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, D M Goldenberg, , A Radbruch, G R Burmester, T Dörner
Published: 2 August 2007
by BMJ
Annals of the Rheumatic Diseases, Volume 67, pp 450-457; https://doi.org/10.1136/ard.2007.075762

Abstract:
B lymphocytes have been implicated in the pathogenesis of lupus and other autoimmune diseases, resulting in the introduction of B cell-directed therapies. Epratuzumab, a humanised anti-CD22 monoclonal antibody, is currently in clinical trials, although its effects on patients’ B cells are not completely understood. This study analysed the in vivo effect of epratuzumab on peripheral B cell subsets in 12 patients with systemic lupus erythematosus, and also addressed the in vitro effects of the drug by analysing anti-immunoglobulin-induced proliferation of isolated B cells obtained from the peripheral blood of 11 additional patients with lupus and seven normal subjects. Upon treatment, a pronounced reduction of CD27 B cells and CD22 surface expression on CD27 B cells was observed, suggesting that these cells, which mainly comprise naïve and transitional B cells, are preferentially targeted by epratuzumab in vivo. The results of in vitro studies indicate additional regulatory effects of the drug by reducing the enhanced activation and proliferation of anti-immunoglobulin-stimulated lupus B cells after co-incubation with CD40L or CpG. Epratuzumab inhibited the proliferation of B cells from patients with systemic lupus erythematosus but not normal B cells under all culture conditions. Epratuzumab preferentially modulates the exaggerated activation and proliferation of B cells from patients with lupus in contrast to normal subjects, thus suggesting that epratuzumab might offer a new therapeutic option for patients with systemic lupus erythematosus, as enhanced B cell activation is a hallmark of this disease.
A. Y. Goedkoop, M. C. Kraan, M. B. M. Teunissen, D. I. Picavet, M. A. De Rie, J. D. Bos,
Published: 1 July 2004
by BMJ
Annals of the Rheumatic Diseases, Volume 63, pp 769-773; https://doi.org/10.1136/ard.2003.018085

Abstract:
Background: Tumour necrosis factor α (TNFα) blockade using infliximab, a chimeric anti-TNFα antibody, is an effective treatment for both psoriasis and psoriatic arthritis (PsA). Objective: To analyse the early effects of infliximab treatment on serial skin and synovial tissue biopsy samples. Methods: Twelve patients with both active psoriasis and PsA received a single infusion of either infliximab (3 mg/kg) (n = 6) or placebo (n = 6) intravenously. Synovial tissue and lesional skin biopsy specimens were obtained at baseline and 48 hours after treatment. Immunohistochemical analysis was performed to analyse the inflammatory infiltrate. In situ detection of apoptotic cells was performed by TUNEL assay and by immunohistochemical staining with anti-caspase-3 antibodies. Stained tissue sections were evaluated by digital image analysis. Results: A significant reduction in mean (SEM) T cell numbers was found in both lesional epidermis (baseline 37 (11) cells/mm, 48 hours 26 (11), p = 0.028) and synovial tissue (67 (56) cells/mm2v 32 (30), p = 0.043) after infliximab treatment, but not after placebo treatment (epidermis 18 (8) v 43 (20), NS; synovium 110 (62) v 46 (21), NS). Similarly, the number of macrophages in the synovial sublining was significantly reduced after anti-TNFα treatment (100 (73) v 10 (8), p = 0.043). The changes in cell numbers could not be explained by induction of apoptosis at the site of inflammation. Conclusions: The effects of anti-TNFα therapy in psoriasis and psoriatic arthritis may be explained by decreased cell infiltration in lesional skin and inflamed synovial tissue early after initiation of treatment.
, Anna Tjärnlund, Matteo Bottai, Victoria P. Werth, Clarissa Pilkington, Marianne De Visser, Lars Alfredsson, Anthony A Amato, Richard J Barohn, Matthew H. Liang, et al.
Published: 27 October 2017
by BMJ
Annals of the Rheumatic Diseases, Volume 76, pp 1955-1964; https://doi.org/10.1136/annrheumdis-2017-211468

Abstract:
ObjectiveTo develop and validate new classification criteria for adult and juvenile idiopathic inflammatory myopathies (IIM) and their major subgroups.MethodsCandidate variables were assembled from published criteria and expert opinion using consensus methodology. Data were collected from 47 rheumatology, dermatology, neurology and paediatric clinics worldwide. Several statistical methods were used to derive the classification criteria.ResultsBased on data from 976 IIM patients (74% adults; 26% children) and 624 non-IIM patients with mimicking conditions (82% adults; 18% children), new criteria were derived. Each item is assigned a weighted score. The total score corresponds to a probability of having IIM. Subclassification is performed using a classification tree. A probability cut-off of 55%, corresponding to a score of 5.5 (6.7 with muscle biopsy) ‘probable IIM’, had best sensitivity/specificity (87%/82% without biopsies, 93%/88% with biopsies) and is recommended as a minimum to classify a patient as having IIM. A probability of ≥90%, corresponding to a score of ≥7.5 (≥8.7 with muscle biopsy), corresponds to ‘definite IIM’. A probability of ConclusionsThe European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria for IIM have been endorsed by international rheumatology, dermatology, neurology and paediatric groups. They employ easily accessible and operationally defined elements, and have been partially validated. They allow classification of ‘definite’, ‘probable’ and ‘possible’ IIM, in addition to the major subgroups of IIM, including juvenile IIM. They generally perform better than existing criteria.
Comment
Chaohua Deng, , Nathalie Presle, , Meriem Koufany, Cécile Guillaume, , Anne Pizard
Published: 7 October 2017
by BMJ
Annals of the Rheumatic Diseases, Volume 77; https://doi.org/10.1136/annrheumdis-2017-212003

Abstract:
We thank Dr Chan and Dr Wen for their interest in our report1 and their resulting eLetter.2 We fully agree that, among the different components of metabolic syndrome (MetS), hypertension has very recently been brought out as a critical feature in the development of osteoarthritis (OA) in humans.3 4 In these reports using either data from the Framingham OA study3 or the Osteoarthritis Initiative study,4 it has been emphasised that high blood pressure (diastolic or systolic, respectively) was associated with increased incidence of radiographic knee OA. In order to further experimentally investigate the actual role of hypertension in OA onset and development, Chan and colleagues describe in a yet unpublished study the development of OA features in the spontaneous hypertensive rat (SHR) model, a widely characterised model of systemic hypertension.2 5 Although the spontaneous hypertensive heart failure (SHHF) rat strain we employed is deriving from the SHR strain6 and suffers high …
, , Christine Peloquin, Devyani Misra,
Published: 7 October 2017
by BMJ
Annals of the Rheumatic Diseases, Volume 77, pp 92-97; https://doi.org/10.1136/annrheumdis-2017-211811

Abstract:
PurposeBone remodelling as a therapeutic target in knee osteoarthritis (OA) has gained much interest, but the effects of antiresorptive agents on knee OA have been conflicting, with no studies to date examining the effects of bisphosphonate use on the clinically relevant endpoint of knee replacement (KR) surgery.MethodsWe used data from The Health Improvement Network (THIN), a general practitioner electronic medical records representative of the general UK population. We identified older women who had initiated bisphosphonate use after their incident knee OA diagnosis. Each bisphosphonate initiator was propensity score-matched with a non-initiator within each 1-year cohort accrual block. The effect of bisphosphonates on the risk of KR was assessed using Cox proportional hazard regression. Sensitivity analyses to address residual confounding were also conducted.ResultsWe identified 2006 bisphosphonate initiators, who were matched to 2006 non-initiators(mean age 76, mean body mass index 27), with mean follow-up time of 3 years. The crude incidence rate of KR was 22.0 per 1000 person-years among the initiators, and 29.1 among the non-initiators. Bisphosphonate initiators had 26% lower risk of KR than non-initiators(HR 0.74, 95% CI 0.59 to 0.93); these results were similar when additionally adjusted for potential confounders in the propensity score (HR 0.76, 95% CI 0.60 to 0.95). Results of sensitivity analyses supported this protective effect.ConclusionsIn this population-based cohort of older women with incident knee OA, those with incident bisphosphonate users had lower risk of KR than non-users of bisphosphonates, suggesting a potential beneficial effect of bisphosphonates on knee OA.
, Sara K. Tedeschi, Bing Lu, Susan Malspeis, David Kreps, , Elizabeth W. Karlson, Karen H. Costenbader
Published: 7 October 2017
by BMJ
Annals of the Rheumatic Diseases, Volume 77, pp 196-202; https://doi.org/10.1136/annrheumdis-2017-211675

