Orbital/ocular inflammatory involvement in VEXAS syndrome: Data from the international AIDA network VEXAS registry.

VEXAS syndrome is a recently described monogenic autoinflammatory disease capable of manifesting itself with a wide array of organs and tissues involvement. Orbital/ocular inflammatory manifestations are frequently described in VEXAS patients. The objective of this study is to further describe orbital/ocular conditions in VEXAS syndrome while investigating potential associations with other disease manifestations. In the present study, twenty-seven out of 59 (45.8 %) VEXAS patients showed an inflammatory orbital/ocular involvement during their clinical history. The most frequent orbital/ocular affections were represented by periorbital edema in 8 (13.6 %) cases, episcleritis in 5 (8.5 %) patients, scleritis in 5 (8.5 %) cases, uveitis in 4 (6.8 %) cases, conjunctivitis in 4 (6.8 %) cases, blepharitis in 3 (5.1 %) cases, orbital myositis in 2 (3.4 %) cases. A diagnosis of systemic immune-mediated disease was observed in 15 (55.6 %) cases, with relapsing polychondritis diagnosed in 12 patients. A significant association was observed between relapsing polychondritis and orbital/ocular involvement in VEXAS syndrome (Relative Risk: 2.37, 95 % C.I. 1.03-5.46, p = 0.048). Six deaths were observed in the whole cohort of patients after a median disease duration of 1.2 (IQR=5.35) years, 5 (83.3 %) of which showed orbital/ocular inflammatory involvement. In conclusion, this study confirms that orbital/ocular inflammatory involvement is a common finding in VEXAS patients, especially when relapsing polychondritis is diagnosed. This makes ophthalmologists a key figure in the diagnostic process of VEXAS syndrome. The high frequency of deaths observed in this study seems to suggest that patients with orbital/ocular involvement may require increased attention and more careful follow-up.

Anticoagulant and non-anticoagulant therapy in thrombotic antiphospholipid syndrome: old drugs and new treatment targets.

In this review, we discuss the current evidence on classic and newer oral anticoagulant therapy, older drugs such as HCQ and statins, and new potential treatment targets in APS. Vitamin K antagonists (VKAs) remain the cornerstone treatment for thrombotic events in APS. In patients fulfilling criteria for definite APS presenting with a first venous thrombosis, treatment with VKAs with a target international normalized ratio (INR) 2.0-3.0 is recommended. In patients with arterial thrombosis, treatment with VKA with target INR 2.0-3.0 or 3.0-4.0 is recommended by recent guidelines, considering the individual's bleeding and thrombosis recurrence risk. A combination of VKAs and low-dose aspirin (75-100 mg/daily) may also be considered. According to available evidence direct oral anticoagulants should be avoided in patients with arterial thrombosis and/or those with triple aPL positivity. Adjunctive treatment with HCQ and/or statins can be considered, especially in anticoagulation treatment-refractory APS. Potential targeted treatments in APS include B-cell targeting, complement inhibition, mammalian target of rapamycin inhibition, IFN targeting, adenosine receptors agonists, CD38 targeting or chimeric antigen receptor T-cell therapy. The safety and efficacy of these treatment targets needs to be examined in well-designed randomized controlled trials.

Impact of cardiovascular risk factors in antiphospholipid syndrome: an observational study from the Spanish national registry.

