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Background Lupus patients are at risk for pregnancy loss, and it has been generally accepted that women with SLE should have low disease activity prior to conception. However, there are conflicting results regarding the effect of pregnancy on SLE flares. This study aims to identify predictors of flares during and after pregnancy in SLE patients with inactive or stable disease activity during the first trimester and to characterize and estimate the frequency of post-partum flares in these patients. Methods SLE patients in the multicenter, prospective PROMISSE (Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus) study were evaluated for flares during and after pregnancy using the SELENA-SLEDAI Flare Index. Flares during pregnancy were assessed in all 384 patients and post-partum flares in 234 patients with study visits 2–6 months post-partum. Logistic regression models were fit to the data to identify independent risk factors for flare. Results During pregnancy, 20.8% of patients had mild/moderate flares and 6.25% had severe. Post-partum, 27.7% of patients had mild/moderate flares and 1.7% had severe. The mild flares rarely required treatment. Younger age, low C4 and higher PGA at baseline were independently associated with higher risk of having at least one mild/moderate or severe flare during pregnancy. Older patients were at decreased risk of flare, as well as those with quiescent disease at baseline. No variables evaluated at baseline or the visit most proximal to delivery was significantly associated with risk of flare post-partum. Medications were not associated with flare during or after pregnancy. Conclusion In patients with inactive or stable mild disease activity at the time of conception, lupus disease flares during and after pregnancy are typically mild and occur at similar rates. Flares during pregnancy are predicted by the patients’ age and clinical and serological activity at baseline.

Healthy and uncomplicated lupus pregnancies exhibit early and sustained transcriptional modulation of lupus-related pathways. This might contribute to fetal tolerance while predisposing pregnant women to certain infections. Failure to modulate these pathways is associated with lupus pregnancy complications., Systemic lupus erythematosus carries an increased risk of pregnancy complications, including preeclampsia and fetal adverse outcomes. To identify the underlying molecular mechanisms, we longitudinally profiled the blood transcriptome of 92 lupus patients and 43 healthy women during pregnancy and postpartum and performed multicolor flow cytometry in a subset of them. We also profiled 25 healthy women undergoing assisted reproductive technology to monitor transcriptional changes around embryo implantation. Sustained down-regulation of multiple immune signatures, including interferon and plasma cells, was observed during healthy pregnancy. These changes appeared early after embryo implantation and were mirrored in uncomplicated lupus pregnancies. Patients with preeclampsia displayed early up-regulation of neutrophil signatures that correlated with expansion of immature neutrophils. Lupus pregnancies with fetal complications carried the highest interferon and plasma cell signatures as well as activated CD4+ T cell counts. Thus, blood immunomonitoring reveals that both healthy and uncomplicated lupus pregnancies exhibit early and sustained transcriptional modulation of lupus-related signatures, and a lack thereof associates with adverse outcomes., Graphical Abstract

ObjectiveStudies in mouse models implicate complement activation as a causative factor in adverse pregnancy outcomes (APOs). We investigated whether activation of complement early in pregnancy predicts APOs in women with systemic lupus erythematosus (SLE) and/or antiphospholipid (aPL) antibodies.MethodsThe PROMISSE Study enrolled pregnant women with SLE and/or aPL antibodies (n=487) and pregnant healthy controls (n=204) at ResultsAPO occurred in 20.5% of SLE and/or aPL pregnancies. As early as 12–15 weeks, levels of Bb and sC5b-9 were significantly higher in patients with APOs and remained elevated through 31 weeks compared with those with normal outcomes. Moreover, Bb and sC5b-9 were significantly higher in patients with SLE and/or aPL without APOs compared with healthy controls. In logistic regression analyses, Bb and sC5b-9 at 12–15 weeks remained significantly associated with APO (ORadj=1.41 per SD increase; 95% CI 1.06 to 1.89; P=0.019 and ORadj=1.37 per SD increase; 95% CI 1.05 to 1.80; P=0.022, respectively) after controlling for demographic and clinical risk factors for APOs in PROMISSE. When analyses were restricted to patients with aPL (n=161), associations between Bb at 12–15 weeks and APOs became stronger (ORadj=2.01 per SD increase; 95% CI 1.16 to 3.49; P=0.013).ConclusionIn pregnant patients with SLE and/or aPL, increased Bb and sC5b-9 detectable early in pregnancy are strongly predictive of APOs and support activation of complement, particularly the alternative pathway, as a contributor to APOs.

