Identification of distinct subgroups of Sjögren's disease by cluster analysis based on clinical and biological manifestations: data from the cross-sectional Paris-Saclay and the prospective ASSESS cohorts.

BACKGROUND: Sjögren's disease is a heterogenous autoimmune disease with a wide range of symptoms-including dryness, fatigue, and pain-in addition to systemic manifestations and an increased risk of lymphoma. We aimed to identify distinct subgroups of the disease, using cluster analysis based on subjective symptoms and clinical and biological manifestations, and to compare the prognoses of patients in these subgroups. METHODS: This study included patients with Sjögren's disease from two independent cohorts in France: the cross-sectional Paris-Saclay cohort and the prospective Assessment of Systemic Signs and Evolution of Sjögren's Syndrome (ASSESS) cohort. We first used an unsupervised multiple correspondence analysis to identify clusters within the Paris-Saclay cohort using 26 variables comprising patient-reported symptoms and clinical and biological manifestations. Next, we validated these clusters using patients from the ASSESS cohort. Changes in disease activity (measured by the European Alliance of Associations for Rheumatology [EULAR] Sjögren's Syndrome Disease Activity Index [ESSDAI]), patient-acceptable symptom state (measured by the EULAR Sjögren's Syndrome Patient Reported Index [ESSPRI]), and lymphoma incidence during follow-up were compared between clusters. Finally, we compared our clusters with the symptom-based subgroups previously described by Tarn and colleagues. FINDINGS: 534 patients from the Paris-Saclay cohort (502 [94%] women, 32 [6%] men, median age 54 years [IQR 43-64]), recruited between 1999 and 2022, and 395 patients from the ASSESS cohort (370 [94%] women, 25 [6%] men, median age 53 years [43-63]), recruited between 2006 and 2009, were included in this study. In both cohorts, hierarchical cluster analysis revealed three distinct subgroups of patients: those with B-cell active disease and low symptom burden (BALS), those with high systemic disease activity (HSA), and those with low systemic disease activity and high symptom burden (LSAHS). During follow-up in the ASSESS cohort, disease activity and symptom states worsened for patients in the BALS cluster (67 [36%] of 186 patients with ESSPRI score <5 at month 60 vs 92 [49%] of 186 at inclusion; p<0·0001). Lymphomas occurred in patients in the BALS cluster (five [3%] of 186 patients; diagnosed a median of 70 months [IQR 42-104] after inclusion) and the HSA cluster (six [4%] of 158 patients; diagnosed 23 months [13-83] after inclusion). All patients from the Paris-Saclay cohort with a history of lymphoma were in the BALS and HSA clusters. This unsupervised clustering classification based on symptoms and clinical and biological manifestations did not correlate with a previous classification based on symptoms only. INTERPRETATION: On the basis of symptoms and clinical and biological manifestations, we identified three distinct subgroups of patients with Sjögren's disease with different prognoses. Our results suggest that these subgroups represent different heterogeneous pathophysiological disease mechanisms, stages of disease, or both. These findings could be of interest when stratifying patients in future therapeutic trials. FUNDING: Fondation pour la Recherche Médicale, French Ministry of Health, French Society of Rheumatology, Innovative Medicines Initiative 2 Joint Undertaking, Medical Research Council UK, and Foundation for Research in Rheumatology.

Accuracy of self-reported diagnoses of polymyalgia rheumatica and giant cell arteritis in the French prospective E3N- EPIC cohort: A validation study.

