Hal Scofield

2016 American College of Rheumatology/European League Against Rheumatism classification criteria for primary Sjögren's syndrome A consensus and data-driven methodology involving three international patient cohorts

Objectives To develop and validate an international set of classification criteria for primary Sjögrens syndrome (SS) using guidelines from the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR). These criteria were developed for use in individuals with signs and/or symptoms suggestive of SS. Methods We assigned preliminary importance weights to a consensus list of candidate criteria items, using multi-criteria decision analysis. We tested and adapted the resulting draft criteria using existing cohort data on primary SS cases and non-SS controls, with case/non-case status derived from expert clinical judgement. We then validated the performance of the classification criteria in a separate cohort of patients. Results The final classification criteria are based on the weighted sum of five items: anti-SSA/Ro antibody positivity and focal lymphocytic sialadenitis with a focus score of ≥1 foci/4 mm2, each scoring 3; an abnormal Ocular Staining Score of ≥5 (or van Bijsterveld score of ≥4), a Schirmers test result of ≤5 mm/5 min and an unstimulated salivary flow rate of ≤0.1 mL/min, each scoring 1. Individuals with signs and/or symptoms suggestive of SS who have a total score of ≥4 for the above items meet the criteria for primary SS. Sensitivity and specificity against clinician-expert—derived case/non-case status in the final validation cohort were high, that is, 96% (95% CI92% to 98%) and 95% (95% CI 92% to 97%), respectively. Conclusion Using methodology consistent with other recent ACR/EULAR-approved classification criteria, we developed a single set of data-driven consensus classification criteria for primary SS, which performed well in validation analyses and are well suited as criteria for enrolment in clinical trials.

Treatment Guidelines for Rheumatologic Manifestations of Sjögren's Syndrome: Use of Biologic Agents, Management of Fatigue, and Inflammatory Musculoskeletal Pain

The Sjögrens Syndrome Foundation clinical practice guidelines (CPGs) are designed to improve quality and consistency of care in Sjögrens syndrome by offering recommendations for management.

Case Report: Gastrocolic Fistula Mimicking Zollinger-Ellison Syndrome

Fasting serum gastrin levels greater than 1000 pg/ml are said to establish the diagnosis of gastrinoma in a patient with peptic ulcer disease. The authors observed a patient with recurrent peptic ulcer disease, diarrhea, and a fasting serum gastrin of 1044 pg/ml who had a gastrocolic fistula, not the Zollinger-Ellison syndrome. The provocative tests of gastrin secretion, including secretin infusion and standard meal test, were helpful in ruling out a gastrinoma. This is the first reported association of gastrocolic fistula and hypergastrinemia. The patient demonstrates that the differential diagnosis of markedly elevated serum gastrin should be expanded to include gastrocolic fistula.

Authors' Response to Tezcan and Colleagues' Letter to the Editor

ogren’s syndrome: a data-driven, expert consensus approach in the Sj€ ogren’s International Collaborative Clinical Alliance cohort. Arthritis Care Res (Hoboken) 2012;64:475–87. 4. Vitali C, Bombardieri S, Jonsson R, Moutsopoulos HM, Alexander EL, Carsons SE, et al. Classification criteria for Sj€ ogren’s syndrome: a revised version of the European criteria proposed by the AmericanEuropean Consensus Group. Ann Rheum Dis 2002;61:554–8. 5. Vitali C, Bombardieri S, Moutsopoulos HM, Coll J, Gerli R, Hatron PY, et al. Assessment of the European classification criteria for Sj€ ogren’s syndrome in a series of clinically defined cases: results of a prospective multicentre study. Ann Rheum Dis 1996;55:116–21. 6. Kabasakal Y, Kitapcioglu G, Karabulut G, Tezcan ME, Balkarli A, Aksoy A, et al. Criteria sets for primary Sj€ ogren’s syndrome are not adequate for those presenting with extraglandular organ involvements as their dominant clinical features. Rheumatol Int 2017;37:675–84. In press. 7. Petri M, Orbai AM, Alarcon GS, Gordon C, Merrill JT, Fortin PR, et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum 2012;64:2677–86.