Treating patients with osteoarthritis requires careful individualization in order to achieve patient-specific goals, which may vary from obtaining short-term pain relief to achieving long-term maintenance of function or even preservation of cartilage. In response to specific patient goals, the provider makes use of a toolbox of physical, adjunctive, alternative, pharmacologic, and operative interventions. Among the alternative category are the nutraceuticals, which will be reviewed here with particular attention given to those agents with randomized control trial (RCT) data showing statistically significant benefits. Some of these can be used to minimize patient symptoms with very low risks. The safety of these agents is particularly important in treating patients with osteoarthritis as many of the patients are older with significant comorbidities. Further, it is very likely that it will be necessary for the patients to continue treatment for many years.

Background and objectives Kidney disease is a critical concern in counseling patients with lupus considering pregnancy. This study sought to assess the risk of renal flares during pregnancy in women with previous lupus nephritis in partial or complete remission, particularly in those with antidouble-stranded DNA antibodies and low complement levels, and the risk of new-onset nephritis in patients with stable/mildly active SLE. Design, setting, participants, & measurements We assessed active nephritis (renal flares and de novo kidney disease) and associated predictors during pregnancy in patients with lupus with urine protein ≤1000 mg and serum creatinine 500 mg and/or red blood cell casts. Results Of 118 patients with previous kidney disease, 13 renal flares (11%) occurred (seven of 89 in complete remission and six of 29 in partial remission) compared with four with de novo kidney involvement (2%) in 255 patients without past kidney disease (P Conclusions De novo kidney involvement in SLE, even in ethnic/racial minorities, is uncommon during pregnancy. Past kidney disease and low C4 at baseline independently associate with higher risk of developing active nephritis. Antibodies to dsDNA alone should not raise concern, even in patients with past kidney disease, if in remission.

Background A low cost and accurate method for detecting high-risk (HR) human papillomavirus (HPV) is important to permit HPV testing for cervical cancer prevention. We used a commercially available HPV method (H13, Hybribio) which was documented to function accurately in a reduced volume of cervical specimen to determine the most prevalent HPV types and the distribution of HPV infections in over 1795 cancer-free women in Guatemala undergoing primary screening for cervical cancer by cytology. Methods HR-HPV detection was attempted in cervical samples from 1795 cancer-free women receiving Pap smears using the Hybribio™ real-time PCR assay of 13 HR types. The test includes a globin gene internal control. HPV positive samples were sequenced to determine viral type. Age-specific prevalence of HPV was also assessed in the study population. Results A total of 13% (226/1717) of women tested HPV+, with 78 samples (4.3%) failing to amplify the internal control. The highest prevalence was found in younger women (

Osteoarthritis (OA) is a common debilitating disease characterized by abnormal remodeling of the cartilage and bone of the articular joint. Ameliorating therapeutics are lacking due to limited understanding of the molecular pathways affecting disease initiation and progression. Notably, although a link between inflammation and overt OA is well established, the role of inflammation as a driver of disease occurrence is highly disputed. We analyzed a family with dominant inheritance of early-onset OA and found that affected individuals harbored a rare variant allele encoding a significant amino acid change (p.Asn104Asp) in the kinase domain of receptor interacting protein kinase 2 (RIPK2), which transduces signals from activated bacterial peptidoglycan sensors through the NF-κB pathway to generate a proinflammatory immune response. Functional analyses of RIPK2 activity in zebrafish embryos indicated that the variant RIPK2104Asp protein is hyperactive in its signaling capacity, with augmented ability to activate the innate immune response and the NF-κB pathway and to promote upregulation of OA-associated genes. Further we show a second allele of RIPK2 linked to an inflammatory disease associated with arthritis also has enhanced activity stimulating the NF-κB pathway. Our studies reveal for the first time the inflammatory response can function as a gatekeeper risk factor for OA.

