Should we vaccinate during an active rheumatic disease?

Timing of vaccination and its relationship with concomitant immunosuppressive therapy has been a matter of debate in the field of AutoImmune Inflammatory Rheumatic Diseases (AIIRD). Vaccination is crucial in the prevention of infections, which, in the setting of AIIRD, are known risk factors for disease flare and expose patients to increase risk of complications and mortality. As evidenced from real-life studies, vaccines do not significantly affect disease activity. Conversely, disease activity (especially in Systemic Lupus Erythematosus) may predict for vaccine response: high disease activity correlates with decreased seroconversion. For this reason, according to the EULAR 2019 recommendation, vaccination should preferably be administered during quiescent AIIRD. Beside disease activity, background immunosuppressive therapy should be considered when performing vaccination, as different Disease Modifying Anti-Rheumatic Drugs (DMARDs) decrease vaccine immunogenicity. AIIRD patients should be vaccinated, independently from the vaccine type, before starting immunosuppression. If the patient is on active immunosuppressive therapy, the best window of opportunity to boost vaccine response is during AIIRD quiescence, as low disease activity increases seroconversion and allows safe immunosuppressant spacing. In conclusion, the majority of AIIRD patients should receive vaccination, preferably during quiescent disease and taking into consideration immunosuppressant spacing.

Management of adult-onset Still's disease: evidence- and consensus-based recommendations by experts.

BACKGROUND: Adult-onset Still's disease (AOSD) is a rare condition characterized by fevers, rash, and arthralgia/arthritis. Most doctors treating AOSD in the Netherlands treat <5 patients per year. Currently, there is no internationally accepted treatment guideline for AOSD. OBJECTIVES: To conduct a Delphi panel aimed at reaching consensus about diagnostic and treatment strategies for patients with AOSD and to use the outcomes as a basis for a treatment algorithm. METHODS: The Delphi panel brought together 18 AOSD experts: rheumatologists, internists and paediatricians. The Delphi process consisted of 3 rounds. In the first two rounds, online list of questions and statements were completed. In the third round, final statements were discussed during a virtual meeting and a final vote took place. Consensus threshold was set at 80%. Two targeted literature searches were performed identifying the level of evidence of the consensus-based statements. RESULTS: Consensus was reached on 29 statements, including statements related to diagnosis and diagnostic tests, definition of response and remission, the therapy, the use of methotrexate, and tapering of treatment. The panel consented on reduction of the use of glucocorticoids to avoid side-effect, and preferred the use of biologics over conventional treatment. The role of interleukin-1 and interleukin-6 blocking agents was considered important in the treatment of AOSD. CONCLUSIONS: In this Delphi panel, a high level of consensus was achieved on recommendations for diagnosis and therapy of AOSD that can serve as a basis for a treatment guideline.

EULAR/PRES recommendations for vaccination of paediatric patients with autoimmune inflammatory rheumatic diseases: update 2021.

OBJECTIVES: Recent insights supporting the safety of live-attenuated vaccines and novel studies on the immunogenicity of vaccinations in the era of biological disease-modifying antirheumatic drugs in paediatric patients with autoimmune/inflammatory rheumatic diseases (pedAIIRD) necessitated updating the EULAR recommendations. METHODS: Recommendations were developed using the EULAR standard operating procedures. Two international expert committees were formed to update the vaccination recommendations for both paediatric and adult patients with AIIRD. After a systematic literature review, separate recommendations were formulated for paediatric and adult patients. For pedAIIRD, six overarching principles and seven recommendations were formulated and provided with the level of evidence, strength of recommendation and Task Force level of agreement. RESULTS: In general, the National Immunisation Programmes (NIP) should be followed and assessed yearly by the treating specialist. If possible, vaccinations should be administered prior to immunosuppressive drugs, but necessary treatment should never be postponed. Non-live vaccines can be safely given to immunosuppressed pedAIIRD patients. Mainly, seroprotection is preserved in patients receiving vaccinations on immunosuppression, except for high-dose glucocorticoids and B-cell depleting therapies. Live-attenuated vaccines should be avoided in immunosuppressed patients. However, it is safe to administer the measles-mumps-rubella booster and varicella zoster virus vaccine to immunosuppressed patients under specific conditions. In addition to the NIP, the non-live seasonal influenza vaccination should be strongly considered for immunosuppressed pedAIIRD patients. CONCLUSIONS: These recommendations are intended for paediatricians, paediatric rheumatologists, national immunisation agencies, general practitioners, patients and national rheumatology societies to attain safe and effective vaccination and optimal infection prevention in immunocompromised pedAIIRD patients.

