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The prevalence of multimorbidity among rheumatoid arthritis (RA) patients is increasing and associated with worse outcomes. Therefore, management of multimorbid patients requires a multidisciplinary approach. However, healthcare systems consist of mono-disciplinary subsystems, which limits collaboration across subsystems. To study the importance of a multidisciplinary, integrated approach, associations between expenditures and multimorbidity are assessed in real-life data. Retrospective data on RA patients from a Dutch single-hospital are analyzed and compared to the Dutch RA population data. The Elixhauser index is used to measure the multimorbidity prevalence. Regression analyses were conducted to derive the relationship between multimorbidity, healthcare costs and self-reported quality of life (e.g. EQ-5D). When analyzing the impact of multimorbidity within RA patients in context of a single-hospital context, multimorbidity is only partially captured: 13% prevalence versus 24% of the Dutch population. Multimorbidity is associated with higher care expenditures. Depending on the type of multimorbidity, expenditures are €43–€5821 higher in a single-hospital and from €2259–€9648 in population data. Finally, medication use associated with chronic diseases and self-reported aspects of well-being are associated with similar increases in healthcare expenditures as multimorbidity based on hospital care. Within RA, a single-hospital approach underestimates the association between multimorbidity and healthcare expenditures as 43% of healthcare utilization and expenditures are missed. To overcome a single-provider perspective in healthcare and efficiently coordinate multimorbid patients, besides providing holistic care, professionals also need to use data providing comprehensive pictures of patients.

Rheumatoid Arthritis (RA) is a chronic disease that impacts patients’ quality of life. Sophisticated organization of care delivery drives quality improvement. Therefore, the study objective was establishing a validated process map of the care cycle for RA patients. Hence, increasing transparency and optimizing care delivery and identifying areas of improvement. To map the RA care cycle, the care delivery value chain (CDVC) approach was used as framework to document activities and resources systematically. A mixed method study was conducted where quantitative data on activities were collected from health records and unstructured interviews with medical staff were held. Consequently, the process map was separately validated in a consensus meeting with a delegation of the medical staff and patient advisory board. At the start of the care cycle, the focus is predominantly on defining the treat-to-target strategy and examining disease activity. Towards the monitoring phase, tapering medication and managing the disease through patient-reported outcome measures are becoming increasingly important. Although patient’s functioning, quality of care and patient’s evaluation of received care are monitored, reflection of CDVC and engaging patients in the evaluation process resulted in improvement actions on outcome and process level. Mapping the RA care cycle following a systematic approach, provides insight and transparency in delivered activities, involved resources and the engagement of patients and caregivers at multiple levels, contributing to a system facilitating value-based care delivery. The CDVC framework and applied methodology is recommended in other conditions. Future research will focus at assigning outcomes and costs to activities and evaluating interventions to explore patient value.

Objectives We studied discordance between health literacy of people with rheumatic and musculoskeletal diseases (RMDs) and assessment of health literacy by their treating health professionals, and explored whether discordance is associated with the patients’ socioeconomic background. Methods Patients with RA, spondyloarthritis (SpA) or gout from three Dutch outpatient rheumatology clinics completed the nine-domain Health Literacy Questionnaire (HLQ). Treating health professionals assessed their patients on each HLQ domain. Discordance per domain was defined as a ≥2-point difference on a 0–10 scale (except if both scores were below three or above seven), leading to three categories: ‘negative discordance’ (i.e. professional scored lower), ‘probably the same’ or ‘positive discordance’ (i.e. professional scored higher). We used multivariable multilevel multinomial regression models with patients clustered by health professionals to test associations with socioeconomic factors (age, gender, education level, migration background, employment, disability for work, living alone). Results We observed considerable discordance (21–40% of patients) across HLQ domains. Most discordance occurred for ‘Critically appraising information’ (40.5%, domain 5). Comparatively, positive discordance occurred more frequently. Negative discordance was more frequently and strongly associated with socioeconomic factors, specifically lower education level and non-Western migration background (for five HLQ domains). Associations between socioeconomic factors and positive discordance were less consistent. Conclusion Frequent discordance between patients’ scores and professionals’ estimations indicates there may be hidden challenges in communication and care, which differ between socioeconomic groups. Successfully addressing patients’ health literacy needs cannot solely depend on health professionals’ estimations but will require measurement and dialogue.