OBJECTIVES: To determine the burden and impact of cardiovascular risk factors (CRF) in antiphospholipid syndrome (APS) patients. METHODS: Analysis of the patients diagnosed with APS identified in the Spanish Hospital Discharge Database between 2016 and 2017. We analysed the admissions due to arterial (ATE) and venous thromboembolic events (VTE) and evaluated the incidence and the attributed risk of each CRF. RESULTS: 5424 admissions in patients diagnosed with APS were identified. 64.6% were women and the mean age was 54.6. The mortality rate was 3.1%. Overall, 35.8% of patients had hypertension, 14% were diabetic, 21.7% hypercholesterolaemic, 9.9% obese and 26.7% smokers. Thromboembolic events (67.9% arterial and 32.1% venous) accounted for 11.9% of admissions and 7.1% of deaths. Male sex (OR 1.83, 95% CI 1.41-2.21), cholesterol (OR 1.25, 95% CI 1.01-1.54) and smoking (OR 1.49, 95% CI 1.22-1.81) were independently associated with thromboembolic events. Meanwhile, patients with ATE were older (57 vs. 54.1 years p=0.033), and presented more secondary APS (17.1% vs. 10.6%, p=0.034), hypertension (47.7% vs. 33.5%, p=0.001), diabetes (16.9% vs. 9.6%, p=0.017), cholesterol (34.3% vs. 17.8%, p<0.001) and smoking habit (41.2% vs. 24%, p<0.001) when compared with VTE. Risk factors independently associated with ATE events were male sex (OR=1.61, 95% CI=1.30-2.03), hypertension (OR=1.30, 95% CI=1.03-1.64), cholesterol (OR=1.51, 95% CI=1.18-1.94) and smoking habit (OR=1.84, 95% CI=1.47-2.32), while VTE events were determined by male sex (OR=2.06, 95% CI=1.53-2.77) and obesity (OR=1.61, CI=1.02-2.52). CONCLUSIONS: Thromboembolic events in APS were in part determined by a high prevalence of CRF. The identification of distinct profiles may allow us to undertake a more personalised approach to reduce thromboembolic events and to individualise anticoagulant and antiplatelet therapy.

Trends in Hospital Admissions and Death Causes in Patients with Systemic Lupus Erythematosus: Spanish National Registry.

BACKGROUND: the admission and death causes of SLE patients might have changed over the last years. METHODS: Analysis of the Spanish National Hospital Discharge database. All individuals admitted with SLE, according to ICD-9, were selected. The following five admission categories were considered: SLE, cardiovascular disease (CVD), neoplasm, infection, and venous-thromboembolic disease (VTED), along four periods of time (1997-2000, 2001-2005, 2006-2010, and 2011-2015). RESULTS: The admissions (99,859) from 43.432 patients with SLE were included. The absolute number of admissions increased from 15,807 in 1997-2000 to 31,977 in 2011-2015. SLE decreased as a cause of admission (from 47.1% to 20.8%, p < 0.001), while other categories increased over the time, as follows: 5% to 8.6% for CVD, 8.2% to 13% for infection, and 1.4% to 5.5% for neoplasm (p < 0.001 for all). The admission mortality rate rose from 2.22% to 3.06% (p < 0.001) and the causes of death evolved in parallel with the admission categories. A significant trend to older age was observed over time in the overall population and deceased patients (p < 0.001). CONCLUSIONS: Better control of SLE over the past two decades has led to a decrease in early admissions, and disease chronification. As a counterpart, CVD, infections, and neoplasm have become the main causes of admissions and mortality.

Eurolupus cyclophosphamide plus repeated pulses of methyl-prednisolone for the induction therapy of class III, IV and V lupus nephritis.

OBJECTIVE: To study whether adding repeated 125 mg methyl-prednisolone pulses (MP) to Eurolupus fortnightly intravenous cyclophosphamide (CYC) improves remission of lupus nephritis (LN) compared with recommended schedules. METHODS: Observational comparative study of patients with biopsy-confirmed class III, IV or V LN: 30 in the mycophenolate (MMF) group, 25 in the CYC group and 38 in the CYC-MP group. The main efficacy outcome was complete response at 12 months. RESULTS: Patients in the CYC-MP group received lower doses of prednisone within 6 months (mean 8.5 mg/d, vs. 15 mg/d in the MMF group vs. 24 mg/d in the CYC group, respectively). The complete response rates at 12 months were: CYC-MP 86%; CYC 56%; MMF 47% (p = 0.002) at Pr/Cr <0.5; CYC-MP 86%; CYC 65%; MMF 63% (p = 0.07) at Pr/Cr ≤0.7. The cumulative 12-month response rates for the CYC-MP, CYC and MMF groups were, respectively, 0.90, 0.58 and 0.63 (p = 0.004). In the adjusted Cox model, patients receiving CYC-MP were more likely to achieve complete response at Pr/Cr <0.5 than those in the MMF (HR vs. CYC-MP 0.33, 95%CI 0.16-0.65) and the CYC groups (HR vs. CYC-MP 0.47, 95%CI 0.21-1.04). Glucocorticoid-related toxicity was seen in 2.6% of the CYC-MP group, 24% of the CYC group and 20% of the MMF group (p = 0.029). CONCLUSION: The addition MP of 125 mg to each fortnightly dose of 500 mg of CYC improves response rates and reduces the need for oral glucocorticoids in patients with class III, IV and V LN.