OBJECTIVES: To assess the accuracy of self-reported giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) diagnoses in a large French population-based prospective cohort, and to devise algorithms to improve their accuracy. METHODS: The E3N-EPIC cohort study (Etude Epidémiologique auprès des femmes de la Mutuelle Générale de l'Education Nationale) includes 98,995 French women born between 1925 and 1950, recruited in 1990 to study risk factors of cancer and chronic diseases. They completed biennially mailed questionnaires to update their health-related information and lifestyle characteristics. In three questionnaires, women could self-report a diagnosis of GCA/PMR. Those women were additionally sent a specific questionnaire, designed to ascertain self-reported diagnoses of GCA/PMR. Four algorithms were then devised to improve their identification. Accuracies of self-reported diagnoses and of each algorithm were calculated by comparing the diagnoses with a blinded medical chart review. RESULTS: Among 98,995 participants, 1,392 women self-reported GCA/PMR. 830 women sent back the specific questionnaire, and 202 women provided medical charts. After independent review of the 202 medical charts, 87.6 % of the self-reported diagnoses of GCA/PMR were accurate. Using additional data from a specific questionnaire (diagnosis confirmation by a physician, and self-report of >3-month of glucocorticoids), and from a reimbursement database (at least two deliveries of glucocorticoids in less than 3 consecutive months) improved their accuracy (91.8 % to 92.8 %). CONCLUSION: The accuracy of self-reported diagnosis of GCA/PMR was high in the E3N-cohort but using additional data as a specific GCA/PMR questionnaire and/or corticosteroid reimbursement database further improved this accuracy. With nearly 600 detected cases of GCA/PMR, we will be able to investigate risk factors for GCA/PMR in women.

Lifetime female hormonal exposure and risk of rheumatoid arthritis in postmenopausal women: Results from the French E3N cohort.

OBJECTIVE: To assess the relationships between lifetime female hormonal exposures and the risk of incident RA in postmenopausal women. METHODS: E3N is an ongoing French prospective cohort of 98,995 women since 1990 aged 40-65 years at enrolment. Data on reproductive/hormonal factors and treatments were regularly recorded. Exposures were defined as follows: - reproductive span (in years)=duration from menarche to menopause; - total ovulatory years=reproductive span-(number of full-term pregnancies×0.75+number of miscarriages×0.25+total duration of breast feeding+total duration of oral contraception); - lifetime duration of hormonal exposure (in years)=reproductive span+total duration of menopausal hormonal therapy; - composite estrogen score (CES, range=0-6): 1 point for each item: early menarche, high parity, history of hysterectomy, use of oral contraception, use of menopausal hormonal therapy and late menopause. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of incident RA were estimated using Cox proportional hazards regression models with age as the time scale. RESULTS: Among the 78,391 postmenopausal cohort women, 637 validated incident RA cases occurred. Lifetime durations of hormonal exposures were not associated with incident RA in postmenopausal women. High (CES=4-6) versus low (CES=0-1) estrogen exposure was inversely associated with the risk of RA: HR 0.37; 95% CI 0.2-0.8. CONCLUSION: In the E3N cohort, high lifetime estrogen exposure, that summarizes cumulative endogenous and exogenous exposures, was associated with a decreased risk of RA in postmenopausal women.

Anthropometric Measures and Risk of Rheumatoid Arthritis in the French E3N Cohort Study.

We aimed to assess the relationships between anthropometric measures and risk of rheumatoid arthritis (RA). The E3N cohort included 98,995 women (aged 40−65 years at the recruitment) who completed mailed questionnaires on reproductive factors, lifestyle, and health-related information, including anthropometric measures, every 2−3 years. Cox proportional hazards regression models with age as the time scale and adjusted on known RA risk factors were used to estimate hazard ratios (HRs) and 95% confidence intervals for the risk of incident RA in the overall population (n = 78,452) and after stratification on smoking exposure. Incident RA diagnosis was validated in 698 women. Abdominal obesity (waist circumference >88 cm) was associated with RA (HR = 1.2 (1.0−1.5)), independent of BMI; whereas obesity, defined as BMI ≥ 30 kg/m2, was marginally associated with RA (HR = 1.26 (0.9−1.5), ptrend = 0.0559). Taking lean body shape (BS) as reference, medium BS at puberty (HR = 1.3 (1.0−1.7)) and medium-large BS at perimenopausal period (HR = 1.5 (1.1−1.9)) were associated with the risk of RA among never-smoker women, independent of BMI. Regarding BS trajectory, taking constantly lean BS as reference, constantly large BS from puberty to perimenopause was associated with RA among non-smokers (HR = 2.10 (1.2−3.6)), independent of BMI.

Fish Consumption and Risk of Rheumatoid Arthritis: Findings from the E3N Cohort Study.