Objectives Rituximab (RTX) is a safe and effective treatment for RA. A dose-dependent infection risk was found in the REDO trial. Some studies associate RTX use with higher infection risks, possibly explained by low immunoglobulin levels and/or neutropenia. Additionally, a higher infection risk shortly after RTX infusion is reported. The objectives of this study were (i) to compare incidence rates of infections between doses and over time, and (ii) to assess B-cell counts, immunoglobulin levels, neutrophil counts and corticosteroid/disease modifying rheumatic drug use as mediating factors between RTX study dose and infection risk. Methods Post hoc analyses of the REDO trial were performed. Infection incidence rates between RTX dosing groups and between time periods were compared using Poisson regression. A step-wise mediation analysis was performed to investigate if any of the factors mentioned above act as a mediator in the observed dose-dependent difference in infection risk. Results The potential mediators that were investigated (circulating B-cell counts, immunoglobulin levels, neutrophil counts and drug use) did not explain the dose-dependent infection risk observed in the REDO trial. Additionally, a trend towards a time-dependent infection risk was found, with higher infection rates shortly after RTX infusion. Conclusions These secondary analyses of the REDO trial confirmed the observed dose-dependent infection risk. Additionally, we found that infection risks were higher shortly after RTX infusion. However, a mediating pathway was not found.

Lymphatic endothelial cells (LECs) line the lymphatic vasculature and play a central role in the immune response. LECs have abilities to regulate immune transport, to promote immune cell survival, and to cross present antigens to dendritic cells. Single-cell RNA sequencing (scRNA) technology has accelerated new discoveries in the field of lymphatic vascular biology. This review will summarize these new findings in regard to embryonic development, LEC heterogeneity with associated functional diversity, and interactions with other cells. Depending on the organ, location in the lymphatic vascular tree, and micro-environmental conditions, LECs feature unique properties and tasks. Furthermore, adjacent stromal cells need the support of LECs for fulfilling their tasks in the immune response, such as immune cell transport and antigen presentation. Although aberrant lymphatic vasculature has been observed in a number of chronic inflammatory diseases, the knowledge on LEC heterogeneity and functional diversity in these diseases is limited. Combining scRNA sequencing data with imaging and more in-depth functional experiments will advance our knowledge of LECs in health and disease. Building the case, the LEC could be put forward as a new therapeutic target in chronic inflammatory diseases, counterweighting the current immune-cell focused therapies.

ObjectivesThe impact of inflammatory arthritis (IA) on male fertility remains unexplored. Our objective was to evaluate the impact of IA on several male fertility outcomes; fertility rate (number of biological children per man), family planning, childlessness and fertility problems.MethodsWe performed a multicentre cross-sectional study (iFAME-Fertility). Men with IA 40 years or older who indicated that their family size was complete were invited to participate. Participants completed a questionnaire that included demographic, medical and fertility-related questions. To analyse the impact of IA on fertility rate, patients were divided into groups according to the age at the time of their diagnosis: ≤30 years (before the peak of reproductive age), between 31 and 40 years (during the peak) and ≥41 years (after the peak).ResultsIn total 628 participants diagnosed with IA were included. Men diagnosed ≤30 years had a lower mean number of children (1.32 (SD 1.14)) than men diagnosed between 31 and 40 years (1.60 (SD 1.35)) and men diagnosed ≥41 years (1.88 (SD 1.14)).This was statistically significant (p=0.0004).The percentages of men diagnosed ≤30 and 31–40 years who were involuntary childless (12.03% vs 10.34% vs 3.98%, p=0.001) and who reported having received medical evaluations for fertility problems (20.61%, 20.69% and 11.36%, p=0.027) were statistically significant higher than men diagnosed ≥41 years.ConclusionsThis is the first study that shows that IA can impair male fertility. Men diagnosed with IA before and during the peak of reproductive age had a lower fertility rate, higher childlessness rate and more fertility problems. Increased awareness and more research into the causes behind this association are urgently needed.