Osteoarthritis (OA) is a chronic, highly prevalent and disabling disease that is expected to increase in prevalence secondary to longer life expectancy and a disproportionately aging population. Treatment of OA is only marginally effective and has been focused primarily on symptom control using weight loss, physical therapy, nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, intra-articular steroids or viscosupplementation, topical NSAIDs and analgesics, diacerein (an oral interleukin-1β inhibitor) and finally joint replacement surgery. The use of nutraceuticals in the treatment of OA is common, and scientific studies examining the effects of nutraceuticals on the pathogenesis and treatment of OA are increasing. This review examines the efficacy and safety of select nutraceuticals for the treatment of OA. The reviewed nutraceuticals include glucosamine, chondroitin, collagen hydrolysates (CHs) and avocado-soybean unsaponifiables (ASUs). There have been several clinical trials examining the efficacy of these products and the results demonstrate significant heterogeneity. Significant improvements in pain, function and structural outcomes have been shown for some of the treatment arms or subgroups of patients, but the effects are not consistent across the studies. Glucosamine, chondroitin and the two in combination have been the most extensively studied. Significant improvement in pain and functional indices and a decrease in the loss of joint space width were demonstrated in some but not all studies. CHs showed significant improvement in pain and functional indices for several subgroups of patients, but these findings were not pervasive amongst the treatment arms. ASU has demonstrated positive results with respect to decreased NSAID use in several studies and functional and pain end points in most of the reviewed studies; however, in the two studies examining structural end points, the results were mixed. The safety of these nutraceuticals has been demonstrated across all of the reviewed trials, and there were no significant issues with tolerance. Given the good safety profile of nutraceuticals, the marginal efficacy of conventional treatments, the high prevalence and rate of disability from OA and the possible benefit of nutraceuticals to patients with OA, use of nutraceuticals in select patients is appropriate. An overall recommendation to use nutraceuticals in the treatment of all patients with OA is not strongly supported by the available data. Future studies should focus on standardization of symptomatic and structural outcome measures, be of longer duration and pay careful attention to the content of the investigational product.

Objective.The main histopathological focus of systemic sclerosis (SSc) has concentrated on fibrotic changes. We investigated the microvasculature alterations in the skin of patients with SSc at various stages of disease duration with whole-field digital microscopy.Methods.Twenty consecutive patients with SSc, 1 with Raynaud’s phenomenon (RP) without SSc, and 4 healthy controls underwent punch biopsy on the medial forearm. Eighteen patients were included in the primary analysis. Two with recent-onset diffuse cutaneous disease, 1 repeat SSc biopsy, and 1 patient with RP without SSc were also evaluated. All specimens were processed with histochemical stains and immunohistochemistry. We analyzed microvasculature abnormalities in an objective and systematic manner taking advantage of recent advances in whole-field digital microscopy. This analysis was coupled with ultrastructural evaluation performed with transmission electron microscopy (TEM).Results.Whole-field digital microscopy and TEM of SSc skin biopsies revealed that endothelial abnormalities are a universal feature regardless of clinical features and/or duration of disease. These features were not seen in any healthy control specimens or in the single RP patient samples. Whole-field digital microscopy identified increased interstitial edema (31.0% ± 9.6% vs 17.6% ± 3.3% in controls; p = 0.009) and fibrosis (75.6% ± 5.7% vs 66.1% ± 9.8% in controls; p = 0.02) in all patients with SSc. Lower CD34 staining was seen in SSc compared to healthy controls (0.32% ± 0.22% vs 1.31% ± 0.34%; p < 0.0001) and within the SSc population with interstitial lung disease (0.55% ± 0.22% vs 0.15% ± 0.16%; p = 0.01). Perivascular and interstitial infiltrate of mast cells was present in all SSc specimens.Conclusion.Whole-field digital microscopy offers a means of rapidly carrying out objective, fully quantitative, and reproducible measurements of microscopic features of SSc microvascular change. The universal morphologically abnormal endothelial cells and interstitial edema in all patients with SSc biopsied suggests that SSc may be intrinsically a disease of the endothelium characterized by vascular leak.