Fish consumption has been thought to reduce the risk of rheumatoid arthritis (RA), but the reported data are conflicting. We aimed to assess the association between fish consumption (overall, lean fish, and oily fish) and the risk of RA. The E3N Study is a French prospective cohort study including 98,995 women since 1990. Dietary data were collected via a validated food frequency questionnaire in 1993. Cox proportional hazards models were used to calculate HRs and 95% CIs for incident RA. Models were adjusted for age and for the main potential confounders including cigarette smoking. Among 62,629 women, 480 incident cases of RA were identified. In the overall population, we did not find a linear association between overall fish consumption and RA risk (p for trend 0.65), but a moderate consumption of fish was associated with a decreased risk of RA (HR 0.74; 95% CI 0.59-0.94 for tertile 2 compared with tertile 1), especially among current or former smokers (HR 0.61; 95% CI 0.44-0.85). Although not statistically significant, a trend towards an inverse association was only found with oily fish consumption (HR 0.81; 95% CI 0.65-1.02), but not with lean fish. Our results suggest that moderate fish consumption could reduce the risk or RA and potentially counterbalance the increased risk of RA induced by smoking. This inverse association might be explained by the omega-3 fatty acid content of oily fish.

Passive smoking in childhood and adulthood and risk of rheumatoid arthritis in women: results from the French E3N cohort study.

OBJECTIVE: The association between passive smoking exposure in childhood or in adulthood, and the risk of rheumatoid arthritis (RA) has been incompletely investigated. We aimed to assess the relationship between exposure to passive smoking and the risk of incident RA in a French prospective cohort of healthy women. METHODS: The E3N Study (Etude Epidémiologique auprès des femmes de la Mutuelle générale de l'Education Nationale) is a French prospective cohort of women included in 1990. Exposures to passive smoking were assessed using self-reported questionnaires. RA cases were self-reported and subsequently validated. Cox proportional hazards regression models adjusted for age and for potential confounders were used to estimate HRs and 95% CIs for incident RA. RESULTS: Among 79 806 women, 698 incident cases of RA were identified; 10 810 (13.5%) women were exposed to passive smoking in childhood, and 42 807 (53.6%) in adulthood. Median age at inclusion was 47.8 years. Passive smoking in childhood and in adulthood was associated with RA risk in all models (HRs (95% CIs) 1.24 (1.01 to 1.51) and 1.19 (1.02 to 1.40), respectively). The absolute risk of RA among never smokers with exposure to passive smoking in childhood and/or adulthood (47.6/100 000 person-years) was close to the risk of ever smokers with no passive smoking exposure (47.2/100 000 person-years), while it was highest in ever smokers also exposed to passive smoking (53.7/100 000 person-years). CONCLUSION: Exposure to passive smoking in childhood and/or adulthood increases the risk of RA by the same order than active smoking. Such exposure should be suppressed, especially in individuals at risk of RA.

Concomitant fibromyalgia in primary Sjögren's syndrome in the French ASSESS cohort: comparison of the ACR 1990 and ACR 2016 criteria, FiRST questionnaire and physician's opinion.

OBJECTIVES: Dryness, fatigue, and pain are classic symptoms in primary Sjögren's syndrome (pSS) but are also common in fibromyalgia (FM). We compared the characteristics of FM assessed by different criteria (American College of Rheumatology (ACR) 2016 and 1990 criteria), physician's opinion and Fibromyalgia Rapid Screening Tool (FiRST) questionnaire) in a cohort of patients with pSS. METHODS: Eight hospital departments tested 134 patients with pSS according to AECG criteria from the Assessment of Systemic Signs and Evolution in Sjögren's Syndrome (ASSESS) cohort. RESUKLTS: FM was present in 19%, 18%, 20%, and 29% of cases according to ACR 2016, ACR 1990 criteria, physician's opinion and the FiRST questionnaire, respectively. FM criteria-positive patients had higher EULAR SS Patient-Reported Index (ESSPRI) score, but not higher EULAR SS Disease Activity Index (ESSDAI) score. The objective measurements of dryness and the use of corticosteroids and immunosuppressive drugs did not differ between FM positive and negative patients. Regarding the ESSPRI dryness and fatigue subscale scores, depression and anxiety scores and the use of anxiolytics and antidepressants, the FiRST questionnaire exhibited a higher difference between positive and negative patients than ACR 2016 criteria. ACR 1990 and physician's opinion were somewhere in the middle. ACR 2016 exhibited moderate agreement with ACR 1990 (κ=0.52) and the physician's opinion (κ=0.60) and poor agreement with FiRST (κ=0.39). CONCLUSIONS: The FM criteria identified pSS patients with higher ESSPRI scores but not higher ESSDAI systemic disease scores. Agreement between the different FM criteria was moderate, and the characteristics they described did not fully coincide.