Objective.Acute anterior uveitis (AAU) is common in ankylosing spondylitis (AS). Golimumab (GOL), a tumor necrosis factor-α inhibitor (TNFi), has proven to be effective in the treatment of AS. To date, the effect of GOL on the incidence of AAU in AS is unknown. The objective was to study the AAU occurrence rate in patients with AS during GOL treatment and secondarily, the efficacy of GOL in daily clinical practice.Methods.The study was a multicenter prospective study in a real-world setting in patients with AS who were treated with GOL for 12 months. The occurrence of AAU was assessed in the year before the initial TNFi treatment and during GOL treatment and calculated for the period at risk for a new AAU. Measures for disease activity [Ankylosing Spondylitis Disease Activity Score (ASDAS)] and treatment response [Assessment of Spondyloarthritis international Society (ASAS20 score)] were collected.Results.In total, 93 patients (65% male, 55% TNFi-naive, 27% history of AAU) were included, with a median disease duration of 7 years and ASDAS score of 3.1. During GOL treatment, the AAU occurrence rate was reduced from 11.1 to 2.2 per 100 patient-years (rate-ratio 0.20, 95% CI 0.04–0.91). After 3 months of treatment, 41% of the patients experienced a clinically important improvement of the ASDAS score (p < 0.001) and 36% an ASDAS20 response (p < 0.001). At month 12, 49% had achieved an ASAS20 response (p < 0.001).Conclusion.In AS, the AAU occurrence rate and disease activity decreased significantly during GOL treatment. Therefore, GOL can be considered a good choice in patients with AS who need a TNFi, especially in cases of recurrent AAU. (EudraCT number: 2012-002458-21)

Objectives Suboptimal medication adherence is a serious problem in the treatment of chronic inflammatory diseases. To measure medication adherence, electronic monitoring is regarded as superior to pill count. GLORIA is an ongoing two-year trial on the addition of low-dose (5 mg/d) prednisolone or placebo to standard care in older people (65+ years) with RA. During the entire trial, adherence is measured with electronic caps, and with pill counts. The objective is to describe medication adherence patterns, and to compare the adherence results of the two methods. Methods The recorded adherence patterns of patients (blinded for treatment group) were classified according to descriptive categories. The cutoff for good adherence was set at 80% of prescribed pills taken. Results Trial inclusion closed in 2018 at 451 patients, but trial follow-up is ongoing; the current dataset contains adherence data of 371 patients. Mean number of recorded 90-day periods per patient was 4 (range 1–8). Based on pill count over all periods, 90% of the patients had good adherence; based on cap data, only 20%. Cap data classified 30% of patients as non-user ( Conclusion In our trial of older people with RA, the majority appeared to be adherent to medication according to pill count. Results from caps conflicted with those of pill counts, with patterns suggesting patients did not use the bottle for daily dispensing, despite specific advice to do so. Trial registration NCT02585258. ClinicalTrials.gov (https://www.clinicaltrials.gov/)