European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) SLE classification criteria item performance.

BACKGROUND/OBJECTIVES: The European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) 2019 classification criteria for systemic lupus erythematosus system showed high specificity, while attaining also high sensitivity. We hereby analysed the performance of the individual criteria items and their contribution to the overall performance of the criteria. METHODS: We combined the EULAR/ACR derivation and validation cohorts for a total of 1197 systemic lupus erythematosus (SLE) and n=1074 non-SLE patients with a variety of conditions mimicking SLE, such as other autoimmune diseases, and calculated the sensitivity and specificity for antinuclear antibodies (ANA) and the 23 specific criteria items. We also tested performance omitting the EULAR/ACR criteria attribution rule, which defines that items are only counted if not more likely explained by a cause other than SLE. RESULTS: Positive ANA, the new entry criterion, was 99.5% sensitive, but only 19.4% specific, against a non-SLE population that included other inflammatory rheumatic, infectious, malignant and metabolic diseases. The specific criteria items were highly variable in sensitivity (from 0.42% for delirium and 1.84% for psychosis to 75.6% for antibodies to double-stranded DNA), but their specificity was uniformly high, with low C3 or C4 (83.0%) and leucopenia <4.000/mm³ (83.8%) at the lowest end. Unexplained fever was 95.3% specific in this cohort. Applying the attribution rule improved specificity, particularly for joint involvement. CONCLUSIONS: Changing the position of the highly sensitive, non-specific ANA to an entry criterion and the attribution rule resulted in a specificity of >80% for all items, explaining the higher overall specificity of the criteria set.

Transplantation-mediated alloimmune thrombocytopenia successfully treated by retransplantation.

INTRODUCTION: Transplantation-mediated alloimmune thrombocytopenia (TMAT) is a rare complication affecting the recipient of an organ from a donor with immune thrombocytopenia (ITP). METHODS: We present a case of TMAT following liver transplantation successfully treated by retransplantation, along with a review of previously published cases.Clinical presentation: The liver donor had lupus and ITP and died from an intracranial hemorrhage. The recipient's platelet count fell to 2x109/L on postoperative day 2. Due to the lack of response to medical treatment, emergency retransplantation was undertaken with a steady recovery of the platelet count within a few days. DISCUSSION: Six additional cases of transplantation-mediated alloimmune thrombocytopenia after liver transplantation have been reported. In all cases, severe thrombocytopenia ensued within 3 days after liver transplantation. Four patients suffered hemorrhagic complications. Three patients died. Early retransplantation was needed in three out of four patients receiving a graft from a donor with ITP and splenectomy. All recovered shortly after the new graft was in place. CONCLUSION: Severe refractory transplantation-mediated alloimmune thrombocytopenia can develop in liver recipients from donors with ITP, especially those with previous splenectomy. Early retransplantation should be considered if there is no rapid response to medical therapy.

Cancer Risk in a Large Inception Systemic Lupus Erythematosus Cohort: Effects of Demographic Characteristics, Smoking, and Medications.

OBJECTIVE: To assess cancer risk factors in incident systemic lupus erythematosus (SLE). METHODS: Clinical variables and cancer outcomes were assessed annually among incident SLE patients. Multivariate hazard regression models (overall risk and most common cancers) included demographic characteristics and time-dependent medications (corticosteroids, antimalarial drugs, immunosuppressants), smoking, and the adjusted mean Systemic Lupus Erythematosus Disease Activity Index 2000 score. RESULTS: Among 1,668 patients (average 9 years follow-up), 65 cancers occurred: 15 breast, 10 nonmelanoma skin, 7 lung, 6 hematologic, 6 prostate, 5 melanoma, 3 cervical, 3 renal, 2 each gastric, head and neck, and thyroid, and 1 each rectal, sarcoma, thymoma, and uterine cancers. Half of the cancers (including all lung cancers) occurred in past/current smokers, versus one-third of patients without cancer. Multivariate analyses indicated that overall cancer risk was related primarily to male sex and older age at SLE diagnosis. In addition, smoking was associated with lung cancer. For breast cancer risk, age was positively associated and antimalarial drugs were negatively associated. Antimalarial drugs and higher disease activity were also negatively associated with nonmelanoma skin cancer risk, whereas age and cyclophosphamide were positively associated. Disease activity was associated positively with hematologic and negatively with nonmelanoma skin cancer risk. CONCLUSION: Smoking is a key modifiable risk factor, especially for lung cancer, in SLE. Immunosuppressive medications were not clearly associated with higher risk except for cyclophosphamide and nonmelanoma skin cancer. Antimalarials were negatively associated with breast cancer and nonmelanoma skin cancer risk. SLE activity was associated positively with hematologic cancer and negatively with nonmelanoma skin cancer. Since the absolute number of cancers was small, additional follow-up will help consolidate these findings.