Abstract:
ObjectivesSystemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease, subtyped according to clinical manifestations and autoantibodies. Evidence concerning cigarette smoking and SLE risk has been conflicting. We investigated smoking and SLE risk, overall and by anti-double stranded DNA (dsDNA) presence, in two prospective cohort studies.MethodsThe Nurses’ Health Study (NHS) enrolled 121 701 US female nurses in 1976; Nurses’ Health Study II (NHSII) enrolled 116 430 in 1989. Lifestyle, environmental and medical data were collected through biennial questionnaires. Incident SLE was confirmed by medical record review. Cox regression models estimated HRs of SLE, overall and by dsDNA subtype, in association with time-varying smoking status and cumulative smoking pack-years through the 2-year cycle prior to diagnosis, controlling for potential confounders.ResultsAmong 286 SLE cases identified (159 in NHS (1978–2012) and 127 in NHSII (1991–2013)), mean age was 49.2 (10.3) years and 42% were dsDNA+ at SLE diagnosis. At baseline, 45% of women had ever smoked, 51% of whom currently smoked. Compared with never smokers, current smokers had increased dsDNA+ SLE risk (HR 1.86 (1.14–3.04)), whereas past smokers did not (HR 1.31 (0.85–2.00)). Women who smoked >10 pack-years (vs never) had an elevated dsDNA+ SLE risk (HR 1.60(95% CI 1.04 to 2.45)) compared with never smokers. No associations were observed between smoking status or pack-years and overall SLE or dsDNA− SLE.ConclusionStrong and specific associations of current smoking and >10 pack-years of smoking with dsDNA+ SLE were observed. This novel finding suggests smoking is involved in dsDNA+ SLE pathogenesis.
Comment
, , Ombretta Viapiana, , Angelo Fassio, , Cristian Caimmi, Giovanni Orsolini,
Published: 26 October 2017
by BMJ
Annals of the Rheumatic Diseases, Volume 77; https://doi.org/10.1136/annrheumdis-2017-212510

Abstract:
We read with great interest the results of the study of Mo et al .1 The authors suggest that γδ T cells are involved in the pathogenesis of rheumatoid arthritis (RA). The study showed a significant reduction, in patients with RA, of peripheral total γδ T cells (particularly Vδ2 T cells, the major population of peripheral blood γδ T cells). The percentage of peripheral Vδ2 T cells of RA was negatively correlated with the levels of inflammatory markers, including C-reactive protein, erythrocyte sedimentation rate as well as the Disease Activity Score in 28 joints. The peripheral reduction of Vδ2 …
, , , V Barskova, Pierre-André Guerne, , B F Leeb, , J Pimentao, , et al.
Published: 7 January 2011
by BMJ
Annals of the Rheumatic Diseases, Volume 70, pp 563-570; https://doi.org/10.1136/ard.2010.139105

Abstract:
ObjectivesTo agree terminology and to develop recommendations for the diagnosis of calcium pyrophosphate deposition (CPPD).MethodsThe European League Against Rheumatism (EULAR) CPPD Task Force, comprising 15 experts from 10 countries, agreed the terms and recommendations for diagnosis of CPPD using a Delphi consensus approach. Evidence was systematically reviewed and presented in terms of sensitivity, specificity and positive likelihood ratio (LR) to support diagnosis; ORs were used for association. Strength of recommendation (SOR) was assessed by the EULAR visual analogue scale.ResultsIt was agreed that ‘CPPD’ should be the umbrella term that includes acute calcium pyrophosphate (CPP) crystal arthritis, osteoarthritis (OA) with CPPD and chronic CPP crystal inflammatory arthritis. Chondrocalcinosis (CC) defines cartilage calcification, most commonly due to CPPD and detected by imaging or histological examination. A total of 11 key recommendations were generated on the topics of clinical features, synovial fluid (SF) examination, imaging, comorbidities and risk factors. Definitive diagnosis of CPPD relies on identification of SF CPP crystals. Rapid onset inflammatory symptoms and signs are suggestive but not definitive for acute CPP crystal arthritis. Radiographic CC is not highly sensitive or specific, whereas ultrasonography appears more useful (LR=24.2, 95% CI 3.51 to 168.01) for peripheral joints. Recognised risk factors for CPPD include ageing, OA and metabolic conditions such as primary hyperparathyroidism, haemochromatosis and hypomagnesaemia; familial forms are rare. SORs varied from 53 to 99 (maximum 100).ConclusionNew terms for CPPD were agreed and 11 key recommendations for diagnosis of CPPD were developed using research evidence and expert consensus.
, Rodolfo Gomez, Giuseppe Bianco, , Pamela Lear, Carlos Dieguez, Juan Gomez-Reino, Francisca Lago,
Published: 7 January 2011
by BMJ
Annals of the Rheumatic Diseases, Volume 70, pp 551-559; https://doi.org/10.1136/ard.2010.132399

Abstract:
Background Obesity is a major risk factor for a plethora of diseases including joint disorders associated with cartilage destruction. Recently, it has been demonstrated that adipose tissue might contribute to degenerative joint diseases via the secretion of potent bioactive molecules termed adipokines. Objective To study expression of the novel adipokines chemerin, lipocalin 2 (LCN2) and serum amyloid A3 (SAA3) in murine and human chondrocytes, under basal conditions, in response to a range of biological and pharmacological treatments, and during chondrocyte differentiation. Methods Chemerin, LCN2 and SAA3 mRNA and protein expression were evaluated by quantitative real-time reverse transcription PCR and western blot analysis, respectively, in the ATDC-5 murine chondrocyte cell line, a human immortalised chondrocyte cell line (T/C-28a2) and primary cultured human chondrocytes. Results Human and murine chondrocytes expressed chemerin, LCN2 and SAA3 mRNA; interleukin (IL)-1β was a potent inducer of these novel adipokines. Moreover, dexamethasone, lipopolysaccharides (LPS) and other relevant adipokines such as leptin and adiponectin were able to modulate chemerin, LCN2 and SAA3 mRNA expression alone and when coadministered. Intracellular signal transducers involved in the IL-1β-mediated upregulation of LCN2 and SAA3 included Janus kinase (JAK) 2, phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein (MAP) kinases. Finally, expression of chemerin, LCN2 and SAA3 mRNA expression were modulated throughout chondrocyte differentiation. Conclusion Chemerin, LCN2 and SAA3 are implicated in chondrocyte pathophysiology, and regulated by other relevant factors that drive inflammatory process such as IL-1β, LPS and adipokines including leptin and adiponectin. It seems likely that JAK2, PI3K and MAP kinases are involved in mediating these responses.
, , Johan Askling
Published: 26 September 2017
by BMJ
Annals of the Rheumatic Diseases, Volume 77, pp 85-91; https://doi.org/10.1136/annrheumdis-2017-212131

Abstract:
ObjectiveTo investigate if, and when, patients diagnosed with rheumatoid arthritis (RA) in recent years are at increased risk of death.MethodsUsing an extensive register linkage, we designed a population-based nationwide cohort study in Sweden. Patients with new-onset RA from the Swedish Rheumatology Quality Register, and individually matched comparators from the general population were followed with respect to death, as captured by the total population register.Results17 512 patients with new-onset RA between 1 January 1997 and 31 December 2014, and 78 847 matched general population comparator subjects were followed from RA diagnosis until death, emigration or 31 December 2015. There was a steady decrease in absolute mortality rates over calendar time, both in the RA cohort and in the general population. Although the relative risk of death in the RA cohort was not increased (HR=1.01, 95% CI 0.96 to 1.06), an excess mortality in the RA cohort was present 5 years after RA diagnosis (HR after 10 years since RA diagnosis=1.43 (95% CI 1.28 to 1.59)), across all calendar periods of RA diagnosis. Taking RA disease duration into account, there was no clear trend towards lower excess mortality for patients diagnosed more recently.ConclusionsDespite decreasing mortality rates, RA continues to be linked to an increased risk of death. Thus, despite advancements in RA management during recent years, increased efforts to prevent disease progression and comorbidity, from disease onset, are needed.
Comment
, Sebastian Costa, Sandrine Jousse-Joulin, Pascale Marcorelles, Jacques-Olivier Pers, Alain Saraux, Valérie Devauchelle-Pensec, Divi Cornec
Published: 29 September 2017
by BMJ
Annals of the Rheumatic Diseases, Volume 77; https://doi.org/10.1136/annrheumdis-2017-212289