Recurrence risk of venous thromboembolism associated with systemic lupus erythematosus: A retrospective cohort study.

Background: Recurrence risk of systemic lupus erythematosus (SLE)-associated venous thromboembolism (VTE) is unclear. Aim: To determine the recurrence risk of SLE-associated VTE overall and by presence of provoking factors and SLE flares. Methods: A multicenter, retrospective cohort study was conducted among patients with first SLE-associated VTE who discontinued anticoagulation. SLE flares were defined as Systemic Lupus Erythematosus Disease Activity Index 2000 greater than 4. The primary outcome was recurrent VTE. Incidence rates and cumulative incidences were calculated by presence of provoking factors and antiphospholipid syndrome (APS) at index VTE. The hazard ratio (HR) for recurrence after SLE flare-associated index VTE was estimated with Cox regression, adjusted for provoking factor presence and APS. Results: Eighty patients were included with 21 recurrent VTEs in median 8 years. For provoked index VTE, the recurrence rate in patients without APS was 1.1 per 100 person-years (PY; 95% confidence interval [CI], 0.1-3.1) and in the presence of APS 3.5 per 100 PY (95% CI, 0.9-8.9), yielding cumulative incidences of 7.5% (95% CI, 1.2%-21.7%) and 31.4% (95% CI, 6.3%-61.6%) respectively. For unprovoked index VTE, these analogous rates were 3.8 per 100 PY (95% CI, 1.2-9.0) and 16.7 per 100 PY (95% CI, 4.5-42.7), with cumulative incidences of 33.7% (95% CI, 10.7%-58.9%) and 54.2% (95% CI, 10.7%-84.5%), respectively. Forty-six index VTEs were flare associated, and the adjusted HR for recurrence was 0.4 (95% CI, 0.1-1.8) compared to those without flares at their index VTE. Conclusion: Antiphospholipid syndrome is the main determinant for recurrence risk of SLE-associated VTE irrespective of presence of a provoking factor. Future research should attempt to confirm that flare-associated VTE has a lower recurrence risk.

Efficacy, Immunogenicity and Safety of Vaccination in Pediatric Patients With Autoimmune Inflammatory Rheumatic Diseases (pedAIIRD): A Systematic Literature Review for the 2021 Update of the EULAR/PRES Recommendations.

Background: In 2011, the first European League Against Rheumatism (EULAR) vaccination recommendations for pediatric patients with autoimmune inflammatory rheumatic diseases (pedAIIRD) were published. The past decade numerous new studies were performed to assess the safety, efficacy and immunogenicity of vaccinations in pedAIIRD. A systematic literature review (SLR) was therefore performed to serve as the basis for the updated 2021 EULAR/PRES recommendations. Methods: An SLR was performed according to the standard operating procedures for EULAR-endorsed recommendations. Primary outcomes were efficacy, immunogenicity and safety of vaccination in pedAIIRD. The search was performed in Medline, Embase and the Cochrane Library and included studies published from November 2010 until July 2020. Results: The SLR yielded 57 studies which were included for critical appraisal and data extraction. Only 8 studies described the occurrence of vaccine-preventable infections after vaccination (efficacy), none of these studies were powered to assess efficacy. The majority of studies assessed (humoral) immune responses as surrogate endpoint for vaccine efficacy. Studies on non-live vaccines showed that these were safe and in general immunogenic. Biologic disease-modifying antirheumatic drugs (bDMARDs) in general did not significantly reduce seroprotection rates, except for B-cell depleting therapies which severely hampered humoral responses. Four new studies on human papilloma virus vaccination showed that this vaccine was safe and immunogenic in pedAIIRD. Regarding live-attenuated vaccinations, level 1 evidence of the measles mumps rubella (MMR) booster vaccination became available which showed the safety of this booster for patients treated with methotrexate. In addition, level 3 evidence became available that suggested that the MMR and varicella zoster virus (VZV) vaccination for patients on low dose glucocorticosteroids and bDMARDs might be safe as well. Conclusions: The past decade, knowledge on the safety and immunogenicity of (live-attenuated) vaccines in pedAIIRD significantly increased. Data on efficacy (infection prevention) remains scarce. The results from this SLR are the basis for the updated EULAR/PRES vaccination recommendations in pedAIIRD.