Female hormonal exposures and risk of rheumatoid arthritis in the French E3N-EPIC cohort study.

OBJECTIVE: To assess the relationships between female hormonal exposures and risk of RA in a prospective cohort of French women. METHODS: E3N (Etude Epidémiologique auprès des femmes de la Mutuelle générale de l'Education Nationale) is an on-going French prospective cohort that included 98 995 women aged 40-65 years in 1990. Every 2-3 years, women completed mailed questionnaires on their lifestyles, reproductive factors and health conditions. Cox proportional hazards regression models were used to determine factors associated with risk of incident RA, with age as the time scale, adjusted for known risk factors of RA, and considering endogenous and exogenous hormonal factors. Hazard ratios (HRs) and 95% CIs were estimated. Effect modification by smoking history was investigated. RESULTS: A total of 698 incident cases of RA were ascertained among 78 452 women. In multivariable-adjusted Cox regression models, risk of RA was increased with early age at first pregnancy (<22 vs ≥27 years; HR = 1.34; 95% CI 1.0, 1.7) and menopause (≤45 vs ≥53 years; HR = 1.40; 95% CI 1.0, 1.9). For early menopause, the association was of similar magnitude in ever and never smokers, although the association was statistically significant only in ever smokers (HR = 1.54; 95% CI 1.0, 2.3). We found a decreased risk in nulliparous women never exposed to smoking (HR = 0.44; 95% CI 0.2, 0.8). Risk of RA was inversely associated with exposure to progestogen only in perimenopause (>24 vs 0 months; multi-adjusted HR = 0.77; 95% CI 0.6, 0.9). CONCLUSIONS: These results suggest an effect of both endogenous and exogenous hormonal exposures on RA risk and phenotype that deserves further investigation.

Mediterranean Diet and Risk of Rheumatoid Arthritis: Findings From the French E3N-EPIC Cohort Study.

OBJECTIVE: The Mediterranean diet has been reported to be associated with a significant reduction in risk of noncommunicable diseases. We undertook this study to assess the relationship between adherence to the Mediterranean diet and the risk of rheumatoid arthritis (RA), especially in high-risk individuals. METHODS: The E3N study (Etude Epidémiologique Auprès des Femmes de la Mutuelle Générale de l'Education Nationale) is a French prospective cohort study that has included 98,995 women since 1990. Dietary data were collected via a validated food frequency questionnaire in 1993. Adherence to the Mediterranean diet was assessed using a 9-unit dietary score evaluating consumption of vegetables, legumes, cereal products, fish, meat, dairy products, olive oil, and alcohol. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) for incident RA were estimated using Cox proportional hazards regression models adjusted for age and the main potential confounders, including smoking. RESULTS: Among 62,629 women, we identified 480 incident cases of RA. In the entire study population, the Mediterranean diet adherence score was not associated with RA risk (HR 0.86 [95% CI 0.67-1.09] for high score versus low score; P for trend = 0.09); however, among ever-smokers, a higher score was associated with a decreased risk of RA (HR 0.91 [95% CI 0.84-0.99] for 1-point increase in score; P = 0.03). In ever-smokers, the absolute risks of RA in those with high scores and those with low scores were 38.3 and 51.5 per 100,000 person-years, respectively, compared to 35.8 per 100,000 person-years in never-smokers with high Mediterranean diet scores. CONCLUSION: Our results suggest that adherence to the Mediterranean diet could reduce the high risk of RA among ever-smoking women. Our results must be confirmed in future research.