Economic Evaluation of Lupus Nephritis in the Systemic Lupus International Collaborating Clinics Inception Cohort Using a Multistate Model Approach.

OBJECTIVE: Little is known about the long-term costs of lupus nephritis (LN). The costs were compared between patients with and without LN using multistate modeling. METHODS: Patients from 32 centers in 11 countries were enrolled in the Systemic Lupus International Collaborating Clinics inception cohort within 15 months of diagnosis and provided annual data on renal function, hospitalizations, medications, dialysis, and selected procedures. LN was diagnosed by renal biopsy or the American College of Rheumatology classification criteria. Renal function was assessed annually using the estimated glomerular filtration rate (GFR) or estimated proteinuria. A multistate model was used to predict 10-year cumulative costs by multiplying annual costs associated with each renal state by the expected state duration. RESULTS: A total of 1,545 patients participated; 89.3% were women, the mean ± age at diagnosis was 35.2 ± 13.4 years, 49% were white, and the mean followup duration was 6.3 ± 3.3 years. LN developed in 39.4% of these patients by the end of followup. Ten-year cumulative costs were greater in those with LN and an estimated glomerular filtration rate (GFR) <30 ml/minute ($310,579 2015 Canadian dollars versus $19,987 if no LN and estimated GFR >60 ml/minute) or with LN and estimated proteinuria >3 gm/day ($84,040 versus $20,499 if no LN and estimated proteinuria <0.25 gm/day). CONCLUSION: Patients with estimated GFR <30 ml/minute incurred 10-year costs 15-fold higher than those with normal estimated GFR. By estimating the expected duration in each renal state and incorporating associated annual costs, disease severity at presentation can be used to anticipate future health care costs. This is critical knowledge for cost-effectiveness evaluations of novel therapies.

Systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease that can affect many organs, including the skin, joints, the central nervous system and the kidneys. Women of childbearing age and certain racial groups are typically predisposed to developing the condition. Rare, inherited, single-gene complement deficiencies are strongly associated with SLE, but the disease is inherited in a polygenic manner in most patients. Genetic interactions with environmental factors, particularly UV light exposure, Epstein-Barr virus infection and hormonal factors, might initiate the disease, resulting in immune dysregulation at the level of cytokines, T cells, B cells and macrophages. Diagnosis is primarily clinical and remains challenging because of the heterogeneity of SLE. Classification criteria have aided clinical trials, but, despite this, only one drug (that is, belimumab) has been approved for use in SLE in the past 60 years. The 10-year mortality has improved and toxic adverse effects of older medications such as cyclophosphamide and glucocorticoids have been partially offset by newer drugs such as mycophenolate mofetil and glucocorticoid-sparing regimes. However, further improvements have been hampered by the adverse effects of renal and neuropsychiatric involvement and late diagnosis. Adding to this burden is the increased risk of premature cardiovascular disease in SLE together with the risk of infection made worse by immunosuppressive therapy. Challenges remain with treatment-resistant disease and symptoms such as fatigue. Newer therapies may bring hope of better outcomes, and the refinement to stem cell and genetic techniques might offer a cure in the future.

[Hydroxychloroquine for autoimmune diseases]. / Hidroxicloroquina en el tratamiento de las enfermedades autoinmunes sistémicas.