Increased microchimerism in peripheral blood of women with systemic lupus erythematosus: relation with pregnancy.

OBJECTIVES: We aimed to determine the presence, amount and origin of microchimerism in peripheral blood of pregnant and non-pregnant parous women with systemic lupus erythematosus (SLE) as compared to control subjects. METHODS: We performed a comparative study in which peripheral blood was drawn from eleven female non-pregnant SLE-patients and 22 control subjects, and from six pregnant SLE-patients and eleven control subjects during gestation and up to six months postpartum. Quantitative PCR for insertion-deletion polymorphisms and null alleles was used to detect microchimerism in peripheral blood mononuclear cells and granulocytes. RESULTS: Microchimerism was detected more often in non-pregnant SLE-patients than control subjects (54.4% vs. 13.6%, respectively; p=0.03). When present, the median total number of foetal chimeric cells was 5 gEq/106 in patients and 2.5gEq/106 in control subjects (p=0.048). Microchimerism was mostly foetal in origin; maternal microchimerism was detected in one patient and one control subject. In control subjects, microchimerism was always derived from only one source whereas in 50% of patients it originated from multiple sources. The pregnant patients had a significantly higher median number of foetal chimeric cells in the granulocyte fraction just after delivery than control subjects (7.5 gEq/106 vs. 0 gEq/106, respectively; p=0.02). CONCLUSIONS: Just after delivery, SLE-patients had more microchimerism than control subjects. Three months post-partum, microchimerism was no longer detectable, only to reappear many years after the last pregnancy, more often and at higher levels in SLE-patients than in control subjects. This suggests that these chimeric cells may originate from non-circulating foetal chimeric stem cells.

Effect of Anti-Rheumatic Treatment on the Periodontal Condition of Rheumatoid Arthritis Patients.

Periodontitis, a bacterial-induced infection of the supporting soft and hard tissues of the teeth (the periodontium), is common in patients with rheumatoid arthritis (RA). As RA and periodontitis underlie common inflammatory pathways, targeting the progression of RA might mediate both periodontitis and RA. On the other hand, patients with RA on immunosuppressive medication have an increased risk of infection. Therefore, the objective of this longitudinal observation study was to assess the effect of methotrexate (MTX) and anti-tumor necrosis factor-α (anti-TNF, etanercept) treatment on the periodontal condition of RA patients. Overall, 14 dentate treatment-naive RA patients starting with MTX and 12 dentate RA patients starting with anti-TNF therapy in addition to MTX were included. Follow-up was scheduled matching the routine protocol for the respective treatments. Prior to the anti-rheumatic treatment with MTX or the anti-TNF therapy in addition to MTX, and during follow-up, i.e., 2 months for MTX, and 3 and 6 months for the anti-TNF therapy in addition to MTX, the periodontal inflamed surface area (PISA) was measured. The efficacy of the anti-rheumatic treatment was assessed by determining the change in RA disease activity (DAS28-ESR). Furthermore, the erythrocyte sedimentation rates were determined and the levels of C-reactive protein, IgM-rheumatoid factor, anti-cyclic citrullinated protein antibodies, and antibodies to the periodontal pathogen Porphyromonas gingivalis, were measured. Subgingival sampling and microbiological characterization of the subgingival microflora was done at baseline. MTX or anti-TNF treatment did not result in an improvement of the periodontal condition, while both treatments significantly improved DAS28 scores (both p < 0.01), and reduced C-reactive protein levels and erythrocyte sedimentation rates (both p < 0.05). It is concluded that anti-rheumatic treatment (MTX and anti-TNF) has negligible influence on the periodontal condition of RA patients.