Environment and Lifestyle: Their Influence on the Risk of RA.

BACKGROUND: Rheumatoid arthritis (RA) is a complex disease in which environmental agents are thought to interact with genetic factors that lead to triggering of autoimmunity. METHODS: We reviewed environmental, hormonal, and dietary factors that have been suggested to be associated with the risk of RA. RESULTS: Smoking is the most robust factor associated with the risk of RA, with a clear gene-environment interaction. Among other inhalants, silica may increase the risk of RA in men. There is less evidence for pesticides, pollution, and other occupational inhalants. Regarding female hormonal exposures, there is some epidemiological evidence, although not consistent in the literature, to suggest a link between hormonal factors and the risk of RA. Regarding dietary factors, available evidence is conflicting. A high consumption of coffee seems to be associated with an increased risk of RA, whereas a moderate consumption of alcohol is inversely associated with the risk of RA, and there is less evidence regarding other food groups. Dietary pattern analyses (Mediterranean diet, the inflammatory potential of the diet, or diet quality) suggested a potential benefit of dietary modifications for individuals at high risk of RA. CONCLUSION: To date, smoking and silica exposure have been reproducibly demonstrated to trigger the emergence of RA. However, many other environmental factors have been studied, mostly with a case-control design. Results were conflicting and studies rarely considered potential gene-environment interactions. There is a need for large scale prospective studies and studies in predisposed individuals to better understand and prevent the disease and its course.

2020 French recommendations on the management of septic arthritis in an adult native joint.

Septic arthritis (SA) in an adult native joint is a rare condition but a diagnostic emergency due to the morbidity and mortality and the functional risk related to structural damage. Current management varies and the recommendations available are dated. The French Rheumatology Society (SFR) Bone and Joint Infection Working Group, together with the French Language Infectious Diseases Society (SPILF) and the French Orthopaedic and Trauma Surgery Society (SOFCOT) have worked according to the HAS methodology to devise clinical practice recommendations to diagnose and treat SA in an adult native joint. One new focus is on the importance of microbiological documentation (blood cultures and joint aspiration) before starting antibiotic treatment, looking for differential diagnoses (microcrystal detection), the relevance of a joint ultrasound to guide aspiration, and the indication to perform a reference X-ray. A cardiac ultrasound is indicated only in cases of SA involving Staphylococcus aureus, oral streptococci, Streptococcus gallolyticus or Enterococcus faecalis, or when infective endocarditis is clinically suspected. Regarding treatment, we stress the importance of medical and surgical collaboration. Antibiotic therapies (drugs and durations) are presented in the form of didactic tables according to the main bacteria in question (staphylococci, streptococci and gram-negative rods). Probabilistic antibiotic therapy should only be used for patients with serious symptoms. Lastly, non-drug treatments such as joint drainage and early physical therapy are the subject of specific recommendations.

Chronic diarrhoea and risk of rheumatoid arthritis: findings from the French E3N-EPIC Cohort Study.

OBJECTIVES: To assess the relationship between gastrointestinal disorders and the risk of further development of RA. METHODS: The Etude Epidémiologique auprès des femmes de la Mutuelle générale de l'Education Nationale-European Prospective Investigation into Cancer and Nutrition Study is a French prospective cohort including 98 995 healthy women since 1990. Participants completed mailed questionnaires on their lifestyles and health-related information. Gastrointestinal disorders were assessed in the third questionnaire (sent in 1993). Hazard ratios and 95% CIs for incident RA were estimated using Cox proportional hazards regression models with age as the time scale. Models were age adjusted, and then additionally adjusted for known risk factors of RA such as smoking, and for potential cofounders. RESULTS: Among 65 424 women, 530 validated incident RA cases were diagnosed after a mean (s.d.) of 11.7 (5.9) years after study baseline. In comparison with no gastrointestinal disorder, chronic diarrhoea was associated with an increased risk of developing RA during follow-up (hazard ratio = 1.70, 95% CI 1.13, 2.58), independently of dysthyroidism or dietary habits. The association was stronger among ever-smokers (hazard ratio = 2.21, 95% CI 1.32, 3.70). There was no association between RA risk and constipation or alternating diarrhoea/constipation. CONCLUSION: Chronic diarrhoea was associated with an increased risk of subsequent RA development, particularly among ever-smokers. These data fit with the mucosal origin hypothesis of RA, where interaction between intestinal dysbiosis and smoking could occur at an early stage to promote emergence of autoimmunity, followed years later by clinical disease.

