Davis, John M.

INTRODUCTION: Spondyloarthritis (SpA), the most common extraintestinal manifestation of inflammatory bowel disease (IBD), is reported in up to 39% of patients with IBD. Despite this high prevalence, risk factors of developing SpA in patients with IBD are not well described. In this study, we aimed to determine the factors associated with SpA symptoms and their prevalence in an IBD cohort. METHODS: Two validated screening questionnaires for the detection of SpA in IBD (DETAIL = DETection of Arthritis in Inflammatory boweL diseases, IBIS-Q = IBD Identification of Spondyloarthritis Questionnaire) were administered to patients with IBD without a prior diagnosis of SpA in 6 US academic medical centers. Demographic data, IBD characteristics, and medication history were recorded. RESULTS: Screening questionnaires were completed by 588 patients (220 ulcerative colitis, 349 Crohn's disease, and 19 IBD-unclassified), with a median age of 40 years (interquartile range 30–53) and median disease duration of 12 years (interquartile range 6–22). The number of positive screens was 130 (22%) for DETAIL, 196 (33%) for IBIS-Q, and 204 (35%) for either DETAIL or IBIS-Q. Age, female sex, history of smoking, prior bowel surgery, and history of any biologic or targeted small molecule exposure were associated with a positive screen on univariate analysis. After multivariate analysis, female sex (odds ratio [OR] 2.03, 95% confidence interval [CI] 1.41–2.93), older age (OR 1.02, 95% CI 1.01–1.04), history of smoking (OR 1.67, 95% CI 1.04–2.69), and history of any biologic or targeted small molecule exposure (OR 2.27, 95% CI 1.34–3.84) were independently associated with positive screens. Higher number of biologic exposures was associated with higher risk of positive screens, with the highest risk seen with 3 or more exposures (OR 3.25, 95% CI 1.75–6.03). DISCUSSION: A substantial number of patients with IBD screen positive for SpA symptoms, indicating a potentially high burden of undiagnosed illness. Factors associated with SpA symptoms include older age, female sex, and more severe disease (based on increased number of advanced therapies or prior surgery), whereas IBD phenotype does not independently increase the risk of a positive SpA screen. Further studies are needed to confirm these findings and better characterize SpA in IBD.

ObjectiveSpondyloarthritis (SpA) is the most common extraintestinal manifestation of inflammatory bowel disease (IBD). The application of screening tools to detect SpA in patients with IBD may lead to earlier recognition of SpA and affect treatment decisions.MethodsA combination of two previously described SpA screening questionnaires, the Detection of Arthritis in Inflammatory Bowel Disease (DETAIL) and IBD Identification of Spondyloarthritis Questionnaire (IBIS‐Q), was administered to consecutive patients with IBD attending IBD specialty clinics in six US academic medical centers. Demographic data, IBD, and rheumatology history were extracted by chart review.ResultsA total of 669 patients were analyzed. The median age was 40 years (interquartile range [IQR] 30–54) with a median disease duration of 12 years (IQR 6–22) and moderate to severe IBD based on medication exposure and history of bowel surgery. A total of 81 patients (12%) carried a diagnosis of an inflammatory rheumatic disease, whereas 75 (11%) had consulted a rheumatologist during the previous year. Using published cutoffs, 180 out of 669 patients (27%) screened positive with DETAIL, 266 (40%) with IBIS‐Q, and 275 (41%) with either questionnaire. Axial symptoms were more frequently reported than peripheral musculoskeletal complaints. Notably, 189 out of 275 (69%) screen‐positive patients had neither a documented inflammatory rheumatic disease diagnosis nor a visit with a rheumatologist within the past year.ConclusionA substantial proportion of patients with IBD have symptoms suggestive of SpA, and many of these may have undiagnosed SpA. The IBIS‐Q questionnaire appears to identify more potential SpA cases than DETAIL. Strategies are needed to prioritize rheumatology consultations for those patients with IBD who are most likely to benefit.

AbstractYao syndrome (YAOS) is a novel systemic autoinflammatory disease linked to the nucleotide‐binding oligomerization domain (NOD2) gene. It is characterized by periodic fevers, gastrointestinal (GI) symptoms, arthritis, and dermatitis, among other symptoms. A sparse literature exists on this disease, and little is known about its dermatological manifestations. A review of available literature was performed to characterize the cutaneous manifestations of Yao syndrome. Cutaneous manifestations were documented in 85.7% of patients, with common characteristic descriptions of erythematous patches and plaques involving the face, trunk, abdomen, and extremities. Based on our review of treatment modalities employed for Yao syndrome, prednisone is an appropriate initial approach, with oral sulfasalazine and other disease‐modifying antirheumatic drugs serving as appropriate secondary options. YAOS should be considered in the differential diagnosis of patients presenting with a dermatitic rash, especially in the context of concurrent articular symptoms, periodic fever, and GI symptoms.