Abstract:
We read with a great interest the recent contribution by Mossel et al ,1 which brings new important data on the diagnostic value of major salivary ultrasonography (SGUS) for primary Sjögren’s syndrome (pSS), as reported in previous studies2–10 and stresses the need to evaluate the inclusion of SGUS into future classification criteria for the disease. In their cohort of 103 consecutive patients clinically suspected for pSS, Mossel et al reported a good agreement between SGUS and labial and parotid salivary gland biopsy. Agreement was reported to be marginally higher for parotid gland biopsy (absolute agreement of 83%) than for minor labial salivary gland biopsy (absolute agreement 79%). However, the …
Comment
Lorenzo Cavagna, Santos Castañeda, Carlo Sciré, Miguel A Gonzalez-Gay
Published: 25 September 2017
by BMJ
Annals of the Rheumatic Diseases, Volume 77; https://doi.org/10.1136/annrheumdis-2017-212368

Abstract:
We read with great interest the extended report by Lilleker et al 1 on the EuroMyositis registry. Our attention was particularly addressed to antisynthetase syndrome (ASSD) because in the last years we and all members of the AENEAS (American and European Network of Antisynthetase Syndrome) collaborative group strongly contributed2–7 to increase the knowledge on this peculiar disease. We think that a comparison between our cohorts could be of interest and useful for clinicians, even if the lack of some data in the EuroMyositis paper does not allow us to perform statistical analysis. Both groups collected a very large number of patients (AENEAS collaborative group 813 cases, EuroMyositis 512 cases). The comparison of available …
Comment
Published: 28 September 2017
by BMJ
Annals of the Rheumatic Diseases, Volume 77; https://doi.org/10.1136/annrheumdis-2017-212229

Abstract:
We thank Dr Oiwa for the letter discussing the use of glucocorticoids1 as presented in the most recent update of the European League Against Rheumatism …
, Lotte Heimans, Sytske Anne Bergstra, , Maikel Van Oosterhout, Johannes H L M Van Groenendael, André J Peeters, Gerda M Steup-Beekman, Leroy R Lard, Peter B J De Sonnaville, et al.
Published: 28 September 2017
by BMJ
Annals of the Rheumatic Diseases, Volume 77, pp 111-118; https://doi.org/10.1136/annrheumdis-2017-211375

Abstract:
Objectives: To determine the 5-year outcomes of early remission induction therapy followed by targeted treatment aimed at drug-free remission (DFR) in patients with early arthritis.Methods: In 12 hospitals, 610 patients with early (<2 years) rheumatoid arthritis (RA) or undifferentiated arthritis (UA) started on methotrexate (MTX) 25 mg/week and prednisone (60 mg/day tapered to 7.5 mg/day). Patients not in early remission (Disease Activity Score <1.6 after 4 months) were randomised (single blind) to arm 1, adding hydroxychloroquine 400 mg/day and sulfasalazine 2000 mg/day, or arm 2, switching to MTX plus adalimumab 40 mg/2 weeks. Treatment adjustments over time aimed at DFR. Outcomes were remission percentages, functional ability, toxicity and radiological damage progression after 5 years.Results: After 4 months, 387 patients were in early remission, 83 were randomised to arm 1 and 78 to arm 2. After 5 years, 295/610 (48%) patients were in remission, 26% in sustained DFR (SDFR) (≥1 year) (220/387 (57%) remission and 135/387 (35%) SDFR in the early remission group, 50% remission, 11% SDFR in the randomisation arms without differences between the arms). More patients with UA (37% vs 23% RA, p=0.001) and more anticitrullinated protein antibody (ACPA)-negative patients (37% vs 18% ACPA-positive, p25 points in 5 years.Conclusions: Five years of DFR-steered treatment in patients with early RA resulted in almost normal functional ability without clinically relevant joint damage across treatment groups. Patients who achieved early remission had the best clinical outcomes. There were no differences between the randomisation arms. SDFR is a realistic treatment goal.
Comment
Esther Mossel, , Jolien F van Nimwegen, Alja J Stel, Erlin A Haacke, Frans G M Kroese, Fred K L Spijkervet, Arjan Vissink, Suzanne Arends, Hendrika Bootsma
Published: 29 September 2017
by BMJ
Annals of the Rheumatic Diseases, Volume 77; https://doi.org/10.1136/annrheumdis-2017-212331

Comment
Ritu Valiyil, Bruce Schechter
Published: 28 September 2017
by BMJ
Annals of the Rheumatic Diseases, Volume 77; https://doi.org/10.1136/annrheumdis-2017-212266

Abstract:
In his recent editorial commenting on the Combining Lesinurad with Allopurinol in Inadequate Responders studies,1 Dr Singh provides a thorough overview of the phase 3 trials demonstrating the efficacy and safety of lesinurad given in combination with allopurinol for the treatment of gout in patients who do not reach serum uric acid goal on …
, Stephanie Wichuk, Maxime Dougados, Heather E Jones, Ron Pedersen, Annette Szumski, Lisa Marshall, Jack F Bukowski, Robert G Lambert
Published: 29 September 2017
by BMJ
Annals of the Rheumatic Diseases, Volume 77, pp 78-84; https://doi.org/10.1136/annrheumdis-2017-211605

Abstract:
ObjectiveTo evaluate the impact on structural lesions observed on MRI in the sacroiliac joints (SIJ) at 12 weeks in patients with non-radiographic axial spondyloarthritis (nr-axSpA) receiving etanercept or placebo in EMBARK (Effect of Etanercept on Symptoms and Objective Inflammation in nr-axSpA, a 104 week study).MethodsPatients were randomised to double-blind etanercept 50 mg/week or placebo for 12 weeks. Structural lesions at baseline and 12 weeks were scored by two independent readers using the Spondyloarthritis Research Consortium of Canada (SPARCC) SIJ structural score (SSS) on T1-weighted MRI. Change in SPARCC SSS and correlation with improvement in clinical outcomes was evaluated.ResultsMRI scans from 185 patients (etanercept, n=88; placebo, n=97) were reviewed. At baseline, there were no significant differences in mean SPARCC SSS between etanercept and placebo. From baseline to 12 weeks, change in mean SPARCC SSS was significantly greater for etanercept than placebo for erosion (–0.57 vs –0.08, respectively, adjusted p value=0.017) and backfill (0.36 vs 0.06, adjusted p value=0.022). A treatment difference was also present for the subgroup of patients with SIJ inflammation on MRI (SPARCC bone marrow oedema ≥2): erosion: –0.81 versus –0.13 for etanercept versus placebo, respectively, p=0.007; backfill: 0.48 versus 0.08, respectively, p=0.032. Decrease in erosion and increase in backfill correlated with improvement in more clinical outcomes for etanercept than placebo.ConclusionTreatment with etanercept was associated with significantly greater reduction in erosions and increase in backfill at 12 weeks compared with placebo, consistent with a very early reparative response to antitumour necrosis factor therapy. The impact on disease progression in spondyloarthritis should be studied further.Trial registration numberNCT01258738; Post-results.
Claire Rempenault, Bernard Combe, Thomas Barnetche, Cécile Gaujoux-Viala, Cédric Lukas, Jacques Morel, Charlotte Hua
Published: 25 September 2017
by BMJ
Annals of the Rheumatic Diseases, Volume 77, pp 98-103; https://doi.org/10.1136/annrheumdis-2017-211836

Abstract:
ObjectiveCardiovascular disease (CVD) is the leading cause of mortality in patients with rheumatoid arthritis (RA). Hydroxychloroquine (HCQ) has been shown to improve survival rates in other inflammatory diseases. We aimed to assess the available literature on the cardiovascular impact of HCQ in patients with RA.MethodsWe systematically searched for studies evaluating the effects of HCQ on cardiovascular outcomes of known risk factors for CVD in patients with RA. Databases searched were MEDLINE (via PubMed), EMBase, Cochrane Library and the American College of Rheumatology and European League Against Rheumatism annual meetings. A meta-analysis was performed with a random-effects model, estimating mean differences (MDs), HRs and 95% CIs. Data were extracted by one investigator and independently checked by another.ResultsThe literature search revealed 185 articles and abstracts of interest; further examination resulted in 16 studies fulfilling the criteria. The MDs between HCQ users and non-users in levels of total, low-density and high-density cholesterol and triglycerides were −9.8 (95% CI −14.0 to −5.6), −10.6 (95% CI −14.2 to −7.0), +4.1 (95% CI 2.2 to 6.0) and −19.2 (95% CI −27.2 to −11.1), respectively. Diabetes incidence was lower for HCQ ever users than never users (HR 0.59 (95% CI 0.49 to 0.70)). HCQ seemed to decrease insulin resistance and incidence of CVD, but data were too few for meta-analysis.ConclusionBesides its limited efficacy for disease activity and progression, HCQ may benefit the metabolic profile and to a lesser extent cardiovascular events in patients with RA, which suggests its usefulness combined with other conventional synthetic disease-modifying antirheumatic drugs.
Comment
Published: 28 September 2017
by BMJ
Annals of the Rheumatic Diseases, Volume 77; https://doi.org/10.1136/annrheumdis-2017-212330