Objective To identify and describe health literacy profiles of patients with rheumatic diseases and explore whether the identified health literacy profiles can be generalized to a broader rheumatology context. Methods Patients with rheumatoid arthritis, spondyloarthritis, and gout from 3 hospitals in different regions in The Netherlands completed the Health Literacy Questionnaire (HLQ). Hierarchical cluster analysis was used to identify patients' health literacy profiles based on 9 HLQ domains. A multinomial regression model with the identified health literacy profiles as the dependent variable was fitted to assess whether patients with a given disease type or attending a given hospital were more likely to belong to a specific profile. Results Among 895 participating patients, the lowest mean HLQ domain scores (indicating most difficulty) were found for "critical appraisal," "navigating the health system," and "finding good health information." The 10 identified profiles revealed substantial diversity in combinations of strengths and weaknesses. While 42% of patients scored moderate to high on all 9 domains (profiles 1 and 3), another 42% of patients (profiles 2, 4, 5, and 6) clearly struggled with 1 or several aspects of health literacy. Notably, 16% (profiles 7-10) exhibited difficulty across a majority of health literacy domains. The probability of belonging to one of the profiles was independent of the hospital where the patient was treated or the type of rheumatic disease. Conclusion Ten distinct health literacy profiles were identified among patients with rheumatic diseases, independent of disease type and treating hospital. These profiles can be used to facilitate the development of health literacy interventions in rheumatology.

Angiopoietin-2 (Ang-2), a ligand of the tyrosine kinase receptor Tie2, is essential for vascular development and blood vessel stability and is also involved in monocyte activation. Here, we examined the role of Ang-2 on monocyte activation in patients with systemic sclerosis (SSc). Ang-2 levels were measured in serum and skin of healthy controls (HCs) and SSc patients by ELISA and array profiling, respectively. mRNA expression of ANG2 was analyzed in monocytes, dermal fibroblasts, and human pulmonary arterial endothelial cells (HPAECs) by quantitative PCR. Monocytes were stimulated with Ang-2, or with serum from SSc patients in the presence of a Tie2 inhibitor or an anti-Ang2 neutralizing antibody. Interleukin (IL)-6 and IL-8 production was analyzed by ELISA. Ang-2 levels were elevated in the serum and skin of SSc patients compared to HCs. Importantly, serum Ang-2 levels correlated with clinical disease parameters, such as skin involvement. Lipopolysaccharide (LPS) LPS, R848, and interferon alpha2a (IFN-&alpha, ) stimulation up-regulated the mRNA expression of ANG2 in monocytes, dermal fibroblasts, and HPAECs. Finally, Ang-2 induced the production of IL-6 and IL-8 in monocytes of SSc patients, while the inhibition of Tie2 or the neutralization of Ang-2 reduced the production of both cytokines in HC monocytes stimulated with the serum of SSc patients. Therefore, Ang-2 induces inflammatory activation of SSc monocytes and neutralization of Ang-2 might be a promising therapeutic target in the treatment of SSc.

ObjectivesMethotrexate (MTX) is currently the recommended first-line therapy for treating psoriatic arthritis (PsA), despite lacking clear evidence. No estimates of efficacy of MTX in usual care and no clear MTX responsive clinical or laboratory variables are currently available. This study describes the response to MTX monotherapy in newly diagnosed patients with PsA in usual care. Second, we compared clinical variables and cytokine profiles in patients responding and not responding to MTX monotherapy.MethodsWe used data collected in the Dutch southwest Early Psoriatic Arthritis cohoRt study to select patients with PsA with oligoarthritis or polyarthritis, and at least 1 year follow-up. We analysed disease activity at 6 months of patients who started MTX monotherapy and still used MTX monotherapy 1 year after diagnosis. Cytokine profiles were determined at baseline and after 3 and 6 months with a bead-based multi-immunoassay.ResultsWe identified 219 patients of which 183 (84%) patients started MTX monotherapy within 6 months after diagnosis. 90 patients used MTX monotherapy throughout the first year of which 44 patients (24%) reached minimal disease activity(MDA) at 6 months, decreasing to 33 patients (18%) after 1 year. Non-responders had significantly higher concentrations of interleukin (IL) 23 and IL-10 before and during MTX therapy.ConclusionsOur results showed that only 18% of patients with PsA are in sustained MDA after 1 year of MTX monotherapy and non-responders more often had IL-23-driven disease. Our results indicate the need for more treat-to-target and personalised therapy strategies in PsA.

Recruitment of patients in randomized controlled trials is a well-known problem. Recruitment may be difficult and often takes more time than expected. Most trials adapt their recruitment target or ...