Abstract Objectives To examine multimorbidity in psoriasis and its association with the development of psoriatic arthritis (PsA). Methods A retrospective cohort study was performed using the Rochester Epidemiology Project. Population-based incidence (2000–09) and prevalence (1 January 2010) cohorts of psoriasis were identified by manual chart review. A cohort of individuals without psoriasis (comparators) were identified (1:1 matched on age, sex and county). Morbidities were defined using two or more Clinical Classification Software codes ≥30 days apart within prior 5 years. PsA was defined using ClASsification of Psoriatic ARthritis (CASPAR) criteria. χ2 and rank-sum tests were used to compare morbidities, and age-, sex- and race-adjusted Cox models to examine the association of baseline morbidities in psoriasis with development of PsA. Results Among 817 incident psoriasis patients, the mean age was 45.2 years with 52.0% females, and 82.0% moderate/severe psoriasis. No multimorbidity differences were found between incident psoriasis patients and comparators. However, in the 1088 prevalent psoriasis patients, multimorbidity was significantly more common compared with 1086 comparators (odds ratio 1.35 and 1.48 for two or more and five or more morbidities, respectively). Over a median 13.3-year follow-up, 23 patients (cumulative incidence: 2.9% by 15 years) developed PsA. Multimorbidity (two or more morbidities) was associated with a 3-fold higher risk of developing PsA. Conclusion Multimorbidity was more common in the prevalent but not incident cohort of psoriasis compared with the general population, suggesting that patients with psoriasis may experience accelerated development of multimorbidity. Moreover, multimorbidity at psoriasis onset significantly increased the risk of developing PsA, highlighting the importance of monitoring multimorbid psoriasis patients for the development of PsA.

Objectives The objective is to examine utilisation of cardiovascular preventive services in patients with rheumatoid arthritis (RA), compared with a non-RA population, and to examine cardiovascular disease (CVD) screening rates among RA patients without diabetes mellitus (DM), hypertension or hyperlipidaemia to non-RA patients with one of these diagnoses. Methods All ≥18-year-old patients with an RA diagnosis living in one of eight Minnesota counties on 1 January 2015 were included and matched (1:1) by sex, age and county to non-RA comparators. Rates of screening for CVD risk factors, including DM (ie, glucose), hypertension (ie, blood pressure) and hyperlipidaemia (ie, lipids), were compared between groups using Cox models. Results The study included 1614 patients with RA and 1599 non-RA comparators. DM screening was more common among patients with RA (HR: 1.10, 95% CI: 1.01 to 1.19), as was hypertension screening (HR: 1.37, 95% CI: 1.24 to 1.52). Hyperlipidaemia screening in RA was similar to comparators (HR: 0.99, 95% CI: 0.89 to 1.10). Conversely, patients with RA and no CVD risk factors had a lower probability of undergoing diabetes (HR: 0.67, 95% CI: 0.57 to 0.78) and hyperlipidaemia screening (HR: 0.65, 95% CI: 0.54 to 0.79) than non-RA patients with only one CVD risk factor diagnosis. Hypertension screening was similar between both groups. Conclusions RA patients undergo CVD preventive screening at rates at least comparable to the general population. However, patients with RA as their sole CVD risk factor were less likely to undergo screenings, despite an equivalent-to-higher risk as the traditional CVD risk factors. These findings demonstrate opportunities for improvement of RA patient care.

ObjectiveThe focus of this study was to assess changes in the cumulative incidence of extra‐articular manifestations of rheumatoid arthritis (ExRAs) and associated mortality risk.MethodsThis study evaluated trends in occurrence of ExRAs using a population‐based inception cohort that included all adult patients with incident rheumatoid arthritis (RA) from 1985 through 2014 meeting the 1987 American College of Rheumatology criteria. Patients were divided into two cohorts based on the incidence date of RA, 1985 to 1999 and 2000 to 2014. The occurrence of ExRAs was determined by manual chart review, and the 10‐year cumulative incidence was estimated for each ExRA in both cohorts. Cox proportional hazard models were used to determine associations between specific demographic and RA disease characteristics and ExRAs and between ExRAs and mortality.ResultsThere were 907 patients included, 296 in the 1985 to 1999 cohort and 611 in the 2000 to 2014 cohort. The 10‐year cumulative incidence of any ExRA decreased significantly between the earlier and later cohorts (45.1% vs 31.6%, P < 0.001). This was largely driven by significant declines in subcutaneous rheumatoid nodules (30.9% vs 15.8%, P < 0.001) and nonsevere ExRAs (41.4% vs 28.8%, P = 0.001). Identified risk factors for the development of any ExRAs include rheumatoid factor positivity (hazard ratio [HR] 2.02, 95% confidence interval [CI] 1.43–2.86) and current smoking (HR 1.61, 95% CI 1.10–2.34). Mortality was increased in patients with either nonsevere (HR 1.83, 95% CI 1.18–2.85) or severe ExRAs (HR 3.05, 95% CI 1.44–6.49).ConclusionsThe incidence of ExRAs has decreased over time. Mortality remains increased in patients with ExRAs.