Point of view on the vaccination against COVID-19 in patients with autoimmune inflammatory rheumatic diseases.

In view of the COVID-19 pandemic, there is an unmet clinical need for the guidelines on vaccination of patients with autoimmune inflammatory rheumatic diseases (AIIRD). This position paper summarises the current data on COVID-19 infection in patients with AIIRD and development of vaccines against COVID-19, discusses the aspects of efficacy and safety of vaccination, and proposes preliminary considerations on vaccination against COVID-19 in patients with AIIRD, mainly based on the expert opinion and knowledge on the use of other vaccines in this population of patients.

Erratum to: Diagnosis and treatment of patients with antiphospholipid syndrome: a mixed-method evaluation of care in The Netherlands.

[This corrects the article DOI: 10.1093/rap/rkaa021.].

Effects of Childhood-onset Systemic Lupus Erythematosus on Academic Achievements and Employment in Adult Life.

OBJECTIVE: Long-term outcome data in adults with childhood-onset systemic lupus erythematosus (cSLE) are limited. Here, we report the effects of cSLE on education, vocation, and employment in a large cohort of adults with cSLE. METHODS: Patients were seen for a single study visit comprising a structured history and physical examination. Medical records were retrieved to supplement information obtained during the study visit. Education and employment status were assessed by questionnaires. Health-related quality of life (HRQOL) was measured with the 36-Item Short Form Health Survey (SF-36). RESULTS: One hundred six patients with cSLE (93% female, 73% White), with a median disease duration of 20 years, completed the visit and questionnaires. Almost all patients stated that cSLE had influenced their education, but the level of completed education was similar to the general Dutch population. Half of the patients had adjusted their vocational choice due to the disease. Still, 44% of patients who had finished education did not have a paid job. Of the employed patients, 61% worked part time. Disease damage was equally prevalent in patients with and without paid employment. A high percentage of patients (51%) were declared work disabled, due to disease damage. Patients who did not have paid employment were often work disabled. Both had a negative effect on HRQOL. CONCLUSION: The effect of cSLE on academic achievements and employment is substantial, despite patients adjusting their educational and vocational choices. To optimize participation in the community, ongoing support is necessary, not only to help patients find suitable education and vocations but also to offer guidance regarding potential adjustments during their career.

Diagnosis and treatment of patients with antiphospholipid syndrome: a mixed-method evaluation of care in The Netherlands.

OBJECTIVES: The aims were to gain insight into the care provided to patients with APS in The Netherlands and to identify areas for improvement from the perspective of both patients and medical specialists. METHODS: APS care was evaluated using qualitative and quantitative methods. Perspectives on APS care were explored using semi-structured interviews with medical specialists, patient focus groups and a cross-sectional, online patient survey. In order to assess current practice, medical records were reviewed retrospectively to collect data on clinical and laboratory manifestations and pharmacological treatment in six Dutch hospitals. RESULTS: Fourteen medical specialists were interviewed, 14 patients participated in the focus groups and 79 patients completed the survey. Medical records of 237 patients were reviewed. Medical record review showed that only one-third of patients were diagnosed with APS within 3 months after entering specialist care. The diagnostic approach and management varied between centres and specialists. Almost 10% of all patients and 7% of triple-positive patients with thrombotic APS were not receiving any anticoagulant treatment at the time of medical record review. Correspondingly, poor recognition and fragmentation of care were reported as the main problems by medical specialists. Additionally, patients reported the lack of accessible, reliable patient education, psychosocial support and trust in physicians as important points for improvement. CONCLUSION: Delayed diagnosis, variability in management strategies and fragmentation of care were important limitations of APS care identified in this study. A remarkable 10% of patients did not receive any anticoagulant treatment.

2019 update of EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases.

