Colin Pease

Reduction of fatigue in Sjögren syndrome with rituximab: results of a randomised, double-blind, placebo-controlled pilot study

Objective: Primary Sjögren syndrome (pSS) causes significant systemic symptoms including fatigue as well as glandular dysfunction. There are currently no effective systemic therapies; however, open label series have suggested that rituximab may be beneficial for systemic and glandular manifestations. Therefore, we performed a double blind, placebo-controlled, randomised pilot study of the efficacy of rituximab in reducing fatigue in pSS. Methods: A total of 17 patients with pSS and a score on fatigue visual analogue scale (VAS) >50 were randomised to receive either 2 infusions of rituximab 1 g or placebo; patients also received oral and intravenous steroids. Outcome measures included: the proportion of patients with >20% reduction in fatigue VAS, changes in pSS related symptoms, health related quality of life and immunological parameters of pSS. These were measured 6 months after therapy. Results: There was significant improvement from baseline in fatigue VAS in the rituximab group (p<0.001) in contrast to the placebo group (p = 0.147). There was a significant difference between the groups at 6 months in the social functioning score of SF-36 (p = 0.01) and a trend to significant difference in the mental health domain score of SF-36 (p = 0.06). There was one episode of serum sickness in the rituximab treated group. Conclusions: This is the first double blind study of rituximab in pSS to show benefit; further studies are justified.

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.

B cell biomarkers of rituximab responses in systemic lupus erythematosus

OBJECTIVE Rituximab appears to be effective in many studies of systemic lupus erythematosus (SLE), with variable initial clinical response and time to relapse. However, results of a randomized controlled trial of rituximab were negative. This study was undertaken to evaluate the effectiveness of rituximab in SLE, using highly sensitive flow cytometry (HSFC), which can define B cell numbers 50-100 times lower than conventional techniques and predicts responses in rheumatoid arthritis. METHODS Thirty-nine patients with active SLE were started on a standard regimen of rituximab with intravenous and oral steroids. Clinical response and relapse were defined using the British Isles Lupus Assessment Group (BILAG) index with criteria for major clinical response, partial clinical response, and nonresponse. HSFC, including analysis of B cell subsets, was performed. RESULTS There was a significant reduction from baseline in global BILAG score at all time points analyzed (P<0.0001), and major clinical response and partial clinical response rates were 51% and 31%, respectively. Time to relapse was highly variable. Fifty percent of the patients relapsed after 6-18 months (earlier relapse); the remainder relapsed at a slower rate (later relapse). B cell depletion and repopulation were variable and were predictive of these clinical outcomes. There was a persistent B cell presence in 21 patients after 2 infusions of rituximab, which included all 7 patients with no response (P=0.012 versus patients with complete depletion of B cells). Memory B cell (P=0.02) and plasmablast (P<0.001) repopulation after 26 weeks was markedly faster in patients with earlier relapse versus patients with later relapse. CONCLUSION Our findings indicate that rituximab is effective in SLE, and clinical responses are supported by close correlation with B cell numbers. HSFC is a valuable tool in the assessment and prediction of response in SLE.

Successful treatment of resistant giant cell arteritis with etanercept

Giant cell arteritis (GCA) is a systemic medium to large cell vasculitis that predominantly affects the elderly population.1 Initial high dose corticosteroids are the cornerstone of treatment, which is subsequently tapered.2 However, disease flares are not uncommon and corticosteroid related side effects are frequent.3 The limitations of corticosteroids in the treatment of some cases of GCA have led to the evaluation of other strategies using steroid sparing agents.4–7 In two previous studies patients with resistant GCA were treated with infliximab, a monoclonal chimeric antibody directed against tumour necrosis factor α (TNFα) that binds circulating and membrane bound TNF, with promising results.6,7 The rationale for this approach was that the vasculitic lesions in GCA had prominent macrophage infiltration where excess TNFα production had been demonstrated by immunohistochemistry.8 We report the case of a patient who was treated with the anti-TNFα agent etanercept, which is the fusion protein of the extracellular ligand binding portion of the p75 TNF receptor and the Fc portion of IgG1, on the basis that the GCA could not be controlled and that complications of high dose corticosteroid treatment …

2015 Recommendations for the management of polymyalgia rheumatica: a European League Against Rheumatism/American College of Rheumatology collaborative initiative