Although the etiology of rheumatoid arthritis (RA) is unknown, a strong genetic predisposition and the presence of preclinical antibodies before the onset of symptoms is documented. An expansion of Eggerthella lenta is associated with severe disease in RA. Here, using a humanized mouse model of collagen-induced arthritis, we determined the impact of E. lenta abundance on RA severity. Naïve mice gavaged with E. lenta produce preclinical rheumatoid factor and, when induced for arthritis, develop severe disease. The augmented antibody response was much higher in female mice, and among patients with RA, women had higher average load of E. lenta . Expansion of E. lenta increased CXCL5 and CD4 T cells, and both interleukin-17– and interferon-γ–producing B cells. Further, E. lenta gavage caused gut dysbiosis and decline in amino acids and nicotinamide adenine dinucleotide with an increase in microbe-dependent bile acids and succinyl carnitine causing systemic senescent-like inflammation.

Abstract Objectives Multimorbidity is burdensome for people with RA. We investigated differences in multimorbidity and comorbidities by sex and age in the RA population. Methods This cross-sectional analysis used national administrative claims (OptumLabs® Data Warehouse) from people with RA and non-RA comparators (matched on age, sex, race, census region, index year and length of baseline insurance coverage) from 2010–2019. RA was determined using a validated algorithm. Multimorbidity was defined as ≥2 (MM2+) or ≥5 (MM5+) comorbidities from a validated set of 44 chronic conditions. We used logistic regression to assess associations between characteristics and multimorbidity. Results The sample included 154 391 RA patients and 154 391 non-RA comparators. For people aged 18–50 years, RA women (vs RA men) had 7.5 and 4.4 (vs 3.2 and 0.9 in non-RA women vs non-RA men) percentage point increases for MM2+ and MM5+, respectively. For people aged 51+ years, RA women (vs RA men) had 2.1 and 2.5 (vs 1.2 and 0.3 in non-RA women vs non-RA men) percentage point increases for MM2+ and MM5+, respectively. Interactions revealed that differences in multimorbidity between women and men were exacerbated by RA (vs non-RA) (P &lt; 0.05), with more pronounced effects in people aged 18–50. Men had more cardiovascular-related conditions, whereas RA women had more psychological, neurological and general musculoskeletal conditions. Other comorbidities varied by sex and age. Conclusion Multimorbidity disproportionately impacts women with RA. Research, clinical and policy agendas for rheumatic diseases should acknowledge and support the variation in care needs by sex and gender across the lifespan.

Abstract Objectives Whipple’s disease (WD) results from infection of the bacteria Tropheryma whipplei (TW). This disease is characterized by macrophage infiltration of intestinal mucosa and primarily affects Caucasian males. Genetic studies of host susceptibility are scarce. Nucleotide-binding oligomerization domain containing protein 2 (NOD2) is an innate immune sensor, resides mainly in monocytes/macrophages and contributes to defence against infection and inflammatory regulation. NOD2 mutations are associated with autoinflammatory diseases. We report the association of NOD2 mutations with TW and WD for the first time. Methods A multicentre, retrospective study of three patients with WD was conducted. Patients received extensive multidisciplinary evaluations and were cared for by the authors. NOD2 and its association with infection and inflammation were schematically represented. Results All patients were Caucasian men and presented with years of autoinflammatory phenotypes, including recurrent fever, rash, inflammatory arthritis, gastrointestinal symptoms and elevated inflammatory markers. All patients underwent molecular testing using a gene panel for periodic fever syndromes and were identified to carry NOD2 mutations associated with NOD2-associated autoinflammatory disease. Despite initially negative gastrointestinal evaluations, repeat endoscopy with duodenal tissue biopsy ultimately confirmed WD. After initial ceftriaxone and maintenance with doxycycline and/or HCQ, symptoms were largely controlled, though mild relapses occurred in follow-up. Conclusion Both NOD2 and TW/WD are intensively involved in monocytes/macrophages. WD is regarded as a macrophage disease. NOD2 leucin-rich repeat–associated mutations in monocytes/macrophages cause functional impairment of these cells and consequently may make the host susceptible for TW infection and WD, especially in the setting of immunosuppression.

People with rheumatoid arthritis (RA) are often under-recognised as a group with elevated risk of cardiovascular (CV) disease and increased morbidity from CV events. Standard clinical risk assessment tools, which take into account traditional CV risk factors such as smoking, diabetes, hypertension, hyperlipidaemia, and family history do not accurately predict CV risk in patients with autoimmune rheumatic disorders; therefore, there is an unmet need for other methods to assess their risk. Non-invasive CV imaging is evolving as a novel clinical tool to determine subclinical atherosclerotic coronary artery disease in patients with RA. Non-invasive imaging studies, such as tests of endothelial function (i.e. reactive hyperaemia index and flow-mediated dilation) and arterial stiffness (i.e. pulse-wave velocity), have been identified as a potential means for providing accurate assessment of early CV risk in the general population and are evolving in their utility for patients with RA. These types of non-invasive imaging have the potential to eliminate the current use of invasive assessments for identification of precursors to coronary artery disease, such as coronary angiography for early endothelial cell dysfunction. By combining the expertise of subspecialists in cardio-rheumatology clinics, the expectation is to pre-emptively identify RA patients with early coronary artery disease, allowing early modification of risk factors through either medical management or lifestyle modification.