Abstract:
I thank Valiyil and Schechter for their letter1 to the editorial related to clinical studies of lesinurad.2 The letter correctly states that the 200 mg lesinurad dose is the only (initial and maximum) dose that should be prescribed to patients, always in combination with a xanthine oxidase inhibitor. The letter provides an important clarification regarding the dose of lesinurad that was approved by the regulatory agencies. Based on higher toxicity, the sponsor did not pursue regulatory approval (Food and Drug Administration (FDA) and European Medicines Agency (EMEA)) for …
, John D Cleveland
Published: 26 September 2017
by BMJ
Annals of the Rheumatic Diseases, Volume 77, pp 1243-1245; https://doi.org/10.1136/annrheumdis-2017-212094

Abstract:
Few recent studies1–3 reported that hyperuricemia may be protective against dementia, a common disease in the elderly associated with significant morbidity and mortality.4 5 We hypothesised that allopurinol or febuxostat use (the two most common urate-lowering therapies (ULTs)) in the elderly will be associated with a higher risk of dementia. Study methods for this new user design study (a more robust design than a prevalent user design) were similar to those previously reported.6 Patients were eligible for this retrospective cohort study if they were (1) US residents enrolled in Medicare fee-for-service (covers all Americans ≥65 years) with pharmacy coverage, ie, enrolled in Medicare parts A (inpatient care), B (outpatient doctor and laboratory service) and D (prescription drugs) and not enrolled in a Medicare Advantage Plan (a standard approach for analysis)7 during 2006–2012 and (2) filled a new allopurinol (or febuxostat) prescription with a clean baseline period of 365 days with no exposure to either drug. Incident dementia was identified by new occurrence (no diagnosis in the 183-day baseline period) of an International Classification of Diseases, 9th Revision code, 290.xx, 294.1x or 331.2, a valid approach for dementia studies.8 9 We followed each eligible patient until the loss of Medicare coverage, dementia, death or the end of the study period, whichever came first. We used multivariable-adjusted Cox proportional …
Margherita Zen, Luca Iaccarino, Mariele Gatto, Francesca Saccon, Maddalena LaRosa, Anna Ghirardello, ,
Published: 26 September 2017
by BMJ
Annals of the Rheumatic Diseases, Volume 77, pp 104-110; https://doi.org/10.1136/annrheumdis-2017-211613

Abstract:
ObjectiveTo evaluate the prevalence, duration and effect on damage accrual of the ‘Lupus Low Disease Activity State’ (LLDAS) in a monocentric cohort of patients with systemic lupus erythematosus (SLE).MethodsWe studied 293 Caucasian patients with SLE during a 7-year follow-up period. Disease activity was assessed by SLE Disease Activity Index 2000 (SLEDAI-2K) and SELENA-SLEDAI physician global assessment (PGA), and damage by Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). We considered the following definition of LLDAS: SLEDAI-2K ≤4 without major organ activity, no new disease activity, PGA (0–3)≤1, prednisone ≤7.5 mg/day and well-tolerated immunosuppressant dosages. The effect of LLDAS on SDI was evaluated by multivariate regression analysis. We also evaluated remission defined as clinical SLEDAI-2K=0 and prednisone ≤5 mg/day in patients treated with/without stable immunosuppressants and/or antimalarials.ResultsLLDAS lasting 1, 2, 3, 4 or ≥5 consecutive years was achieved by 33 (11.3%), 43 (14.7%), 39 (13.3%), 31 (10.6%) and 109 (37.2%) patients, respectively. Patients who spent at least two consecutive years in LLDAS had significantly less damage accrual compared with patients never in LLDAS (p=0.001), and they were significantly less likely to have an increase in SDI (OR 0.160, 95% CI 0.060 to 0.426, pConclusionsLLDAS was associated with a decrease in damage progression in Caucasian patients with SLE. The majority of patients in LLDAS were in remission, which can largely contribute to the protective effect of LLDAS on damage accrual.
, Monika Hansson, Linda Mathsson-Alm, , Evan Reed, Per-Johan Jakobsson, , , Karl Skriner, Guy Serre, et al.
Published: 25 October 2017
by BMJ
Annals of the Rheumatic Diseases, Volume 77, pp 203-211; https://doi.org/10.1136/annrheumdis-2017-211782

Abstract:
IntroductionThe second generation anticycliccitrullinated peptide (anti-CCP2) assay detects the majority but not all anticitrullinated protein/peptide antibodies (ACPA). Anti-CCP2-positive rheumatoid arthritis (RA) is associated with HLA-DRB1* shared epitope (SE) alleles and smoking. Using a multiplex assay to detect multiple specific ACPA, we have investigated the fine specificity of individual ACPA responses and the biological impact of additional ACPA reactivity among anti-CCP2-negative patients.MethodsWe investigated 2825 patients with RA and 551 healthy controls with full data on anti-CCP2, HLA-DRB1* alleles and smoking history concerning reactivity against 16 citrullinated peptides and arginine control peptides with a multiplex array.ResultsThe prevalence of the 16 ACPA specificities ranged from 9% to 58%. When reactivity to arginine peptides was subtracted, the mean diagnostic sensitivity increased by 3.2% with maintained 98% specificity. Of the anti-CCP2-negative patients, 16% were found to be ACPA positive. All ACPA specificities associated with SE, and all but one with smoking. Correction for arginine reactivity also conveyed a stronger association with SE for 13/16 peptides. Importantly, when all ACPA specificities were analysed together, SE and smoking associated with RA in synergy among ACPA positive, but not among ACPA-negative subjects also in the anti-CCP2-negative subset.ConclusionsMultiplexing detects an enlarged group of ACPA-positive but anti-CCP2-negative patients with genetic and environmental attributes previously assigned to anti-CCP2-positive patients. The individual correction for arginine peptide reactivity confers both higher diagnostic sensitivity and stronger association to SE than gross ACPA measurement.
Christina Bergmann, Amelie Brandt, Benita Merlevede, Ludwig Hallenberger, Clara Dees, Thomas Wohlfahrt, Sebastian Pötter, Yun Zhang, Chih-Wei Chen, Tatiana Mallano, et al.
Published: 25 October 2017
by BMJ
Annals of the Rheumatic Diseases, Volume 77, pp 150-158; https://doi.org/10.1136/annrheumdis-2017-211501

Abstract:
Objectives: Systemic sclerosis (SSc) fibroblasts remain activated even in the absence of exogenous stimuli. Epigenetic alterations are thought to play a role for this endogenous activation. Trimethylation of histone H3 on lysine 27 (H3K27me3) is regulated by Jumonji domain-containing protein 3 (JMJD3) and ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX) in a therapeutically targetable manner. The aim of this study was to explore H3K27me3 demethylases as potential targets for the treatment of fibrosis.Methods: JMJD3 was inactivated by small interfering RNA-mediated knockdown and by pharmacological inhibition with GSKJ4. The effects of targeted inactivation of JMJD3 were analysed in cultured fibroblasts and in the murine models of bleomycin-induced and topoisomerase-I (topoI)-induced fibrosis. H3K27me3 at the FRA2 promoter was analysed by ChIP.Results: The expression of JMJD3, but not of UTX, was increased in fibroblasts in SSc skin and in experimental fibrosis in a transforming growth factor beta (TGFβ)-dependent manner. Inactivation of JMJD3 reversed the activated fibroblast phenotype in SSc fibroblasts and prevented the activation of healthy dermal fibroblasts by TGFβ. Pharmacological inhibition of JMJD3 ameliorated bleomycin-induced and topoI-induced fibrosis in well-tolerated doses. JMJD3 regulated fibroblast activation in a FRA2-dependent manner: Inactivation of JMJD3 reduced the expression of FRA2 by inducing accumulation of H3K27me3 at the FRA2 promoter. Moreover, the antifibrotic effects of JMJD3 inhibition were reduced on knockdown of FRA2.Conclusion: We present first evidence for a deregulation of JMJD3 in SSc. JMJD3 modulates fibroblast activation by regulating the levels of H3K27me3 at the promoter of FRA2. Targeted inhibition of JMJD3 limits the aberrant activation of SSc fibroblasts and exerts antifibrotic effects in two murine models.
Jing Shi, , Gary P. Sims, , Kevon Sampson, , Clifton O. Bingham, Antony Rosen,
Published: 25 October 2017
by BMJ
Annals of the Rheumatic Diseases, Volume 77, pp 141-148; https://doi.org/10.1136/annrheumdis-2017-211489