Hydroxychloroquine (HCQ) is by far the most frequently used antimalarial for the management of Systemic Autoimmune Diseases. It has immunomodulatory, hypolipidemic, hypoglycemic and antithrombotic properties and it diminishes the risk of malignancies. The most important mechanisms to explain the immunomodulatory actions are its ability to reduce inflammatory pathways and Toll-like receptors activation. The safety profile is favorable. In spite of its low frequency, retinal toxicity is potentially severe. In systemic lupus erythematous HCQ therapy reduces activity, the accrual of organ damage, risk of infections and thrombosis and improves the cardiometabolic profile. It contributes to induce lupus nephritis remission, spares steroid use and increases survival rates. In rheumatoid arthritis, it improves cardiometabolic risk and has a favorable effect in joint inflammation. In Sjögren's syndrome, an increased lacrimal quality as well as an improvement in objective and subjective inflammatory markers has been demonstrated with HCQ. In Antiphospholipid Syndrome, HCQ is effective in primary and secondary thrombosis prevention. The effectiveness of the drug in other systemic autoimmune diseases is less established. HCQ therapy may improve dermatological manifestations in Dermatomyositis and may have a positive effects in the treatment of Sarcoidosis and Still disease.

[Clinical practice guidelines for systemic lupus erythematosus: Recommendations for general clinical management]. / Guía de práctica clínica para el lupus eritematoso sistémico: recomendaciones para el abordaje clínico general.

Systemic lupus erythematosus (SLE) is a complex rheumatic multisystemic disease of autoimmune origin with significant potential morbidity and mortality. It is one of the most common autoimmune diseases with an estimated prevalence of 20-150 cases per 100,000 inhabitants. The clinical spectrum of SLE is wide and variable both in clinical manifestations and severity. This prompted the Spanish Ministry of Health, Social Services and Equality to promote and fund the development of a clinical practice guideline (CPG) for the clinical care of SLE patients within the Programme of CPG in the National Health System which coordinates GuiaSalud. This CPG is is intended as the reference tool in the Spanish National Health System in order to support the comprehensive clinical management of people with SLE by all health professionals involved, regardless of specialty and level of care, helping to standardize and improve the quality of clinical decisions in our context in order to improve the health outcomes of the people affected. The purpose of this document is to present and discuss the rationale of the recommendations on the general management of SLE, specifically, clinical follow-up, general therapeutic approach, healthy lifestyles, photoprotection, and training programmes for patients. These recommendations are based on the best available scientific evidence, on discussion and the consensus of expert groups.

A Longitudinal Analysis of Outcomes of Lupus Nephritis in an International Inception Cohort Using a Multistate Model Approach.

OBJECTIVE: To study bidirectional change and predictors of change in estimated glomerular filtration rate (GFR) and proteinuria in lupus nephritis (LN) using a multistate modeling approach. METHODS: Patients in the Systemic Lupus International Collaborating Clinics inception cohort were classified annually into estimated GFR state 1 (>60 ml/minute), state 2 (30-60 ml/minute), or state 3 (<30 ml/minute) and estimated proteinuria state 1 (<0.25 gm/day), state 2 (0.25-3.0 gm/day), or state 3 (>3.0 gm/day), or end-stage renal disease (ESRD) or death. Using multistate modeling, relative transition rates between states indicated improvement and deterioration. RESULTS: Of 1,826 lupus patients, 700 (38.3%) developed LN. During a mean ± SD follow-up of 5.2 ± 3.5 years, the likelihood of improvement in estimated GFR and estimated proteinuria was greater than the likelihood of deterioration. After 5 years, 62% of patients initially in estimated GFR state 3 and 11% of patients initially in estimated proteinuria state 3 transitioned to ESRD. The probability of remaining in the initial states 1, 2, and 3 was 85%, 11%, and 3%, respectively, for estimated GFR and 62%, 29%, and 4%, respectively, for estimated proteinuria. Male sex predicted improvement in estimated GFR states; older age, race/ethnicity, higher estimated proteinuria state, and higher renal biopsy chronicity scores predicted deterioration. For estimated proteinuria, race/ethnicity, earlier calendar years, damage scores without renal variables, and higher renal biopsy chronicity scores predicted deterioration; male sex, presence of lupus anticoagulant, class V nephritis, and mycophenolic acid use predicted less improvement. CONCLUSION: In LN, the expected improvement or deterioration in renal outcomes can be estimated by multistate modeling and is preceded by identifiable risk factors. New therapeutic interventions for LN should meet or exceed these expectations.