To update the European League Against Rheumatism (EULAR) recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases (AIIRD) published in 2011. Four systematic literature reviews were performed regarding the incidence/prevalence of vaccine-preventable infections among patients with AIIRD; efficacy, immunogenicity and safety of vaccines; effect of anti-rheumatic drugs on the response to vaccines; effect of vaccination of household of AIIRDs patients. Subsequently, recommendations were formulated based on the evidence and expert opinion. The updated recommendations comprise six overarching principles and nine recommendations. The former address the need for an annual vaccination status assessment, shared decision-making and timing of vaccination, favouring vaccination during quiescent disease, preferably prior to the initiation of immunosuppression. Non-live vaccines can be safely provided to AIIRD patients regardless of underlying therapy, whereas live-attenuated vaccines may be considered with caution. Influenza and pneumococcal vaccination should be strongly considered for the majority of patients with AIIRD. Tetanus toxoid and human papilloma virus vaccination should be provided to AIIRD patients as recommended for the general population. Hepatitis A, hepatitis B and herpes zoster vaccination should be administered to AIIRD patients at risk. Immunocompetent household members of patients with AIIRD should receive vaccines according to national guidelines, except for the oral poliomyelitis vaccine. Live-attenuated vaccines should be avoided during the first 6 months of life in newborns of mothers treated with biologics during the second half of pregnancy. These 2019 EULAR recommendations provide an up-to-date guidance on the management of vaccinations in patients with AIIRD.

Incidence and prevalence of vaccine preventable infections in adult patients with autoimmune inflammatory rheumatic diseases (AIIRD): a systemic literature review informing the 2019 update of the EULAR recommendations for vaccination in adult patients with AIIRD.

Objectives: The aims of this study were to update the evidence on the incidence and prevalence rates of vaccine preventable infections (VPI) in patients with autoimmune inflammatory rheumatic diseases (AIIRD) and compare the data to the general population when available. Methods: A literature search was performed using Medline, Embase and Cochrane library (October 2009 to August 2018). The primary outcome was the incidence or prevalence of VPI in the adult AIIRD population. Meta-analysis was performed when appropriate. Results: Sixty-three publications out of 3876 identified records met the inclusion criteria: influenza (n=4), pneumococcal disease (n=7), hepatitis B (n=10), herpes zoster (HZ) (n=29), human papillomavirus (HPV) infection (n=13). An increased incidence of influenza and pneumococcal disease was reported in patients with AIIRD. HZ infection-pooled incidence rate ratio (IRR) was 2.9 (95% CI 2.4 to 3.3) in patients with AIIRD versus general population. Among AIIRD, inflammatory myositis conferred the highest incidence rate (IR) of HZ (pooled IRR 5.1, 95% CI 4.3 to 5.9), followed by systemic lupus erythematosus (SLE) (pooled IRR 4.0, 95% CI 2.3 to 5.7) and rheumatoid arthritis (pooled IRR 2.3, 95% CI 2.1 to 2.6). HPV infection-pooled prevalence ratio was 1.6, 95% CI 0.7 to 3.4 versus general population, based on studies mainly conducted in the SLE population in Latin America and Asia. Pooled prevalence of hepatitis B surface antigen and hepatitis B core antibody in patients with AIIRD was similar to the general population, 3%, 95% CI 1% to 5% and 15%, 95% CI 7% to 26%, respectively. Conclusion: Current evidence shows an increased risk of VPI in patients with AIIRD, emphasising that prevention of infections is essential in these patients.

Efficacy, immunogenicity and safety of vaccination in adult patients with autoimmune inflammatory rheumatic diseases: a systematic literature review for the 2019 update of EULAR recommendations.

Aim: To present a systematic literature review (SLR) on efficacy, immunogenicity and safety of vaccination in adult patients with autoimmune inflammatory rheumatic diseases (AIIRD), aiming to provide a basis for updating the EULAR evidence-based recommendations. Methods: An SLR was performed according to the standard operating procedures for EULAR-endorsed recommendations. Outcome was determined by efficacy, immunogenicity and safety of vaccination in adult patients with AIIRD, including those receiving immunomodulating therapy. Furthermore, a search was performed on the effect of vaccinating household members of patients with AIIRD on the occurrence of vaccine-preventable infections in patients and their household members (including newborns). The literature search was performed using Medline, Embase and the Cochrane Library (October 2009 to August 2018). Results: While most investigated vaccines were efficacious and/or immunogenic in patients with AIIRD, some were less efficacious than in healthy control subjects, and/or in patients receiving immunosuppressive agents. Adverse events of vaccination were generally mild and the rates were comparable to those in healthy persons. Vaccination did not seem to lead to an increase in activity of the underlying AIIRD, but insufficient power of most studies precluded arriving at definite conclusions. The number of studies investigating clinical efficacy of vaccination is still limited. No studies on the effect of vaccinating household members of patients with AIIRD were retrieved. Conclusion: Evidence on efficacy, immunogenicity and safety of vaccination in patients with AIIRD was systematically reviewed to provide a basis for updated recommendations.