Therapy for polymyalgia rheumatica (PMR) varies widely in clinical practice as international recommendations for PMR treatment are not currently available. In this paper, we report the 2015 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) recommendations for the management of PMR. We used the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology as a framework for the project. Accordingly, the direction and strength of the recommendations are based on the quality of evidence, the balance between desirable and undesirable effects, patients’ and clinicians’ values and preferences, and resource use. Eight overarching principles and nine specific recommendations were developed covering several aspects of PMR, including basic and follow-up investigations of patients under treatment, risk factor assessment, medical access for patients and specialist referral, treatment strategies such as initial glucocorticoid (GC) doses and subsequent tapering regimens, use of intramuscular GCs and disease modifying anti-rheumatic drugs (DMARDs), as well as the roles of non-steroidal anti-rheumatic drugs and non-pharmacological interventions. These recommendations will inform primary, secondary and tertiary care physicians about an international consensus on the management of PMR. These recommendations should serve to inform clinicians about best practices in the care of patients with PMR.

Polymyalgia rheumatica can be distinguished from late onset rheumatoid arthritis at baseline: results of a 5-yr prospective study

OBJECTIVE To describe the pattern of arthropathy and HLA-DRB1 alleles associated with PMR in order to develop a diagnostic algorithm that could help distinguish PMR and RF-negative (RF -ve) late-onset RA (LO-RA) at presentation. METHODS This was a prospective study of all patients presenting with PMR or LO-RA over a 10-yr period to one physician. Demographic, clinical and laboratory data were collected at presentation and during a minimum of 5 yrs of follow-up. The accuracy of the initial diagnosis was systematically reviewed. RESULTS One hundred and forty-two patients with LO-RA, 147 with PMR and 42 with PMR + TA were studied. Peripheral synovitis was observed in 23% of the PMR patients. In comparison with RF -ve LO-RA, PMR patients were younger (P < 0.001), myalgia more frequent [100 vs 16% (P < 0.001)] and arthritis of PIP, MCP and wrist were less frequent (P < 0.001). The combination of wrist + MCP/PIP or wrist + PIP + MCP were highly suggestive of RF -ve LO-RA (P < 0.001). HLA-DRB1*0101/0102 and *0401 were significantly increased in PMR patients compared with healthy controls. Plasma viscosity and arthritis in the wrist, in combination with at least one MCP or PIP joint at disease onset, were predictive of whether a non-erosive RF -ve patient would ultimately be diagnosed as having RF -ve LO-RA or PMR (+/-/arthritis). CONCLUSION Our longitudinal follow-up data were consistent with RF -ve LO-RA being a separate disease entity to PMR despite some phenotypic and immunogenetic similarities at disease onset. A diagnostic algorithm was derived using baseline clinical features to predict the final diagnosis of RF -ve, non-erosive patients.

Patient-reported Outcomes in Polymyalgia Rheumatica

Objective. To prospectively evaluate the disease course and the performance of clinical, patient-reported outcome (PRO) and musculoskeletal ultrasound measures in patients with polymyalgia rheumatica (PMR). Methods. The study population included 85 patients with new-onset PMR who were initially treated with prednisone equivalent dose of 15 mg daily tapered gradually, and followed for 26 weeks. Data collection included physical examination findings, laboratory measures of acute-phase reactants, and PRO measures. Ultrasound evaluation was performed at baseline and Week 26 to assess for features previously reported to be associated with PMR. Response to corticosteroid treatment was defined as 70% improvement in PMR on visual analog scale (VAS). Results. At baseline, 77% had hip pain in addition to shoulder pain and 100% had abnormal C-reactive protein or erythrocyte sedimentation rate. On ultrasound, 84% had shoulder findings and 32% had both shoulder and hip findings. Response to corticosteroid treatment occurred in 73% of patients by Week 4 and was highly correlated with percentage improvement in other VAS measures. Presence of ultrasound findings at baseline predicted response to corticosteroids at 4 weeks. Factor analysis revealed 6 domains that sufficiently represented all the outcome measures: PMR-related pain and physical function, an elevated inflammatory marker, hip pain, global pain, mental function, and morning stiffness. Conclusion. PRO measures and inflammatory markers performed well in assessing disease activity in patients with PMR. A minimum set of outcome measures consisting of PRO measures of pain and function and an inflammatory marker should be used in practice and in clinical trials in PMR.

