients with normal or high ESRs have similar inflammatory shoulder lesions. Moreover, bilateral subacromial/subdeltoid bursitis represents the imaging hallmark in PMR patients with a high or normal ESR. MRI or US of the shoulder may facilitate the proper diagnosis in patients with the typical proximal symptoms of PMR who also have normal ESRs.

Guidance for the management of patients with latent tuberculosis infection requiring biologic therapy in rheumatology and dermatology clinical practice

Since the introduction of biologics for the treatment of rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), and psoriasis (Pso) an increased risk of tuberculosis (TB) reactivation in patients with latent tuberculosis infection (LTBI) has been recorded for anti-TNF agents, while a low or absent risk is associated with the non-anti-TNF targeted biologics. To reduce this risk several recommendation sets have been published over time, but in most of them the host-related risk, and the predisposing role to TB reactivation exerted by corticosteroids and by the traditional disease-modifying anti-rheumatic drugs has not been adequately addressed. Moreover, the management of the underlying disease, and the timing of biologic restarting in patients with TB occurrence have been rarely indicated. A multidisciplinary expert panel, the Italian multidisciplinary task force for screening of tuberculosis before and during biologic therapy (SAFEBIO), was constituted, and through a review of the literature, an evidence-based guidance for LTBI detection, identification of the individualized level of risk of TB reactivation, and practical management of patients with TB occurrence was formulated. The literature review confirmed a higher TB risk associated with monoclonal anti-TNF agents, a low risk for soluble receptor etanercept, and a low or absent risk for non-anti-TNF targeted biologics. Considering the TB reactivation risk associated with host demographic and clinical features, and previous or current non-biologic therapies, a low, intermediate, or high TB reactivation risk in the single patient was identified, thus driving the safest biologic choice. Moreover, based on the underlying disease activity measurement and the different TB risk associated with non-biologic and biologic therapies, practical indications for the treatment of RA, PsA, AS, and Pso in patients with TB occurrence, as well as the safest timing of biologic restarting, were provided.