Transancestral mapping and genetic load in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (∼50% of these regions have multiple independent associations); these include 24 novel SLE regions (P<5 × 10-8), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SLE.

High mobility group box 1 skews macrophage polarization and negatively influences phagocytosis of apoptotic cells.

OBJECTIVES: Decreased phagocytosis of apoptotic cells plays an important role in the pathogenesis of SLE. This can lead to secondary necrosis and release of nuclear proteins, such as high mobility group box 1 (HMGB1). We hypothesized that increased HMGB1 levels, as present in SLE, skew macrophage differentiation towards M1-like phenotypes and thereby diminish uptake of apoptotic cells. The aim of this study was to investigate the effect of HMGB1 on macrophage polarization and on phagocytic capacity of differentiated macrophages. METHODS: SLE patients with quiescent disease (SLEDAI ⩽4) and healthy controls (HCs) were included. Monocytes and differentiated M1 and M2 macrophages were assessed for expression of M1 and M2 markers and for phagocytic capacity. HMGB1 was added during differentiation and during phagocytosis. RESULTS: Expression of CD86 (M1) was not different, whereas CD163 (M2) was significantly lower on SLE monocytes. After differentiation, no differences regarding surface receptor expression and phagocytic capacity were observed between M1 and M2 macrophages from SLE patients and HCs. Addition of HMGB1 during M2 differentiation resulted in high IL-6 and TNF-α mRNA expression and reduced phagocytic capacity of apoptotic cells. Furthermore, adding HMGB1 to apoptotic Jurkat cells diminished phagocytosis of these cells. CONCLUSION: Circulating monocytes from SLE patients display an M1-like phenotype compared with HCs, but in vitro differentiation abolishes this difference. HMGB1 skews differentiation of M2-like macrophages towards an M1-like phenotype and, subsequently, reduces phagocytosis of apoptotic cells. These data imply that the phenotype of monocytes or macrophages is determined by their environment, such as the presence of cytokines and HMGB1.

Treatment with Anti-HMGB1 Monoclonal Antibody Does Not Affect Lupus Nephritis in MRL/lpr Mice.

High mobility group box 1 (HMGB1) is a nuclear DNA binding protein that acts as an alarmin when secreted. HMGB1 is increased in systemic lupus erythematosus and might represent a potential therapeutic target. We investigated whether treatment with an anti-HMGB1 antibody affects the development of lupus nephritis in MRL/lpr mice. Seven-week-old MRL/lpr mice were injected intraperitoneally twice weekly for 10 wks with 50 µg monoclonal anti-HMGB1 (2G7, mouse IgG2b) (n = 12) or control antibody (n = 11). Control MRL/MPJ mice (n = 10) were left untreated. Every 2 wks, blood was drawn and urine was collected at wk 7, 11 and 17. Mice were sacrificed at 17 wks for complete disease evaluation. Plasma HMGB1 and anti-HMGB1 levels were increased in MRL/lpr mice compared with control MRL/MPJ mice. There were no differences in albuminuria, urine HMGB1 and plasma levels of complement C3, anti-dsDNA and proinflammatory cytokines between untreated and treated mice at any time point. Lupus nephritis of mice treated with anti-HMGB1 monoclonal antibody (mAb) was classified as class III (n = 3) and class IV (n = 9), while mice treated with control mAb were classified as class II (n = 4), class III (n = 2) and class IV (n = 5). IgG and C3 deposits in kidneys were similar in mice treated with anti-HMGB1 mAb or control mAb. In conclusion, treatment with monoclonal anti-HMGB-1 antibody 2G7 does not affect development of lupus nephritis, disease progression or proinflammatory cytokine levels in MRL/lpr mice. This result indicates that blocking of HMGB1 by this neutralizing antibody does not affect lupus nephritis in MRL/lpr mice.