An anatomical explanation for good-prognosis rheumatoid arthritis

Although most patients with rheumatoid arthritis (RA) have persistent progressive disease there is a heterogeneity of outcome in early disease. An acute presentation of disease is one of the best predictors of a good outcome. On the basis of magnetic resonance imaging (MRI) studies, it has been suggested that there are two types of inflammatory joint disease, one with an intrasynovial location with a poor prognosis and one with an extrasynovial location which generally has a good prognosis. We wondered whether the good prognosis subset of RA was due to a different primary location of pathology. Untreated patients with RA were selected at presentation to the early arthritis clinic to represent the extremes of acute onset good-prognosis RA (GPRA) or insidious onset poor-prognosis RA (PPRA). 30 patients who fulfilled the American College of Rheumatology criteria for RA and 30 controls were studied by imaging; the latter group did not receive gaddiniumdiethylenetriamine penta-acetic acid contrast. RA patients were selected on the basis of their clinical presentation—22 patients with PPRA and eight patients with GPRA (onset of 24 h). MRI was done with a 1·5 T Gyroscan ACS NT (Philips Medical Systems) within 1 week of presentation to the clinic (table) with image acquisition by a surface coil. The clinicians responsible for patients’ care were unaware of the MRI findings at clinical follow-up. Coronal T1weighted spin echo coronal pulse sequences, T2-weighted turbo spin echo SPIR coronal pulse sequences (T2 fat suppressed), a single 10 mm thick single Spoiled Gradient Echo dynamic subtraction gadolinium-DTPA sequence, and a T1 SE post gadolinium-DTPA sequences of metacarpophalangeal joints 2–5 of the dominant hand were done. Films were scored under masked conditions independently by two musculoskeletal radiologists with consensus opinion in the event of disagreement. Soft tissue inflammation was scored as synovial where maximum in the

Health-related utility values of patients with primary Sjögren's syndrome and its predictors

Objectives EuroQoL-5 dimension (EQ-5D) is a standardised preference-based tool for measurement of health-related quality of life and EQ-5D utility values can be converted to quality-adjusted life years (QALYs) to aid cost-utility analysis. This study aimed to evaluate the EQ-5D utility values of 639 patients with primary Sjögrens syndrome (PSS) in the UK. Methods Prospective data collected using a standardised pro forma were compared with UK normative data. Relationships between utility values and the clinical and laboratory features of PSS were explored. Results The proportion of patients with PSS reporting any problem in mobility, self-care, usual activities, pain/discomfort and anxiety/depression were 42.2%, 16.7%, 56.6%, 80.6% and 49.4%, respectively, compared with 5.4%, 1.6%, 7.9%, 30.2% and 15.7% for the UK general population. The median EQ-5D utility value was 0.691 (IQR 0.587–0.796, range −0.239 to 1.000) with a bimodal distribution. Bivariate correlation analysis revealed significant correlations between EQ-5D utility values and many clinical features of PSS, but most strongly with pain, depression and fatigue (R values>0.5). After adjusting for age and sex differences, multiple regression analysis identified pain and depression as the two most important predictors of EQ-5D utility values, accounting for 48% of the variability. Anxiety, fatigue and body mass index were other statistically significant predictors, but they accounted for <5% in variability. Conclusions This is the first report on the EQ-5D utility values of patients with PSS. These patients have significantly impaired utility values compared with the UK general population. EQ-5D utility values are significantly related to pain and depression scores in PSS.

Should I send my patient with previous giant cell arteritis for imaging of the thoracic aorta? A systematic literature review and meta-analysis

Objectives To review the literature in order to estimate how many previously unknown thoracic aortic aneurysms (TAAs) and thoracic aortic dilatations (TADs) might be detected by systematic, cross-sectional aortic imaging of patients with giant cell arteritis (GCA). Methods A systematic literature review was performed using Ovid Medline, Embase and the Cochrane Library. Studies potentially relevant to TAA/TAD were evaluated by two authors independently for relevance, bias and heterogeneity. Meta-analysis was performed using a random-effects model to estimate pooled prevalence. Results Two analyses of routinely collected administrative data suggested a threefold risk of TAA/dissection in GCA compared with controls. In GCA cohorts without systematic imaging, 2–8% had TAA. In the two best-reported studies, aneurysm dissection/rupture occurred in 1% and 6% of GCA cases. Aortic imaging studies had a variety of TAA/TAD definitions, imaging methods and time points. There were limited data on age-matched controls. Three studies suggested that male sex may be a risk factor for TAA/TAD in GCA. On average, five to ten patients with GCA would need aortic imaging to detect one previously unknown TAA/TAD. Conclusions The data support an association between GCA and TAA/TAD compared with age-matched controls, but the true relative risk, and the time course of that risk, remains unclear. It is also unclear whether chest radiography is a sufficiently sensitive screening tool. Clinicians should retain a high index of suspicion for aortic pathology in patients with GCA. Before ordering imaging, clinicians should consider whether, and how, detecting aortic pathology would affect a patients management.