Background If TNF inhibitors are initiated in the early stages of psoriatic arthritis, this could potentially modulate disease and therefore allow us to discontinue the TNF inhibitor after achieving remission. Objective To investigate whether remission induced by tumour necrosis factor alpha inhibitor (TNFi) and methotrexate in patients with early psoriatic arthritis is sustained after withdrawal of TNFi. Methods Open-label extension of a recently published double-blind, randomized placebo-controlled trial. Patients with psoriatic arthritis fulfilling the CASPAR criteria and with active disease at baseline (swollen and tender joint count ≥ 3) were randomized to either golimumab and methotrexate or matched placebo and methotrexate. Patients in Disease Activity Score (DAS) remission at week 22 continued in the open-label extension on methotrexate monotherapy. The primary end point was the percentage of patients in DAS-CRP remission (DAS Results Eight patients from the original placebo group and 18 patients from the original TNFi group continued in the extension phase. At week 50, 6 out of 8 (75%) patients from the original MTX (methotrexate) group versus 10 out of 18 (56%) patients from the original MTX+TNFi group were in DAS-CRP remission (p = 0.347). Considering the total study population, 6 out of 24 (25%) of the original MTX group versus 10 out of 26 (38.5%) of the original MTX+TNFi group were in DAS remission at week 50 (p = 0.308). Conclusions Remission achieved by initial combination treatment with TNFi and methotrexate in early psoriatic arthritis is maintained on methotrexate monotherapy in approximately half of the patients. Trial registration Registered at Clinicaltrials.gov with number NCT01871649 on June 7, 2013.

OBJECTIVE: To analyze the potential role of semaphorin 4A (Sema4A) in inflammatory and fibrotic processes involved in the pathology of systemic sclerosis (SSc). METHODS: Sema4A levels in the plasma of healthy controls (n = 11) and SSc patients (n = 20) were determined by enzyme-linked immunosorbent assay (ELISA). The expression of Sema4A and its receptors in monocytes and CD4+ T cells from healthy controls and SSc patients (n = 6-7 per group) was determined by ELISA and flow cytometry. Th17 cytokine production by CD4+ T cells (n = 5-7) was analyzed by ELISA and flow cytometry. The production of inflammatory mediators and extracellular matrix (ECM) components by dermal fibroblast cells (n = 6) was analyzed by quantitative polymerase chain reaction, ELISA, Western blotting, confocal microscopy, and ECM deposition assay. RESULTS: Plasma levels of Sema4A, and Sema4A expression by circulating monocytes and CD4+ T cells, were significantly higher in SSc patients than in healthy controls (P < 0.05). Inflammatory mediators significantly up-regulated the secretion of Sema4A by monocytes and CD4+ T cells from SSc patients (P < 0.05 versus unstimulated SSc cells). Functional assays showed that Sema4A significantly enhanced the expression of Th17 cytokines induced by CD3/CD28 in total CD4+ T cells as well in different CD4+ T cell subsets (P < 0.05 versus unstimulated SSc cells). Finally, Sema4A induced a profibrotic phenotype in dermal fibroblasts from both healthy controls and SSc patients, which was abrogated by blocking or silencing the expression of Sema4A receptors. CONCLUSION: Our findings indicate that Sema4A plays direct and dual roles in promoting inflammation and fibrosis, 2 main features of SSc, suggesting that Sema4A might be a novel therapeutic target in SSc.

Objectives: Blocking the interleukin-6 pathway by tocilizumab (TCZ) has been associated with changes in the lipoprotein profile, which could adversely impact cardiovascular (CV) risk in patients with rheumatoid arthritis (RA). In the present study, we addressed the effect of TCZ on lipoproteins in both fasting and non-fasting state in RA patients and tested the effect of TCZ on LDL receptor (LDLr) expression in vitro.Methods: Twenty patients with active RA and an inadequate response to TNF blockers received monthly TCZ intravenously. On week 0, 1 and 6 blood was drawn before and after an oral fat load, the lipid profiles and HDL antioxidative capacity were measured. Effects of TCZ on LDLr expression in transfected HepG2 cells were subjected.Results: After 6 weeks of TCZ, total cholesterol increased by 22% (4.8 +/- 0.9 to 5.9 +/- 1.3 mmol/L; p Conclusions: TCZ adversely impacts on both LDLc as well as fasting and postprandial TG in patients with RA. The changes in hepatic LDLr expression following TCZ imply that adverse lipid changes may be a direct hepatic effect of TCZ. The net effect of TCZ on CV-morbidity has to be confirmed in future clinical trials. (C) 2013 Elsevier Ireland Ltd. All rights reserved.