Fc-gamma receptor polymorphisms differentially influence susceptibility to systemic lupus erythematosus and lupus nephritis.

OBJECTIVE: To determine relevant Fc-gamma receptor (FcγR) polymorphisms in relation to susceptibility to SLE and LN, and to determine the functional consequences of genetic associations found. METHODS: Using multiplex ligation-dependent probe amplification, copy number regions (CNRs) and relevant known functional single nucleotide polymorphisms of FcγRII and FcγRIII were determined in a LN-enriched cohort of 266 Dutch Caucasian SLE patients and 919 healthy Caucasian controls. Expression of FcγRs on leukocytes was assessed using flow cytometry. RESULTS: In multivariable analysis, low copy number of CNR1 (including FCGR3B; odds ratio (OR) 2.04; 95% CI: 1.29, 3.23), FCGR2A-131RR (OR 2.00; 95% CI: 1.33, 2.99), and the 2B.4 haplotype of FCGR2B (OR 1.59; 95% CI: 1.13, 2.24), but not FCGR2C open reading frame, were significantly (all P < 0.01) and independently associated with susceptibility to SLE. The 2B.4 haplotype was negatively associated with LN and led to surface expression of FcγRIIb on neutrophils and monocytes. CONCLUSION: This study is the first to investigate the most relevant and functional single nucleotide polymorphisms and copy number variations of FcγRII and FcγRIII polymorphisms in one study population, enabling the determination of the individual contribution of each polymorphism in multivariable analysis. Three polymorphisms were shown to be independently associated with susceptibility to SLE. The novel findings of a negative association of the 2B.4 haplotype with LN, and increased expression of FcγRIIb on neutrophils and monocytes as a result of this 2B.4 haplotype warrant future research in the role of these cells and FcγRs in the pathogenesis of SLE and LN.

Lupus erythematosus revisited.

Lupus erythematosus (LE) is a multifactorial autoimmune disease with clinical manifestations of differing severity. The exact pathomechanisms and interactions resulting in the inflammatory and immunological processes of this heterogeneous disease remain elusive. Approaches in the understanding of the pathomechanisms revealed that the clinical expression of LE is predisposed by susceptibility genes and that various environmental factors are responsible for an abnormal immune response. Several studies demonstrated that ultraviolet (UV) light is one of the major factors in the pathogenesis of the disease. Standardized photoprovocation in patients with LE has been shown to be a safe and efficient model for evaluating the underlying pathomechanisms which lead to the production of autoantibodies and immune complexes. In particular, interferons were defined as important players in the early activation of the immune system and were observed to play a specific role in the immunological interface between the innate and the adaptive immune system. Abnormalities or disturbances in the different processes of cell death, such as apoptosis or necrosis, have also been recognized as crucial in the pathogenesis of LE. Although each process is different and characterized by unique features, the processes are interrelated and result in a complex disease.

Herpes zoster epidemiology, management, and disease and economic burden in Europe: a multidisciplinary perspective.

Herpes zoster (HZ) is primarily a disease of nerve tissue but the acute and longer-term manifestations require multidisciplinary knowledge and involvement in their management. Complications may be dermatological (e.g. secondary bacterial infection), neurological (e.g. long-term pain, segmental paresis, stroke), ophthalmological (e.g. keratitis, iridocyclitis, secondary glaucoma) or visceral (e.g. pneumonia, hepatitis). The age-related increased incidence of HZ and its complications is thought to be a result of the decline in cell-mediated immunity (immunosenescence), higher incidence of comorbidities with age and social-environmental changes. Individuals who are immunocompromised as a result of disease or therapy are also at increased risk, independent of age. HZ and its complications (particularly postherpetic neuralgia) create a significant burden for the patient, carers, healthcare systems and employers. Prevention and treatment of HZ complications remain a therapeutic challenge despite recent advances. This is an overview of the multidisciplinary implications and management of HZ in which the potential contribution of vaccination to reducing the incidence HZ and its complications are also discussed.