The purpose of this study was to analyze antinuclear antibody (ANA) screening by enzyme-linked immunosorbent assay (ELISA) followed by indirect fluorescent antibody (IFA) testing to confirm and characterize the pattern and titer of the antibody. We evaluated 4 ANA ELISAs and 1 HEp-2 IFA substrate in 224 clinically defined serum samples consisting of 30 from systemic lupus erythematosus (SLE) cases, 94 from rheumatoid arthritis cases, and 100 from healthy donors plus 495 serum samples submitted for routine ANA testing and 12 reference serum samples distributed by the Centers for Disease Control and Prevention. IFA tests were read independently by 2 certified medical technologists. ELISA sensitivities ranged from 90% to 97% compared with 80% by IFA in the SLE serum samples. The ELISAs had specificities of 36% to 94%, whereas the IFA had 99% specificity. Overall, ELISAs for ANA assays demonstrated better sensitivity and good specificity, suggesting ELISA is a more cost-effective alternative to IFA testing for initial ANA screening. Samples positive by ANA ELISA should be tested on HEp-2 to determine the titer and pattern.

Age-related macular degeneration (AMD) is the most common cause of incurable visual impairment in high-income countries. Previous studies report inconsistent associations between AMD and apolipoprotein E (APOE), a lipid transport protein involved in low-density cholesterol modulation. Potential interaction between APOE and sex, and smoking status has been reported. We present a pooled analysis (n = 21,160) demonstrating associations between late AMD and APOe4 (odds ratio [OR] = 0.72 per haplotype; confidence interval [CI]: 0.650.74; P = 4.41 x 10-11) and APOe2 (OR = 1.83 for homozygote carriers; CI: 1.043.23; P = 0.04), following adjustment for age group and sex within each study and smoking status. No evidence of interaction between APOE and sex or smoking was found. Ever smokers had significant increased risk relative to never smokers for both neovascular (OR = 1.54; CI: 1.381.72; P = 2.8 x 10(-15)) and atrophic (OR = 1.38; CI: 1.181.61; P = 3.37 x 10(-5)) AMD but not early AMD (OR = 0.94; CI: 0.861.03; P = 0.16), implicating smoking as a major contributing factor to disease progression from early signs to the visually disabling late forms. Extended haplotype analysis incorporating rs405509 did not identify additional risks beyond e2 and e4 haplotypes. Our expanded analysis substantially improves our understanding of the association between the APOE locus and AMD. It further provides evidence supporting the role of cholesterol modulation, and low-density cholesterol specifically, in AMD disease etiology. 32:14071416, 2011. (C) 2011 Wiley Periodicals, Inc.

Raynaud’s phenomenon (RP) is a stress- or cold-temperature-induced, recurrent, but transient digital ischemia, which is characterized by a demarcated pallor and followed by a re-flow of blood to the digits, that appears as erythema, cyanosis or both. RP is differentiated into primary and secondary forms. Identification of the form secondary to autoimmune phenomenon is essential, because of the potential for complicated outcomes, internal organ involvement and more frequent need for pharmacological treatment. When a secondary form of RP is identified, especially in the case of systemic sclerosis (SSc), internal organ involvement from the disease process directs therapy. It is thought that this internal organ involvement is a manifestation of the same vasospastic propensity that RP represents. Thus, it is possible that a heightened understanding of the pathogenesis of RP demands a more aggressive intervention for secondary RP associated with SSc. This becomes especially important as therapy, in addition to ...

Because systemic lupus erythematosus (SLE) affects women of reproductive age, pregnancy is a major concern.To identify predictors of adverse pregnancy outcomes (APOs) in patients with inactive or stable active SLE.Prospective cohort.Multicenter.385 patients (49% non-Hispanic white; 31% with prior nephritis) with SLE in the PROMISSE (Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus) study. Exclusion criteria were urinary protein-creatinine ratio greater than 1000 mg/g, creatinine level greater than 1.2 mg/dL, prednisone use greater than 20 mg/d, and multifetal pregnancy.APOs included fetal or neonatal death; birth before 36 weeks due to placental insufficiency, hypertension, or preeclampsia; and small-for-gestational-age (SGA) neonate (birthweight below the fifth percentile). Disease activity was assessed with the Systemic Lupus Erythematosus Pregnancy Disease Activity Index and the Physician's Global Assessment (PGA).APOs occurred in 19.0% (95% CI, 15.2% to 23.2%) of pregnancies; fetal death occurred in 4%, neonatal death occurred in 1%, preterm delivery occurred in 9%, and SGA neonate occurred in 10%. Severe flares in the second and third trimesters occurred in 2.5% and 3.0%, respectively. Baseline predictors of APOs included presence of lupus anticoagulant (LAC) (odds ratio [OR], 8.32 [CI, 3.59 to 19.26]), antihypertensive use (OR, 7.05 [CI, 3.05 to 16.31]), PGA score greater than 1 (OR, 4.02 [CI, 1.84 to 8.82]), and low platelet count (OR, 1.33 [CI, 1.09 to 1.63] per decrease of 50 × 109 cells/L). Non-Hispanic white race was protective (OR, 0.45 [CI, 0.24 to 0.84]). Maternal flares, higher disease activity, and smaller increases in C3 level later in pregnancy also predicted APOs. Among women without baseline risk factors, the APO rate was 7.8%. For those who either were LAC-positive or were LAC-negative but nonwhite or Hispanic and using antihypertensives, the APO rate was 58.0% and fetal or neonatal mortality was 22.0%.Patients with high disease activity were excluded.In pregnant patients with inactive or stable mild/moderate SLE, severe flares are infrequent and, absent specific risk factors, outcomes are favorable.National Institutes of Health.