The remarkable advances in understanding the pathogenesis and therapeutic options for rheumatoid arthritis over the last 10 years are a leap forward in the treatment of this disease. This has led to a shift in focus from established disease to early identification and treatment. Actualisation of treatment guidelines aiming for remission, and a vastly growing arsenal of new synthetic and biological agents have been major achievements. An area of ongoing research is the discovery and development of additional and improved biomarkers for (early) disease with the goal of designing a more personalised treatment regimen to prevent structural tissue damage. Developing valid tools to predict response and outcome for the individual patient remains, however, a great challenge. We will herein summarise some of the major achievements in diagnostic and therapeutic discoveries in rheumatoid arthritis of the past decade. (C) 2012 Elsevier Ltd. All rights reserved

The use of critical-for-life organs (e.g., liver or lung) for systemic gene therapeutics can lead to serious safety concerns. To circumvent such issues, we have considered salivary glands (SGs) as an alternative gene therapeutics target tissue. Given the high secretory abilities of SGs, we hypothesized that administration of low doses of recombinant adeno-associated virus (AAV) vectors would allow for therapeutic levels of transgene-encoded secretory proteins in the bloodstream. We administered 10 9 particles of an AAV vector encoding human erythropoietin (hEPO) directly to individual mouse submandibular SGs. Serum hEPO reached maximum levels 8-12 weeks after gene delivery and remained relatively stable for 54 weeks (longest time studied). Hematocrit levels were similarly increased. Moreover, these effects proved to be vector dose-dependent, and even a dosage as low as 10 8 particles per animal led to significant increases in hEPO and hematocrit levels. Vector DNA was detected only within the targeted SGs, and levels of AAV copies within SGs were highly correlated with serum hEPO levels ( r = 0.98). These results show that SGs appear to be promising targets with potential clinical applicability for systemic gene therapeutics.

Introduction Tumor necrosis factor is a pleiotropic cytokine with potent immune regulatory functions. Although tumor necrosis factor inhibitors have demonstrated great utility in treating other autoimmune diseases, such as rheumatoid arthritis, there are conflicting results in Sjögren's syndrome. The aim of this study was to assess the effect of a locally expressed tumor necrosis factor inhibitor on the salivary gland function and histopathology in an animal model of Sjögren's syndrome. Methods Using in vivo adeno associated viral gene transfer, we have stably expressed soluble tumor necrosis factor-receptor 1-Fc fusion protein locally in the salivary glands in the Non Obese Diabetic model of Sjögren's syndrome. Pilocarpine stimulated saliva flow was measured to address the salivary gland function and salivary glands were analyzed for focus score and cytokine profiles. Additionally, cytokines and autoantibody levels were measured in plasma. Results Local expression of tumor necrosis factor-receptor 1:immunoglobulin G fusion protein resulted in decreased saliva flow over time. While no change in lymphocytic infiltrates or autoantibody levels was detected, statistically significant increased levels of tumor growth factor-β1 and decreased levels of interleukin-5, interleukin-12p70 and interleukin -17 were detected in the salivary glands. In contrast, plasma levels showed significantly decreased levels of tumor growth factor-β1 and increased levels of interleukin-4, interferon-γ, interleukin-10 and interleukin-12p70. Conclusions Our findings suggest that expression of tumor necrosis factor inhibitors in the salivary gland can have a negative effect on salivary gland function and that other cytokines should be explored as points for therapeutic intervention in Sjögren's syndrome.