Abstract:
ObjectivesThe citrullinating enzyme peptidylarginine deiminase type 4 (PAD4) is the target of a polyclonal group of autoantibodies in patients with rheumatoid arthritis (RA). A subgroup of such antibodies, initially identified by cross-reactivity with peptidylarginine deiminase type 3 (PAD3), is strongly associated with progression of radiographic joint damage and interstitial lung disease and has the unique ability to activate PAD4. The features of these antibodies in terms of their T cell-dependent origin, genetic characteristics and effect of individual antibody specificities on PAD4 function remain to be defined.MethodsWe used PAD4 tagged with the monomeric fluorescent protein mWasabi to isolate PAD4-specific memory B cells from anti-PAD4 positive patients with RA and applied single cell cloning technologies to obtain monoclonal antibodies.ResultsAmong 44 single B cells, we cloned five antibodies with PAD4-activating properties. Sequence analysis, germline reversion experiments and antigen specificity assays suggested that autoantibodies to PAD4 are not polyreactive and arise from PAD4-reactive precursors. Somatic mutations increase the agonistic activity of these antibodies at low calcium concentrations by facilitating their interaction with structural epitopes that modulate calcium-binding site 5 in PAD4.ConclusionsPAD4-activating antibodies directly amplify a key process in disease pathogenesis, making them unique among other autoantibodies in RA. Understanding the molecular basis for their functionality may inform the design of future PAD4 inhibitors.
Vassilios Vazgiourakis, Maria Zervou, Christianna Choulaki, , Darren Plant, Leendert A Trouw, Rene E Toes, Eleni Kabouraki, Jane Worthington, Prodromos Sidiropoulos, et al.
Published: 22 February 2011
by BMJ
Annals of the Rheumatic Diseases, Volume 70; https://doi.org/10.1136/ard.2010.148965.3

Abstract:
Background There is increasing evidence that different autoimmune diseases may share some common pathogenetic pathways. The CD40 locus has recently been identified by a genome-wide study as a genetic risk factor for rheumatoid arthritis (RA). CD40 is a member of the tumour necrosis factor receptor superfamily which is constitutively or inducible expressed on the surface of a variety of immune and non-immune cell types, indicating that this locus might be involved in several autoimmune diseases. Aim To investigate whether the rs4810485 single-nucleotide polymorphism (SNP) of CD40 gene is associated with the development of RA and systemic lupus erythematosus (SLE) in the genetic homogeneous population of the island of Crete. The functional significance of this gene polymorphism will also be analysed. Materials and methods The SLE and RA sample sets consisted of 351 and 272 patients, respectively, while the control group consisted of 670 samples. Genotyping of the rs4810485 SNP was performed by PCR-restriction fragment length polymorphism or using the Sequenom MassArray technology. Genotyping of rs4810485 was performed by PCR-restriction fragment length polymorphism and by the Sequenom MassArray technology. The expression of CD40 in SLE patients with different genotypes was assessed in peripheral blood mononuclear cells (PBMCs) by flow cytometry. Quantification of CD40 mRNA was performed by quantitative real time PCR in freshly isolated PBMCs from patients with different genotype. Results The risk allele G of the CD40 rs4810485 SNP was more frequent in individuals with SLE and RA than in healthy controls (p<0.0001, OR 1.5, 95% CI 1.3 to 1.9 and p<0.0001, OR 1.6, 95% CI 1.3 to 1.9 respectively). SLE patients with the rs4810485 G/G genotype had significantly higher CD40 mRNA and protein expression in freshly isolated peripheral blood B cells and monocytes, compared to patients with the G/T or T/T genotype. Conclusions The CD40 rs4810485 SNP is associated with increased susceptibility to both SLE and RA in a homogeneous Greek population. Identification of shared genetic susceptibility loci may provide insight to their understanding of the pathophysiology of autoimmune diseases. The risk allele G seems to confer susceptibility to clinically distinct disorders through similar or differential effects on disease-specific cell types. Quantitative analysis of the allelic expression of CD40 in SLE patients demonstrated that the risk allele was accompanied by higher expression of CD40 both at mRNA and protein level especially in B lymphocytes and CD14 monocytes.
, Barbara G Fürnrohr, , Joan T Merrill,
Published: 21 February 2011
by BMJ
Annals of the Rheumatic Diseases, Volume 70; https://doi.org/10.1136/ard.2010.138057

Abstract:
Observations of familial aggregation (λs=8–29) and a 40% identical twin concordance rate prompted recent work towards a comprehensive genetic analysis of systemic lupus erythematosus (SLE). Since 2007, the number of genetic effects known to be associated with human lupus has increased by fivefold, underscoring the complexity of inheritance that probably contributes to this disease. Approximately 35 genes associated with lupus have either been replicated in multiple samples or are near the threshold for genome-wide significance (p>5×10−8). Some are rare variants that convincingly contribute to lupus only in specific subgroups. Strong associations have been found with a large haplotype block in the human leucocyte antigen region, with Fcγ receptors, and with genes coding for complement components, in which a single gene deletion may cause SLE in rare familial cases and copy number variation is more common in the larger population of SLE patients. Examples of newly discovered genes include ITGAM, STAT4 and MECP2/IRAK1. Ongoing studies to build models in which combinations of associated genes might contribute to specific disease manifestations should contribute to improved understanding of disease pathology. In addition, pharmacogenomic components of ongoing clinical trials are likely to provide insights into fundamental disease pathology as well as contributing to informed patient selection for targeted treatments and biomarkers to guide dosing and gauge responsiveness. Besides these potentially valuable new insights into the pathophysiology of an enigmatic, potentially deadly, and, as yet, unsolved disease, genetic studies are likely to suggest novel molecular targets for strategic development of safer and more effective therapeutics.
Published: 21 February 2011
by BMJ
Annals of the Rheumatic Diseases, Volume 70; https://doi.org/10.1136/ard.2010.138024

Abstract:
Antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides are characterised by necrotising inflammation of small vessels in conjunction with ANCA directed to either proteinase 3 (PR3) or myeloperoxidase (MPO). The aetiopathogenesis of these disorders is still not fully elucidated but clinical as well as in vitro and in vivo experimental data strongly suggest a role for the autoimmune responses to PR3 and MPO in disease development. Clinically, PR3-ANCA are strongly associated with granulomatous vasculitis as in Wegener's granulomatosis, and MPO-ANCA with necrotising small vessel vasculitis as in microscopic polyangiitis. Levels of PR3-ANCA and MPO-ANCA do, however, not fully reflect disease activity. In vitro, ANCA activate primed neutrophils to release lytic enzymes and reactive oxygen species, a process reinforced by the alternative pathway of complement. In the context of endothelial cells, this process leads to endothelial detachment and lysis. In vivo experimental studies have clearly demonstrated the pathogenic potential of MPO-ANCA for necrotising glomerulonephritis and pulmonary capillaritis. For PR3-ANCA-associated granulomatous vasculitis, an animal model is lacking. Here, effector T cells, in particular Th17 cells, appear to have a major pathogenic role in addition to ANCA. Finally, microbial factors, derived in particular from S aureus and Gram-negative bacteria, could play a part in disease induction and expression. These new insights into the pathogenesis of ANCA-associated vasculitides have opened new ways for targeted treatment.
, M J Citores, R Castejon, P Tutor-Ureta, M Yebra-Bango, , J A Vargas
Published: 1 April 2006
by BMJ
Annals of the Rheumatic Diseases, Volume 65, pp 553-554; https://doi.org/10.1136/ard.2005.044974

Abstract:
Thirty three patients with SLE (26 women, 7 men) and 14 healthy volunteers matched for age and sex (11 women, 3 men) with a mean age of 39.9 and 36 years, respectively, were studied. All patients fulfilled at least four of the American College of Rheumatology 1982 revised criteria for the classification of SLE.6 Disease activity at the time of blood sampling was assessed using the SLE Disease Activity Index (SLEDAI).7
Carina Mihai, Milos Antic, Rucsandra Dobrota, Diana Bonderman, Harbajan Chadha-Boreham, John Gerry Coghlan, Christopher P Denton, Martin Doelberg, Ekkehard Grünig, , et al.
Published: 23 October 2017
by BMJ
Annals of the Rheumatic Diseases, Volume 77, pp 128-132; https://doi.org/10.1136/annrheumdis-2017-211480