Improving accuracy of self-reported diagnoses of rheumatoid arthritis in the French prospective E3N-EPIC cohort: a validation study.

OBJECTIVES: The French E3N-EPIC (Etude Epidémiologique auprès des femmes de la Mutuelle générale de l'Education Nationale-European Prospective Investigation into Cancer and Nutrition) cohort enrolled 98 995 women aged 40 to 65 years at inclusion since 1990 to study the main risk factors for cancer and severe chronic conditions in women. They were prospectively followed with biennially self-administered questionnaires collecting self-reported medical, environmental and lifestyle data. Our objective was to assess the accuracy of self-reported diagnoses of rheumatoid arthritis (RA) and to devise algorithms to improve the ascertainment of RA cases in our cohort. DESIGN: A validation study. PARTICIPANTS: Women who self-reported an inflammatory rheumatic disease (IRD) were asked to provide access to their medical record, and to answer an IRD questionnaire. Medical records were independently reviewed. PRIMARY AND SECONDARY OUTCOME MEASURES: Positive predictive values (PPV) of self-reported RA alone, then coupled with the IRD questionnaire, and with a medication reimbursement database were assessed. These algorithms were then applied to the whole cohort to ascertain RA cases. RESULTS: Of the 98 995 participants, 2692 self-reported RA. Medical records were available for a sample of 399 participants, including 305 who self-reported RA. Self-reported RA was accurate only for 42% participants. Combining self-reported diagnoses to answers to a specific IRD questionnaire or to the medication reimbursement database improved the PPV (75.6% and 90.1%, respectively). Using the devised algorithms, we could identify 964 RA cases in our cohort. CONCLUSION: Accuracy of self-reported RA is poor but adding answers to a specific questionnaire or data from a medication reimbursement database performed satisfactorily to identify RA cases in our cohort. It will subsequently allow investigating many potential risk factors of RA in women.

Drug maintenance of a second tumor necrosis factor alpha inhibitor in spondyloarthritis patients: A real-life multicenter study.

OBJECTIVES: Five TNF inhibitor (TNFi) agents are marketed for spondyloarthritis (SpA): 1 soluble receptor (SR) and 4 monoclonal antibodies (mAbs). From 15% to 30% of patients stop the first TNFi in the first 2 years, but we lack recommendations on the choice of the second TNFi. The aim here was to assess drug survival of a second TNFi in SpA and its determinants. METHODS: This was a multicenter observational study of SpA patients who started a first TNFi in 2013 and 2014 and were followed to 2018. For the first and second TNFi, we retrospectively collected data on initiation and discontinuation dates, type of TNFi, and reasons for withdrawal. Kaplan-Meier plots and log-rank tests were used to compare drug survival. Factors associated with drug survival of the second TNFi were analyzed by univariate Cox regression analyses. RESULTS: We included 244 patients. During a follow-up of 7,838 patient-months, 101 (41%) received 1 TNFi, and 143 (59%) switched to a second TNFi. Mean drug intake duration was significantly greater with the first than second TNFi: 21.7 (SD 19.6) and 15.4 (SD 13.6) months (P<0.001). When switching to another mAb or from an SR to an mAb (or the reverse), mean drug survival did not differ: 14.4 (SD 12.7) and 16 (SD 14.1) months (P=0.35). Factors associated with retaining the second TNFi were male sex (P=0.054) and age<41 years at SpA diagnosis (P=0.022). On multivariable analysis, only age<41 years at diagnosis remained independently associated with maintenance of the second TNFi. CONCLUSION: In SpA patients, drug survival is significantly longer with the first than second TNFi. Male sex and age<41 years at diagnosis were associated with retaining the second TNFi.