We previously demonstrated that recombinant adeno-associated virus vectors based on serotype 2 (rAAV2) can direct transgene expression in salivary gland cells in vitro and in vivo. However, it is not known how other rAAV serotypes perform when infused into salivary glands. The capsids of serotypes 4 and 5 are distinct from rAAV2 and from each other, suggesting that they may direct binding and entry into different cell types. In the present study, we investigated the tropisms, transduction efficiencies, and antibody response to AAV vectors based on AAV serotypes 2, 4, and 5. Administration of rAAV2beta-galactosidase (betagal), rAAV4betagal, or rAAV5betagal to murine submandibular salivary glands by retrograde ductal instillation resulted in efficient transduction of salivary epithelial cells, with AAV4 and AAV5 producing 2.3 and 7.3 times more betagal activity compared with AAV2. Improved transduction with AAV5 was confirmed by QPCR of DNA extracted from glands and immunohistochemical staining for transgene expression. Like AAV2, AAV5 primarily transduced striated and intercalated ductal cells. AAV4 transduction was evident in striated, intercalated, and excretory ductal cells, as well as in convoluted granular tubules. In keeping with the encapsulated nature of the salivary gland, the majority of persistent viral genomes were found in the gland and not in other tissues. Neutralizing antibodies (NABs) found in the serum of virus-infused animals were serotype specific and there was no crossreactivity between serotypes. No NABs were detected in saliva but sialic acid conjugates present in saliva could neutralize AAV4 at low dilutions. Together our data suggest that because of differences in receptor binding and transduction pathways, other serotypes may have improved utility as gene transfer vectors in the salivary gland and these differences could be exploited in gene therapy applications.

Objectives. Altered lipid levels may occur in autoimmune diseases, for example low cholesterol levels have been described in rheumatoid arthritis (RA). Serum lipid profiles in patients with Sjogren's syndrome (SS) have not been investigated. We hypothesized decreased lipid levels in SS patients and an inverse relationship with disease activity. Methods. Serum lipid levels (total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL) and triglycerides) and additional data regarding disease measures (clinical immunology parameters, focus score from labial salivary gland biopsy, salivary flow and ophthalmological measures) were available for 46 primary SS patients and 12 xerostomic controls. Results. Significant differences between SS patients and controls means (S.D.) were seen for HDL (P^ 0.04) and total cholesterol (P^ 0.02). LDL (P^ 0.12) and triglyceride (P^ 0.08) levels were not different. In SS patients, but not in controls, total cholesterol (P^ 0.003) and HDL cholesterol (P^ 0.003) predicted immunoglobulin G levels. Anti-SSA antibodies were related to a lower total cholesterol (P^ 0.02) and anti-SSB antibodies to a lower HDL cholesterol level (P^ 0.0497). Conclusions. Significant differences were seen in serum lipid levels of primary SS patients and these were associated with serological measures of inflammation. Our results are comparable to earlier findings in RA patients and raise questions related to adverse cardiovascular consequences in SS. Altered lipid levels have been reported in patients with active autoimmune disorders. For example, several groups have reported on various changes in lipid levels in rheumatoid arthritis (RA) patients (1-9). A decreased level of high-density lipoprotein (HDL) cholesterol with inflammation seems to be a consistent finding. Additionally, a higher risk of atherosclerosis and cardiovascular mortality is seen in RA (10). Increased lipid levels have been found in patients with systemic lupus erythematosus (SLE), where disease activity may be related to increases in levels of triglyceride and very low-density lipoprotein (VLDL) cholesterol, while HDL cholesterol was decreased. Inflammatory proteins and autoanti- bodies in SLE are possibly associated with an increased risk of cardiovascular disease (11, 12). Sjogren's syndrome (SS) is a systemic autoimmune disease mainly characterized by ocular and oral dryness (keratoconjuncti- vitis sicca and xerostomia). There is a distinction between primary SS and secondary SS, the latter developing in the presence of other connective tissue diseases, like SLE or RA (13). Sjogren's syndrome occurs predominantly in peri- and post-menopausal women. Detailed investigations of serum lipid profiles or the prevalence of atherosclerosis in patients with SS have yet to be performed. One of the few studies related to this topic has concentrated on the distinction between pseudo-Sjogren's syndrome in patients with hyperlipidaemia and genuine SS using magnetic resonance imaging (MRI) (14). In the present study, we sought to compare serum lipid profiles in patients with primary SS and non-SS xerostomic patients. We hypothesized that serum lipid levels in SS patients would be lower than those in xerostomic controls. Additionally, we investigated the relationship between serum lipid levels and measures of inflammatory disease activity in patients with SS. Based on reports for other autoimmune diseases, we postulated an inverse relationship for such measures with lipid levels.