Abstract:
ObjectivePulmonary arterial hypertension (PAH) is a severe complication of systemic sclerosis (SSc). In this longitudinal study, we aimed to identify factors associated with an unfavourable outcome in patients with SSc with early PAH (SSc-PAH) from the DETECT cohort.MethodsPatients with SSc-PAH enrolled in DETECT were observed for up to 3 years. Associations between cross-sectional variables and disease progression (defined as the occurrence of any of the following events: WHO Functional Class worsening, combination therapy for PAH, hospitalisation or death) were analysed by univariable logistic regression.ResultsOf 57 patients with PAH (median observation time 12.6 months), 25 (43.9%) had disease progression. The following factors (OR (95% CI)) were associated with disease progression: male gender (4.1 (1.2 to 14.1)), high forced vital capacity % predicted/carbon monoxide lung diffusion capacity (DLCO)% predicted ratio (3.6 (1.2 to 10.7)), high Borg Dyspnoea Index (1.7 (1.1 to 2.6)) and low DLCO% predicted (non-linear relationship).ConclusionMore than 40% of early-diagnosed patients with SSc-PAH had disease progression during a short follow-up time, with male gender, functional capacity and pulmonary function tests at PAH diagnosis being associated with progression. This suggests that even mild PAH should be considered a high-risk complication of SSc.
Comment
, , Johannes W G Jacobs
Published: 22 October 2017
by BMJ
Annals of the Rheumatic Diseases, Volume 77, pp 790-792; https://doi.org/10.1136/annrheumdis-2017-211893

Abstract:
Decades of research led to the current concept that chronic pain encompasses multiple and mutually interacting biological, psychological and social factors. These include—but are not limited to—nature of pain, peripheral and central pain processing mechanisms, physical disability, sleep disturbance, obesity, smoking, alcoholism and other health risks, psychological resilience and vulnerabilities (emotions, cognitions, behaviour) and social factors (work, support, facilities, financial resources). Relations between all factors of this biopsychosocial model are recognised to be dynamic and reciprocal, with mutually influencing pathways similar to a hanging mobile toy, in which movement of one component may induce change in all others and back. The weight of the distinct factors differs between individuals.
, Jung-Yoon Choe, Nenad Prodanovic, Jaroslaw Niebrzydowski, Ivan Staykov, Eva Dokoupilova, Asta Baranauskaite, , Mevludin Mekic, Wieslawa Porawska, et al.
Published: 17 October 2017
by BMJ
Annals of the Rheumatic Diseases, Volume 77, pp 234-240; https://doi.org/10.1136/annrheumdis-2017-211741

Abstract:
ObjectivesEfficacy, safety and immunogenicity results from the phase III study of SB2, a biosimilar of reference infliximab (INF), were previously reported through 54 weeks. This transition period compared results in patients with rheumatoid arthritis (RA) who switched from INF to SB2 with those in patients who maintained treatment with INF or SB2.MethodsPatients with moderate to severe RA despite methotrexate treatment were randomised (1:1) to receive SB2 or INF at weeks 0, 2 and 6 and every 8 weeks thereafter until week 46. At week 54, patients previously receiving INF were rerandomised (1:1) to switch to SB2 (INF/SB2 (n=94)) or to continue on INF (INF/INF (n=101)) up to week 70. Patients previously receiving SB2 continued on SB2 (SB2/SB2 (n=201)) up to week 70. Efficacy, safety and immunogenicity were assessed up to week 78.ResultsEfficacy was sustained and comparable across treatment groups. American College of Rheumatology (ACR) 20 responses between weeks 54 and 78 ranged from 63.5% to 72.3% with INF/SB2, 66.3%%–69.4% with INF/INF and 65.6%–68.3% with SB2/SB2. Treatment-emergent adverse events during this time occurred in 36.2%, 35.6% and 40.3%, respectively, and infusion-related reactions in 3.2%, 2.0% and 3.5%. Among patients who were negative for antidrug antibodies (ADA) up to week 54, newly developed ADAs were reported in 14.6%, 14.9% and 14.1% of the INF/SB2, INF/INF and SB2/SB2 groups, respectively.ConclusionsThe efficacy, safety and immunogenicity profiles remained comparable among the INF/SB2, INF/INF and SB2/SB2 groups up to week 78, with no treatment-emergent issues or clinically relevant immunogenicity after switching from INF to SB2.Trial registration numberNCT01936181; EudraCT number: 2012-005733-37.
Comment
Published: 11 October 2017
by BMJ
Annals of the Rheumatic Diseases, Volume 77; https://doi.org/10.1136/annrheumdis-2017-212483

Abstract:
We read with interest the article by Schönau et al ,1 a rare prospective study performed in the setting of fever/inflammation of unknown origin (FUO/IUO). They concluded that positron emitted tomography (PET)/CT is helpful in the diagnosis of the underlying cause of fever/inflammation not elucidated with a preliminary diagnostic work-up. Notwithstanding the merits of the study, there are aspects that may deserve additional comments. To fulfil the concept of FUO/IUO, the patient has to have a condition whose diagnosis is …
Jasmin B Kuemmerle-Deschner, Sandra Hansmann, , , , , Tadej Avcin, , Isabelle Koné-Paut, Yosef Uziel, et al.
Published: 11 October 2017
by BMJ
Annals of the Rheumatic Diseases, Volume 77, pp 319-327; https://doi.org/10.1136/annrheumdis-2017-211904

Abstract:
Innovative research in childhood rheumatic diseases mandates international collaborations. However, researchers struggle with significant regulatory heterogeneity; an enabling European Union (EU)-wide framework is missing. The aims of the study were to systematically review the evidence for best practice and to establish recommendations for collaborative research. The Paediatric Rheumatology European Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) project enabled a scoping review and expert discussion, which then informed the systematic literature review. Published evidence was synthesised; recommendations were drafted. An iterative review process and consultations with Ethics Committees and European experts for ethical and legal aspects of paediatric research refined the recommendations. SHARE experts and patient representatives vetted the proposed recommendations at a consensus meeting using Nominal Group Technique. Agreement of 80% was mandatory for inclusion. The systematic literature review returned 1319 records. A total of 223 full-text publications plus 22 international normative documents were reviewed; 85 publications and 16 normative documents were included. A total of 21 recommendations were established including general principles (1–3), ethics (4–7), paediatric principles (8 and 9), consent to paediatric research (10–14), paediatric databank and biobank (15 and 16), sharing of data and samples (17–19), and commercialisation and third parties (20 and 21). The refined recommendations resulted in an agreement of >80% for all recommendations. The SHARE initiative established the first recommendations for Paediatric Rheumatology collaborative research across borders in Europe. These provide strong support for an urgently needed European framework and evidence-based guidance for its implementation. Such changes will promote research in children with rheumatic diseases.
Comment
Published: 9 October 2017
by BMJ
Annals of the Rheumatic Diseases, Volume 77; https://doi.org/10.1136/annrheumdis-2017-212463

Abstract:
Statins represent an important therapeutic option for prescription by rheumatologists due to their preventive effects related to cardiovascular disease as well as their immunoregulatory activity. De Jong et al 1 recently published a report emphasising the use of statins as safety drugs, whose diverse effects in immune modulation could be related to autoimmune disorders. Although De Jong’s cohort shows no association with autoimmune disease development such as systemic lupus erythematosus (SLE), in our view, the data could support potential prevention of SLE. Fasano et al 2 recently …
Comment
Young Ho Lee
Published: 9 October 2017
by BMJ
Annals of the Rheumatic Diseases, Volume 77; https://doi.org/10.1136/annrheumdis-2017-212452

Abstract:
I read with great interest the article by Reginster and colleagues1 regarding the effectiveness of chondroitin sulfate (CS) in the treatment of symptomatic knee osteoarthritis (OA). This randomised, double-blind trial demonstrated that pharmaceutical-grade CS is superior to placebo and equivalent to celecoxib in reducing pain and improving function over 6 months in patients with symptomatic knee OA, indicating that this formulation of CS should be considered a first-line treatment in the …
Comment
Mary Safy, , Nicole D Ijff, , J M Van Laar, Maria J H De Hair
Published: 9 October 2017
by BMJ
Annals of the Rheumatic Diseases, Volume 77; https://doi.org/10.1136/annrheumdis-2017-212380

Abstract:
In their letter to the editor ‘Discussion of Methotrexate Dosage’, Maguire et al 1 raised three issues regarding our recent paper.2 We appreciate their interest in our study and will address these issues here. First, regarding the methotrexate dosage, we reiterate what we have discussed in the discussion section of our paper: ‘As in the post-trial follow-up period, the controlled situation was lost and treatment was open to the rheumatologists, long-term outcomes in our study may have been influenced by the use of different antirheumatic drugs’. We did not …
Anna Tjärnlund, , Cecilia Wick, Maryam Dastmalchi, , Jana Tomasová Studýnková, Radka Chura, , Rosaria Salerno, , et al.
Published: 9 October 2017
by BMJ
Annals of the Rheumatic Diseases, Volume 77, pp 55-62; https://doi.org/10.1136/annrheumdis-2017-211751