Genetic fine mapping of systemic lupus erythematosus MHC associations in Europeans and African Americans

Abstract Genetic variation within the major histocompatibility complex (MHC) contributes substantial risk for systemic lupus erythematosus, but high gene density, extreme polymorphism and extensive linkage disequilibrium (LD) have made fine mapping challenging. To address the problem, we compared two association techniques in two ancestrally diverse populations, African Americans (AAs) and Europeans (EURs). We observed a greater number of Human Leucocyte Antigen (HLA) alleles in AA consistent with the elevated level of recombination in this population. In EUR we observed 50 different A—C—B—DRB1—DQA—DQB multilocus haplotype sequences per hundred individuals; in the AA sample, these multilocus haplotypes were twice as common compared to Europeans. We also observed a strong narrow class II signal in AA as opposed to the long‐range LD observed in EUR that includes class I alleles. We performed a Bayesian model choice of the classical HLA alleles and a frequentist analysis that combined both single nucleotide polymorphisms (SNPs) and classical HLA alleles. Both analyses converged on a similar subset of risk HLA alleles: in EUR HLA‐ B*08:01 + B*18:01 + (DRB1*15:01 frequentist only) + DQA*01:02 + DQB*02:01 + DRB3*02 and in AA HLA‐C*17:01 + B*08:01 + DRB1*15:03 + (DQA*01:02 frequentist only) + DQA*02:01 + DQA*05:01+ DQA*05:05 + DQB*03:19 + DQB*02:02. We observed two additional independent SNP associations in both populations: EUR rs146903072 and rs501480; AA rs389883 and rs114118665. The DR2 serotype was best explained by DRB1*15:03 + DQA*01:02 in AA and by DRB1*15:01 + DQA*01:02 in EUR. The DR3 serotype was best explained by DQA*05:01 in AA and by DQB*02:01 in EUR. Despite some differences in underlying HLA allele risk models in EUR and AA, SNP signals across the extended MHC showed remarkable similarity and significant concordance in direction of effect for risk‐associated variants.

Strawberries decrease circulating levels of tumor necrosis factor and lipid peroxides in knee osteoarthritis in obese adults

OBJECTIVE Knee osteoarthritis (OA) is increasingly prevalent in obese people, who often have high cardio-metabolic risk factors. Among the few available non-surgical approaches, nutraceuticals have gained popularity, and dietary berries have mitigated arthritis symptoms in observational and animal studies. Clinical studies in OA are sparse, but recently we reported that strawberry supplementation can mitigate pain and reduce inflammatory markers in adults with knee OA. This study extends those observations. METHODS We conducted a randomized cross-over double-blind placebo-controlled trial on the effects of dietary freeze-dried strawberries on obesity-related hormones, biomarkers of inflammation and lipid peroxidation. Seventeen subjects (4 men, 13 women; age 57 ± 3 year) were randomized to strawberry supplements (50 g day-1 for 12 weeks) vs. placebo (50 g day-1, matched for calories and fiber), for two 12-week intervention periods, separated by 2-week washout phase. RESULTS Among 24 biomarkers of inflammation examined (Bioplex-Pro human inflammation panel), 12 were detectable in all samples. Among these, high-sensitivity TNF-α (hs-TNF-α) and the soluble tumor necrosis factor receptor (sTNF-R2) were significantly decreased after strawberry consumption (p < 0.05). There were no changes in other biomarkers of the TNF super family, such as APRIL and BAFF. Among serum biomarkers of oxidative stress, 4-hydroxy-2-nonenal (4-HNE) and conjugated dienes were also reduced (p < 0.05). No changes were observed in body weight, serum obesity-related hormones, or osteocalcin. CONCLUSION Strawberries lowered TNF-α, and lipid peroxidation products in obese adults with knee OA. Since, they also mitigate pain, these findings merit further investigation in larger trials.

35 GENE EXPRESSION ANALYSIS OF EUROPEAN-AMERICAN LUPUS PATIENTS WITH THYROID DISEASE COMPARED TO MATCHED CONTROLS

Purpose We have studied gene expression in Epstein-Barr virus transformed B cell lines to define differences between SLE patients and matched controls. We used this design to remove, to the extent possible, environmental influences and the secondary changes in gene expression caused by lupus and found in peripheral blood cells from patients who are ill. In the present study, we have focused on gene expression analysis of cell lines derived from European-American lupus patients who also present evidence of thyroid disease compared to unrelated matched controls. Methods 12 European-American SLE patients were selected according to American College of Rheumatology (ACR) criteria for SLE and their contribution to the 5q14 (lupus affected with autoimmune thyroid disease) genetic linkage. 12 controls were matched by age, sex, race, and state of residence. Human genome U133 plus 2.0 arrays (Affymetrix) were used for each subject. Gene expression differences were evaluated for genes with p < .05 for the paired t-test, p < .0001 for the associative t-test, and an apparent ratio of expression of > 2.0 or < 0.5. Results The affecteds from pedigrees linked at 5q14 differently expressed 191 genes when compared to controls (59 up-regulated, 54 down-regulated, 19 only in lupus patients, and 59 only in matched controls). Two of the differentially expressed genes were located in 5q14 intervals. The differentially expressed genes include members of signal transduction pathways, thyroid hormone receptor, small nuclear ribonucleotide proteins and immune response related genes. Conclusions We identified genes by differential gene expression analysis of cell lines derived from European-American lupus patients with thyroid disease. Two of these genes come from within the genetic linkage interval identified in other studies of this subset of lupus patients.