Clinical applications of gene transfer technology initially targeted the treatment of inherited monogenetic disorders and cancers refractory to conventional therapies. Today, gene transfer approaches are being developed for most tissues and for multiple disorders including those affecting quality of life. The focus herein is eventual application of gene transfer technology for the management of organ-directed autoimmunity. A specific example is presented: Sjögren's syndrome and localized salivary gland gene transfer. The status of relevant pre-clinical gene transfer studies is reviewed, with an emphasis on use of adenoviral and adeno-associated viral vectors. Current limitations of effective organ-directed gene transfer are also discussed.

SIR, we would like to thank Gerli et al. [1] for their reply and the post hoc analysis of their recent Sjogren’s syndrome (SS) study [2] performed. This analysis confirmed our findings [3] in relation to the presence of anti-SSA/B autoantibodies and lower total and HDL cholesterol levels. In addition, Gerli et al.’s study showed anti-SSA antibodies, but not lipid levels, to be an independent predictor of mean carotid arterial thickening [2]. As referenced in our article, in RA and SLE several possible factors, including autoantibodies, can lead through vascular damage to a dysfunctional vasculature more susceptible to traditional cardiovascular risk factors, such as cholesterol levels, than in general. In addition, decreased lipid levels tended to predict cardiovascular morbidity and mortality in RA [4]. An association between intima-media thickening and altered lipid levels in SS patients could perhaps, as Gerli and co-authors had suggested, be detected in larger population-based studies with longer follow-up. Gerli et al. believe that the presence of anti-SSA/B autoantibodies is better for disease diagnosis than as a reflection of disease activity. As they indicate, these autoantibodies are thought to be a marker of autoimmune dysregulation characterizing an SS patient’s subset with more severe disease [5, 6]. Indeed, anti-SSA autoantibodies are detected in virtually all SS patients with coexistent vasculitis and in some of these patients it may be the only detectable antibody [7]. Again, this vasculitis can subsequently result in cardiovascular morbidity [8]. Moreover, anti-SSB autoantibody proved to be a highly significant marker of organ involvement in a large cohort of primary SS patients [5]. Interestingly, during an SS outcome measures workshop, Soloman et al. showed in a meta-analysis identifying predictive biomarkers in SS clinical trials that anti-SSB autoantibody may be a promising biomarker, in addition to IgG levels [9]. We agree immune-mediated mechanisms can play a role, but the relative contribution of each of the mechanisms needs to be further elucidated. Precocious atherosclerosis, dyslipidemia and autoimmune dysregulation could all be involved in a potential atherosclerotic risk and subsequently cardiovascular events. Gerli et al.’s and our studies provide the rationale for further research. B. M. LODDE, V. SANKAR, M. R. KOK, R. A. LEAKAN, P. P. TAK, S. R. PILLEMER Gene Therapy and Therapeutics Branch/National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA and Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, The Netherlands Accepted 8 September 2006 Correspondence to: Dr Beatrijs M. Lodde, GTTB/NIDCR, National Institutes of Health, 10 Center Drive, Room 1N114, MSC 1190, Bethesda, MD 20892-1190, USA. E-mail: blodde@mail.nih.gov