Abstract:
Objectives: To study the effects of abatacept on disease activity and on muscle biopsy features of adult patients with dermatomyositis (DM) or polymyositis (PM).Methods: Twenty patients with DM (n=9) or PM (n=11) with refractory disease were enrolled in a randomised treatment delayed-start trial to receive either immediate active treatment with intravenous abatacept or a 3 month delayed-start. The primary endpoint was number of responders, defined by the International Myositis Assessment and Clinical Studies Group definition of improvement (DOI), after 6 months of treatment. Secondary endpoints included number of responders in the early treatment arm compared with the delayed treatment arm at 3 months. Repeated muscle biopsies were investigated for cellular markers and cytokines.Results: 8/19 patients included in the analyses achieved the DOI at 6 months. At 3 months of study, five (50%) patients were responders after active treatment but only one (11%) patient in the delayed treatment arm. Eight adverse events (AEs) were regarded as related to the drug, four mild and four moderate, and three serious AEs, none related to the drug. There was a significant increase in regulatory T cells (Tregs), whereas other markers were unchanged in repeated muscle biopsies.Conclusions: In this pilot study, treatment of patients with DM and PM with abatacept resulted in lower disease activity in nearly half of the patients. In patients with repeat muscle biopsies, an increased frequency of Foxp3+ Tregs suggests a positive effect of treatment in muscle tissue.
, Lena Nise, , Anca Irinel Catrina, Johan Askling, Karin Lundberg, Lars Klareskog,
Published: 6 October 2017
by BMJ
Annals of the Rheumatic Diseases, Volume 77, pp 1236-1238; https://doi.org/10.1136/annrheumdis-2017-212091

Abstract:
An association between periodontitis and rheumatoid arthritis (RA) has been proposed based on observations of increased risk of periodontitis in patients with RA as well as the presence of antibodies to citrullinated protein antigens (ACPAs) and rheumatoid factor (RF) in serum and gingiva of patients with periodontitis.1–3 Additionally, smoking is one of the most important risk factors for both periodontitis and RA, and predispose for the development of seropositive RA.4–6 We have previously reported that smokers with RA have increased prevalence of periodontitis as compared with never smokers in the Swedish population-based case–control study EIRA (Epidemiological Investigation of Rheumatoid Arthritis).7 The objective of the current study was to further investigate the effects of smoking on the risk of periodontitis in seropositive and seronegative (ACPA/RF) subsets of RA. Data on periodontal status (years 2008–2012) were retrieved from the Swedish Dental Health Registry (DHR) for 2327 patients with established RA (1469/852 ACPA-positive/ACPA-negative and 1505/822 RF-positive/RF-negative, respectively) included in the EIRA study (years 1996–2009) as previously described.7 Periodontal diagnosis was based on diagnostic codes for periodontitis, peri-implantitis and …
Comment
Published: 4 October 2017
by BMJ
Annals of the Rheumatic Diseases, Volume 77; https://doi.org/10.1136/annrheumdis-2017-212425

Abstract:
I commend the authors for this very important study.1 There has been an association between obesity and C-reactive protein (CRP) levels. USA has …
, Daniel Wojdyla, , Luis J Catoggio, , Judith Sarano, Guillermo Berbotto, , , João C Tavares Brenol, et al.
Published: 22 September 2017
by BMJ
Annals of the Rheumatic Diseases, Volume 76, pp 2071-2074; https://doi.org/10.1136/annrheumdis-2017-211814

Abstract:
ObjectiveTo evaluate disease activity statuses’ (DAS’) impact on systemic lupus erythematosus (SLE) outcomes.Materials and methodsFour DAS were defined: remission off-therapy: SLE Disease Activity Index (SLEDAI)=0, no prednisone or immunosuppressive drugs (IS); remission on-therapy: SLEDAI=0, prednisone ≤5 mg/day and/or IS (maintenance); low (L) DAS: SLEDAI ≤4, prednisone ≤7.5 mg/day and/or IS (maintenance); non-optimally controlled: SLEDAI >4 and/or prednisone >7.5 mg/day and/or IS (induction). Antimalarials were allowed in all. Predefined outcomes were mortality, new damage (increase of at least one Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) damage index (SDI) point) and severe new damage (increase of at least 3 SDI points). Univariable and multivariable Cox regression models were performed to define the impact of DAS, as time-dependent variable, on these outcomes.Results1350 patients were included, 79 died during follow-up, 606 presented new and 177 severe new damage. In multivariable analyses, remission (on/off-therapy) was associated with a lower risk of new (HR 0.60; 95% CI 0.43 to 0.85), and of severe new damage (HR 0.32; 95% CI 0.15 to 0.68); low disease activity status (LDAS) was associated with a lower risk of new damage (HR 0.66; 95% CI 0.48 to 0.93) compared with non-optimally controlled. No significant effect on mortality was observed.ConclusionsRemission was associated with a lower risk of new and severe new damage; LDAS with a lower risk of new damage after adjusting for other damage confounders.
Comment
Jean-Yves L Reginster
Published: 22 September 2017
by BMJ
Annals of the Rheumatic Diseases, Volume 77; https://doi.org/10.1136/annrheumdis-2017-212165

Abstract:
We are very grateful to our distinguished colleague for his constructive comments.1 However it seems that some keypoints of our study were grossly misunderstood.2 As clearly stated, the objective of the CONCEPT study was to confirm that chondroitin sulfate (CS) is superior to placebo (PLB) in the symptomatic treatment of osteoarthritis, with the addition of a Celebrex (CLB) arm, as requested by the European Medicines Agency, to provide an external validation and to better assess the relevance of the difference in pain relief observed between the CS and PLB arms. There was no intent to demonstrate a non-inferiority of CS versus Celebrex. In such a case, a non-inferiority margin for the comparison would be mentioned in the protocol, and the power calculation would be substantially different. The use of the word similar in describing Visual Analogue Scale (VAS) and Lequesne scoring …
Comment
Published: 22 September 2017
by BMJ
Annals of the Rheumatic Diseases, Volume 77; https://doi.org/10.1136/annrheumdis-2017-212164

Abstract:
We thank Alunno et al 1 for their comments, as a response to our recent publication2 in which we describe that, in contrast to the prevailing view, germinal centres in diagnostic labial gland biopsies are not predictive for the development of mucosa-associated lymphoid tissue (MALT) lymphoma in parotid salivary glands in patients with (primary) Sjögren’s syndrome (pSS). As we2 and others also noted before,3–6 Alunno et al 1 underpin in their comments the need for standardisation of the detection method of germinal centres in salivary gland biopsies in patients with pSS. Germinal centres are structures that arise in B-cell follicles of secondary lymphoid organs as a response to antigenic stimulation. In these structures, high-affinity memory B-cells are generated, as a consequence of an intimate interplay between B-cells, follicular helper T cells (TFH) and immune-complex presenting follicular dendritic cells (FDCs). Germinal centres can also be found within B-cell areas of ectopic (tertiary) lymphoid tissue that develops in target tissues of various rheumatic autoimmune diseases, including pSS.7 While detection in secondary lymphoid tissue is …
Published: 22 September 2017
by BMJ
Annals of the Rheumatic Diseases, Volume 77, pp 484-487; https://doi.org/10.1136/annrheumdis-2017-211781

Abstract:
ObjectiveHigh adalimumab serum concentrations do not result in better response in patients with rheumatoid arthritis (RA), suggesting overexposure. We investigated whether patients with adalimumab concentrations >8 µg/mL can prolong their dosing interval by 50% without a clinically relevant change in disease activity.MethodsConsecutive patients with RA, treated with adalimumab 40 mg every other week for at least 28 weeks, were approached for this randomised, open-label, non-inferiority trial. Patients with adalimumab trough concentrations >8 µg/mL were randomly (1:1) assigned to dose-interval prolongation of once every 3 weeks or continuation of every other week. Primary outcome was the change in disease activity score of 28 joints (ΔDAS28-ESR) after 28 weeks, with a non-inferiority margin of 0.6 points.ResultsIn total, 147 patients were screened. Fifty-five patients had concentrations >8 µg/mL and were randomised. Mean ΔDAS28 after 28 weeks was –0.14±SD 0.61 in the prolongation group and 0.30±0.52 in the continuation group. Mean difference was significantly in favour of the prolongation group: 0.44 (95% CI 0.12 to 0.76, p=0.01).ConclusionsAdalimumab-treated patients with RA with trough concentrations >8 µg/mL can prolong their standard dosing interval to once every 3 weeks without loss of disease control.Trial registration numberNTR3509; Results.
Comment
Published: 22 September 2017
by BMJ
Annals of the Rheumatic Diseases, Volume 77, pp 317-318; https://doi.org/10.1136/annrheumdis-2017-211975