The EULAR points to consider for use of antirheumatic drugs before pregnancy, and during pregnancy and lactation.

A European League Against Rheumatism (EULAR) task force was established to define points to consider on use of antirheumatic drugs before pregnancy, and during pregnancy and lactation. Based on a systematic literature review and pregnancy exposure data from several registries, statements on the compatibility of antirheumatic drugs during pregnancy and lactation were developed. The level of agreement among experts in regard to statements and propositions of use in clinical practice was established by Delphi voting. The task force defined 4 overarching principles and 11 points to consider for use of antirheumatic drugs during pregnancy and lactation. Compatibility with pregnancy and lactation was found for antimalarials, sulfasalazine, azathioprine, ciclosporin, tacrolimus, colchicine, intravenous immunoglobulin and glucocorticoids. Methotrexate, mycophenolate mofetil and cyclophosphamide require discontinuation before conception due to proven teratogenicity. Insufficient documentation in regard to fetal safety implies the discontinuation of leflunomide, tofacitinib as well as abatacept, rituximab, belimumab, tocilizumab, ustekinumab and anakinra before a planned pregnancy. Among biologics tumour necrosis factor inhibitors are best studied and appear reasonably safe with first and second trimester use. Restrictions in use apply for the few proven teratogenic drugs and the large proportion of medications for which insufficient safety data for the fetus/child are available. Effective drug treatment of active inflammatory rheumatic disease is possible with reasonable safety for the fetus/child during pregnancy and lactation. The dissemination of the data to health professionals and patients as well as their implementation into clinical practice may help to improve the management of pregnant and lactating patients with rheumatic disease.

Hidroxicloroquina en el tratamiento de las enfermedades autoinmunes sistémicas / Hydroxychloroquine for autoimmune diseases

Hydroxychloroquine (HCQ) is by far the most frequently used antimalarial for the management of Systemic Autoimmune Diseases. It has immunomodulatory, hypolipidemic, hypoglycemic and antithrombotic properties and it diminishes the risk of malignancies. The most important mechanisms to explain the immunomodulatory actions are its ability to reduce inflammatory pathways and Toll-like receptors activation. The safety profile is favorable. In spite of its low frequency, retinal toxicity is potentially severe. In systemic lupus erythematous HCQ therapy reduces activity, the accrual of organ damage, risk of infections and thrombosis and improves the cardiometabolic profile. It contributes to induce lupus nephritis remission, spares steroid use and increases survival rates. In rheumatoid arthritis, it improves cardiometabolic risk and has a favorable effect in joint inflammation. In Sjögren’s syndrome, an increased lacrimal quality as well as an improvement in objective and subjective inflammatory markers has been demonstrated with HCQ. In Antiphospholipid Syndrome, HCQ is effective in primary and secondary thrombosis prevention. The effectiveness of the drug in other systemic autoimmune diseases is less established. HCQ therapy may improve dermatological manifestations in Dermatomyositis and may have a positive effects in the treatment of Sarcoidosis and Still disease.

Peripheral arterial disease in systemic lupus erythematosus: prevalence and risk factors.

OBJECTIVE: To analyze the prevalence of peripheral arterial disease (PAD) and cardiovascular (CV) risk factors in a cohort of patients with systemic lupus erythematosus (SLE) and to identify variables potentially related to PAD. METHODS: The study included 216 patients with SLE from the Lupus-Cruces prospective observational cohort. The ankle brachial index (ABI) was determined in each patient, with values < 0.9 considered diagnostic of PAD. Demographic and clinical variables, presence of traditional risk factors and CV events, cardiovascular risk calculated by Systematic Coronary Risk Evaluation (SCORE), and treatments received by each patient were analyzed. RESULTS: Ninety-two percent of patients were women. The mean age (SD) was 49 years (15), with a mean followup (SD) of 12 years (9). The prevalence of low ABI was 21%. CV risk factors were frequent: smoking, 30% of patients; high blood pressure, 32.7%; diabetes mellitus, 3.2%; hypercholesterolemia, 34.1%; and metabolic syndrome, 9.7%. The following variables were associated with low ABI in the univariate analysis: age (p < 0.001), hypertension (p = 0.002), diabetes (p = 0.018), hypercholesterolemia (p = 0.018), CV events (p < 0.001), SCORE (p = 0.004), cumulative dose of cyclophosphamide (p = 0.03), and fibrinogen levels (p = 0.002). In the multivariate analysis, the only independent variable in the final model was age (OR 1.04, 95% CI 1.02-1.07, p < 0.001), with a tendency for the presence of any vascular risk factor (diabetes, hypertension, hypercholesterolemia, or current smoking; OR 2.3, 95% CI 0.99-5.1, p = 0.053). CONCLUSION: The prevalence of low ABI in patients with SLE is higher than expected. While the association with CV risk factors and vascular disease in other territories was strong, we could not identify SLE-specific variables independently associated with PAD.