Usefulness of polymerase chain reaction for diagnosing Whipple's disease in rheumatology.

OBJECTIVES: To determine when Tropheryma whipplei polymerase chain reaction (PCR) is appropriate in patients evaluated for rheumatological symptoms. METHODS: In a retrospective observational study done in rheumatology units of five hospitals, we assessed the clinical and radiological signs that prompted T. whipplei PCR testing between 2010 and 2014, the proportion of patients diagnosed with Whipple's disease, the number of tests performed and the number of diagnoses according to the number of tests, the patterns of Whipple's disease, and the treatments used. Diagnostic ascertainment was based on 1- Presence of at least one suggestive clinical finding; 2- at least one positive PCR test, and 3- a response to antibiotic therapy described by the physician as dramatic, including normalization of C Reactive Protein. RESULTS: At least one PCR test was performed in each of 267 patients. Rheumatic signs were peripheral arthralgia (n = 239, 89%), peripheral arthritis (n = 173, 65%), and inflammatory back pain (n = 85, 32%). Whipple's disease was diagnosed in 13 patients (4.9%). The more frequently positive tests were saliva and stool. In the centres with no diagnoses of Whipple's disease, arthritis was less common and constitutional symptoms more common. The group with Whipple's disease had a higher proportion of males, older age, and greater frequency of arthritis. The annual incidence ranged across centres from 0 to 3.6/100000 inhabitants. CONCLUSION: Males aged 40-75 years with unexplained intermittent seronegative peripheral polyarthritis, including those without constitutional symptoms, should have T. whipplei PCR tests on saliva, stool and, if possible, joint fluid.

Application of Recommendations Regarding the Use of Subcutaneous Tumor Necrosis Factor Inhibitors in Spondyloarthritis by Rheumatologists in Daily Practice.

OBJECTIVE: To assess the implementation of European recommendations for use of TNF inhibitors for spondyloarthritis (SpA), rheumatologists' level of knowledge of and adherence to the recommendations, and potential barriers to the application of recommendations. METHODS: We conducted a retrospective study among 42 rheumatologists who initiated a first subcutaneous TNF inhibitor for SpA in 2013 or 2014. Thirty items from national and international recommendations were separated into 3 domains: indication, pretherapeutic monitoring, and management under TNF inhibitors. A standardized data collection procedure was used to gather data from medical files to assess the application of each recommendation. Questionnaires assessing the knowledge, level of adherence to each recommendation, and potential barriers to their implementation were sent to rheumatologists. RESULTS: Rheumatologists applied a mean of 60% of items from domains A and B, but less than 50% from domain C items. Recommendations regarding the search for previous infection and the prevention of future infections were the ones most often applied. However, < 60% of rheumatologists assessed cancer and other diseases before TNF inhibitor initiation. More than 95% of rheumatologists knew of the recommendations and had a high level of adherence. Lack of time, difficulties accessing specialized consultations, and lack of flexibility in the recommendations explained rheumatologists' difficulties in applying the recommendations. CONCLUSION: Despite high levels of knowledge of, and adherence to, recommendations for using TNF inhibitors for SpA, rheumatologists' application was limited because of a lack of human and material resources.

Safety of biologic DMARDs in RA patients in real life: A systematic literature review and meta-analyses of biologic registers.