Abstract:
In ARD, Latourte et al used the data from a community-based prospective French cohort study of healthy 4931 elderly people 65 years or older, examined at six clinical visits (including cognitive examinations) over 12 years, and analysed 1598 participants with a baseline serum urate level (serum uric acid (sUA)), no diagnosis of dementia, a Mini-Mental State Examination (MMSE) score of >24 and at least one follow-up visit.1 Dementia was diagnosed in a 3-step process, screening using the MMSE and the Isaacs Set Test by trained psychologists, additional neuropsychological testing by a physician, and adjudication based on criteria by an independent committee of neurologists. Dementia developed in 110 subjects during the 13 357 person years of follow-up. Multivariable-adjusted HR with the highest (≥5.8 mg/dL in men, ≥4.9 mg/dL in women) versus the lowest sUA quartile (≤4.37 and ≤3.51 mg/dL, respectively) was 1.79 for incident dementia (95% CI 1.17 to 2.73; p=0.007). A strong association was seen with vascular or mixed dementia (HR=3.66 (95% CI 1.29 to 10.41), p=0.015), and no significant association was noted with Alzheimer’s disease (HR=1.55 (95% CI 0.91 to 2.61), p=0.10). Several important aspects of this study need to be carefully considered while interpreting findings: (1) patients on urate-lowering therapies (ULTs) were excluded; (2) there was no significant association between sUA levels and MRI markers of cerebrovascular disease or hippocampal volume; and (3) the association between sUA and vascular or mixed dementia was no longer significant, when adjusted for interim strokes. The authors carefully noted that these findings were not generalisable to hyperuricaemia or gout cohorts or to those younger than 65 years. When one examines other studies in this area, the evidence is contradictory. Some studies showed that hyperuricaemia was associated with a lower risk of dementia,2–4 while other studies showed an opposite effect.5–10 A major limitation is that most of these studies providing the evidence …
Christoph Molnar, Almut Scherer, , Manouk De Hooge, , Pascale Exer, Rudolf O Kissling, Giorgio Tamborrini, Lukas M Wildi, Michael J Nissen, et al.
Published: 22 September 2017
by BMJ
Annals of the Rheumatic Diseases, Volume 77, pp 63-69; https://doi.org/10.1136/annrheumdis-2017-211544

Abstract:
ObjectivesTo analyse the impact of tumour necrosis factor inhibitors (TNFis) on spinal radiographic progression in ankylosing spondylitis (AS).MethodsPatients with AS in the Swiss Clinical Quality Management cohort with up to 10 years of follow-up and radiographic assessments every 2 years were included. Radiographs were scored by two readers according to the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) with known chronology. The relationship between TNFi use before a 2-year radiographic interval and progression within the interval was investigated using binomial generalised estimating equation models with adjustment for potential confounding and multiple imputation of missing values. Ankylosing Spondylitis Disease Activity Score (ASDAS) was regarded as mediating the effect of TNFi on progression and added to the model in a sensitivity analysis.ResultsA total of 432 patients with AS contributed to data for 616 radiographic intervals. Radiographic progression was defined as an increase in ≥2 mSASSS units in 2 years. Mean (SD) mSASSS increase was 0.9 (2.6) units in 2 years. Prior use of TNFi reduced the odds of progression by 50% (OR 0.50, 95% CI 0.28 to 0.88) in the multivariable analysis. While no direct effect of TNFi on progression was present in an analysis including time-varying ASDAS (OR 0.61, 95% CI 0.34 to 1.08), the indirect effect, via a reduction in ASDAS, was statistically significant (OR 0.75, 95% CI 0.59 to 0.97).ConclusionTNFis are associated with a reduction of spinal radiographic progression in patients with AS. This effect seems mediated through the inhibiting effect of TNFi on disease activity.
Comment
Sinead A Maguire, Claire Marie Sheehy
Published: 22 September 2017
by BMJ
Annals of the Rheumatic Diseases, Volume 77; https://doi.org/10.1136/annrheumdis-2017-212358

Abstract:
We thank Safy et al 1 for their recent article discussing clinical outcomes in early treatment of rheumatoid arthritis with methotrexate and 10 mg daily of prednisolone versus methotrexate alone. This was a post-trial follow-up of the CAMERA II trial, which monitored for radiographic evidence of disease progression, use of biologic disease-modifying antirheumatic drugs (DMARDs) and incidence of glucocorticoid comorbidities. We appreciate the work that …
Takayoshi Morita, Kosuke Fujimoto, Yoshihito Shima, , Atsushi Kumanogoh
Published: 22 September 2017
by BMJ
Annals of the Rheumatic Diseases, Volume 77; https://doi.org/10.1136/annrheumdis-2017-212366

Abstract:
Clowse et al 1 have reported minimal to no transfer of certolizumab pegol (CZP) into breast milk, and their findings have supported the continuation of CZP treatment during breast milk feeding. Rheumatoid arthritis (RA) often develops in women of childbearing age. It is generally difficult to treat these patients with methotrexate, which is the anchor drug for RA. Therefore, biologics, such as tumour necrosis factor (TNF) inhibitors, are often considered for active RA during pregnancy. However, the biologics cross the placenta from mother to fetus and transfer into breast milk during lactation. Although a meta-analysis report indicated that anti-TNF-α therapy did not increase the risks, such as congenital malformation or abortion during pregnancy, in patients with inflammatory …
Leonard Calabrese, Xavier Mariette
Published: 19 September 2017
by BMJ
Annals of the Rheumatic Diseases, Volume 77, pp 162-164; https://doi.org/10.1136/annrheumdis-2017-212061

Abstract:
The rapid introduction of immunotherapies for cancer-targeting immunological checkpoints has led to a new class of toxicities that appear to be of autoimmune and or autoinflammatory origin. These disorders are now referred to as immune-related adverse events (irAEs) and pose considerable challenges to patient care in terms of how to optimally manage these formidable toxicities while allowing effective antitumoural therapy to continue. While rheumatologists will naturally be called on to manage those irAEs of rheumatic origin, we believe there is a need and an opportunity for rheumatologists to participate as central figures in this evolving field, in large part because of our familiarity with multiorgan autoimmune disease and our expertise in crafting and utilising both traditional and biological immune-based therapies. Rheumatologists urgently need education in this evolving field to be best positioned as contributors to care of such patients and investigators of the underlying mechanisms of these complications.
Verena Schönau, Kristin Vogel, Matthias Englbrecht, Jochen Wacker, Daniela Schmidt, Bernhard Manger, Torsten Kuwert,
Published: 19 September 2017
by BMJ
Annals of the Rheumatic Diseases, Volume 77, pp 70-77; https://doi.org/10.1136/annrheumdis-2017-211687

Abstract:
Background: Fever of unknown origin (FUO) and inflammation of unknown origin (IUO) are diagnostically challenging conditions. Diagnosis of underlying disease may be improved by 18F-fluorodesoxyglucose positron emission tomography (18F-FDG-PET).Methods: Prospective study to test diagnostic utility of 18F-FDG-PET/CT in a large cohort of patients with FUO or IUO and to define parameters that increase the likelihood of diagnostic 18F-FDG-PET/CT. Patients with FUO or IUO received 18F-FDG-PET/CT scanning in addition to standard diagnostic work-up. 18F-FDG-PET/CT results were classified as helpful or non-helpful in establishing final diagnosis. Binary logistic regression was used to identify clinical parameters associated with a diagnostic 18F-FDG-PET/CT.Results: 240 patients were enrolled, 72 with FUO, 142 with IUO and 26 had FUO or IUO previously (exFUO/IUO). Diagnosis was established in 190 patients (79.2%). The leading diagnoses were adult-onset Still’s disease (15.3%) in the FUO group, large vessel vasculitis (21.1%) and polymyalgia rheumatica (18.3%) in the IUO group and IgG4-related disease (15.4%) in the exFUO/IUO group. In 136 patients (56.7% of all patients and 71.6% of patients with a diagnosis), 18F-FDG-PET/CT was positive and helpful in finding the diagnosis. Predictive markers for a diagnostic 18F-FDG-PET/CT were age over 50 years (p=0.019), C-reactive protein (CRP) level over 30 mg/L (p=0.002) and absence of fever (p=0.001).Conclusion: 18F-FDG-PET/CT scanning is helpful in ascertaining the correct diagnosis in more than 50% of the cases presenting with FUO and IUO. Absence of intermittent fever, higher age and elevated CRP level increase the likelihood for a diagnostic 18F-FDG-PET/CT.
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