Lymphoma risk in systemic lupus: effects of disease activity versus treatment.

OBJECTIVE: To examine disease activity versus treatment as lymphoma risk factors in systemic lupus erythematosus (SLE). METHODS: We performed case-cohort analyses within a multisite SLE cohort. Cancers were ascertained by regional registry linkages. Adjusted HRs for lymphoma were generated in regression models, for time-dependent exposures to immunomodulators (cyclophosphamide, azathioprine, methotrexate, mycophenolate, antimalarial drugs, glucocorticoids) demographics, calendar year, Sjogren's syndrome, SLE duration and disease activity. We used adjusted mean SLE Disease Activity Index scores (SLEDAI-2K) over time, and drugs were treated both categorically (ever/never) and as estimated cumulative doses. RESULTS: We studied 75 patients with lymphoma (72 non-Hodgkin, three Hodgkin) and 4961 cancer-free controls. Most lymphomas were of B-cell origin. As is seen in the general population, lymphoma risk in SLE was higher in male than female patients and increased with age. Lymphomas occurred a mean of 12.4 years (median 10.9) after SLE diagnosis. Unadjusted and adjusted analyses failed to show a clear association of disease activity with lymphoma risk. There was a suggestion of greater exposure to cyclophosphamide and to higher cumulative steroids in lymphoma cases than the cancer-free controls. CONCLUSIONS: In this large SLE sample, there was a suggestion of higher lymphoma risk with exposure to cyclophosphamide and high cumulative steroids. Disease activity itself was not clearly associated with lymphoma risk. Further work will focus on genetic profiles that might interact with medication exposure to influence lymphoma risk in SLE.

Cancer risk in systemic lupus: an updated international multi-centre cohort study.

OBJECTIVE: To update estimates of cancer risk in SLE relative to the general population. METHODS: A multisite international SLE cohort was linked with regional tumor registries. Standardized incidence ratios (SIRs) were calculated as the ratio of observed to expected cancers. RESULTS: Across 30 centres, 16,409 patients were observed for 121,283 (average 7.4) person-years. In total, 644 cancers occurred. Some cancers, notably hematologic malignancies, were substantially increased (SIR 3.02, 95% confidence interval, CI, 2.48, 3.63), particularly non-Hodgkin's lymphoma, NHL (SIR 4.39, 95% CI 3.46, 5.49) and leukemia. In addition, increased risks of cancer of the vulva (SIR 3.78, 95% CI 1.52, 7.78), lung (SIR 1.30, 95% CI 1.04, 1.60), thyroid (SIR 1.76, 95% CI 1.13, 2.61) and possibly liver (SIR 1.87, 95% CI 0.97, 3.27) were suggested. However, a decreased risk was estimated for breast (SIR 0.73, 95% CI 0.61-0.88), endometrial (SIR 0.44, 95% CI 0.23-0.77), and possibly ovarian cancers (0.64, 95% CI 0.34-1.10). The variability of comparative rates across different cancers meant that only a small increased risk was estimated across all cancers (SIR 1.14, 95% CI 1.05, 1.23). CONCLUSION: These data estimate only a small increased risk in SLE (versus the general population) for cancer over-all. However, there is clearly an increased risk of NHL, and cancers of the vulva, lung, thyroid, and possibly liver. It remains unclear to what extent the association with NHL is mediated by innate versus exogenous factors. Similarly, the etiology of the decreased breast, endometrial, and possibly ovarian cancer risk is uncertain, though investigations are ongoing.