OBJECTIVES: In daily practice, safety in rheumatoid arthritis (RA) patients receiving biological treatment is an important issue. Unlike randomized controlled trials, biologic registers provide long-term real life safety data. To identify all biologic registers worldwide, to extract and analyze data regarding safety in RA patients under biologics. METHOD: Systematic review was performed independently by 2 rheumatologists using PUBMED, COCHRANE Library and EMBASE databases, up to December 2014. Worldwide biologic registers and related publications were identified. Data on safety issues in RA patients were extracted for meta-analyses. Random-effect meta-analyses were performed to estimate risk ratios (RRs) of mortality, cardiovascular events, cancer, including lymphoma and melanoma and serious infections between (1) biological and non-biological DMARD (cDMARD), (2) between biologics when data were available. RESULTS: Forty-three biological registers were identified worldwide and 27 publications were included for safety meta-analyses on anti-TNFs. Compared to cDMARD, mortality and cardiovascular events were significantly decreased in patients treated with anti-TNFs: RR=0.60 [95% CI 0.38-0.94] and RR=0.62 [0.44-0.88], respectively. Anti-TNFs did not increase the risk of solid cancer in patients without or with prior malignancy (RR=0.84 [0.60-1.18] and RR=0.77 [0.29-2.03], respectively), lymphoma (RR=0.90 [0.62-1.31]) and melanoma (RR=1.17 [0.86-1.59]). As expected, serious infections were significantly increased during anti-TNF treatment (RR=1.48 [1.18-1.85]) compared to cDMARD. No significant difference was found between soluble receptor to TNF and monoclonal antibodies (RR=0.55 [0.22-1.35]). CONCLUSIONS: By reducing dramatically chronic inflammation in RA patients, anti-TNFs decrease mortality, cardiovascular events without increase significantly the risk of cancer, compared to cDMARDs.

Efficacy of rituximab in systemic manifestations of primary Sjogren's syndrome: results in 78 patients of the AutoImmune and Rituximab registry.

OBJECTIVES: To evaluate the efficacy and safety of rituximab in patients with primary Sjögren's syndrome (pSS). METHODS: The AutoImmune and Rituximab registry has included 86 patients with pSS treated with rituximab, prospectivey followed up every 6 months for 5 years. RESULTS: Seventy-eight patients with pSS (11 men, 67 women), who already had at least one follow-up visit, were analysed. Median age was 59.8 years (29-83), median duration of disease was 11.9 years (3-32). Indications for treatment were systemic involvement for 74 patients and only severe glandular involvement in four patients. The median European Sjögren's Syndrome disease activity index (ESSDAI) was 11 (2-31). 17 patients were concomitantly treated with another immunosuppressant agent. Median follow-up was 34.9 months (6-81.4) (226 patient-years). Overall efficacy according to the treating physician was observed in 47 patients (60%) after the first cycle of rituximab. Median ESSDAI decreased from 11 (2-31) to 7.5 (0-26) (p<0.0001). Median dosage of corticosteroid decreased from 17.6 mg/day (3-60) to 10.8 mg/day (p=0.1). Forty-one patients were retreated with rituximab. Four infusion reactions and one delayed serum sickness-like disease resulted in rituximab discontinuation. Three serious infections (1.3/100 patient-years) and two cancer-related deaths occurred. CONCLUSIONS: In common practice, the use of rituximab in pSS is mostly restricted to patients with systemic involvement. This prospective study shows good efficacy and tolerance of rituximab in patients with pSS and systemic involvement.

Type I cryoglobulinemia in multiple myeloma, a rare entity: analysis of clinical and biological characteristics of seven cases and review of the literature.

The type I cryoglobulins (CGs) account for 10-15% of all cryoglobulins and are found in patients with hematological disorders. We here describe the largest series of seven cases of type I cryoglobulinemia associated with multiple myeloma (MM) and provide a detailed review of the literature associated with this disorder, with the aim of improving the future diagnosis and therapeutic management of this rare disease. Six of the cases in our series were men aged 28-69 years, and most of the subject patients had an immunoglobulin G (IgG) monoclonal component and stage I indolent MM that manifested as cryoglobulin-related symptoms. The patients were all karyotypically normal. Clinical manifestations in this group were: skin lesions (five cases, 71.4%), rheumatologic failure (four cases, 57.1%), neurological abnormalities (two cases, 28.6%), mixed cutaneous/rheumatologic/renal defects (one case, 14.3%) and one case in which the cryoglobulinemia was asymptomatic. Two patients experienced acute renal failure but underwent a full recovery following treatment for MM. We conclude from our analysis that treatment approaches for severe type I cryoglobulinemia should involve plasmapheresis at the onset to achieve a rapid control of the CG-related symptoms, and that specific MM treatments should be introduced also at an early stage to avoid cryoglobulinemia relapse. In this context, bortezomib and lenalidomide are potentially the most effective therapeutic agents.