Trial registration number: NCT01425853. [Abstract] Objectives. To compare the efficacy and safety of chondroitin sulfate plus glucosamine hydrochloride (CS+GH) versus celecoxib in patients with knee osteoarthritis and severe pain. Methods. Double-blind Multicentre Osteoarthritis interVEntion trial with SYSADOA (MOVES) conducted in France, Germany, Poland and Spain evaluating treatment with CS+GH versus celecoxib in 606 patients with Kellgren and Lawrence grades 2–3 knee osteoarthritis and moderate-to-severe pain (Western Ontario and McMaster osteoarthritis index (WOMAC) score ≥301; 0–500 scale). Patients were randomised to receive 400 mg CS plus 500 mg GH three times a day or 200 mg celecoxib every day for 6 months. The primary outcome was the mean decrease in WOMAC pain from baseline to 6 months. Secondary outcomes included WOMAC function and stiffness, visual analogue scale for pain, presence of joint swelling/effusion, rescue medication consumption, Outcome Measures in Rheumatology Clinical Trials and Osteoarthritis Research Society International (OMERACT-OARSI) criteria and EuroQoL-5D. Results. The adjusted mean change (95% CI) in WOMAC pain was −185.7 (−200.3 to −171.1) (50.1% decrease) with CS+GH and −186.8 (−201.7 to −171.9) (50.2% decrease) with celecoxib, meeting the non-inferiority margin of −40: −1.11 (−22.0 to 19.8; p=0.92). All sensitivity analyses were consistent with that result. At 6 months, 79.7% of patients in the combination group and 79.2% in the celecoxib group fulfilled OMERACT-OARSI criteria. Both groups elicited a reduction >50% in the presence of joint swelling; a similar reduction was seen for effusion. No differences were observed for the other secondary outcomes. Adverse events were low and similarly distributed between groups. Conclusions. CS+GH has comparable efficacy to celecoxib in reducing pain, stiffness, functional limitation and joint swelling/effusion after 6 months in patients with painful knee osteoarthritis, with a good safety profile.

Purpose: Cervical cancer is one of the most common causes of cancer mortality for women living in poverty, causing more than 28,000 deaths annually in Latin America and 266,000 worldwide. To better understand the molecular basis of the disease, we ascertained blood and tumor samples from Guatemala and Venezuela and performed genomic characterization. Experimental Design: We performed human papillomavirus (HPV) typing and identified somatically mutated genes using exome and ultra-deep targeted sequencing with confirmation in samples from Mexico. Copy number changes were also assessed in the exome sequence. Results: Cervical cancer cases in Guatemala and Venezuela have an average age of diagnosis of 50 years and 5.6 children. Analysis of 675 tumors revealed activation of PIK3CA and other PI3K/AKT pathway genes in 31% of squamous carcinomas and 24% of adeno- and adenosquamous tumors, predominantly at two sites (E542K, E545K) in the helical domain of the PIK3CA gene. This distribution of PIK3CA mutations is distinct from most other cancer types and does not result in the in vitro phosphorylation of AKT. Somatic mutations were more frequent in squamous carcinomas diagnosed after the age of 50 years. Frequent gain of chromosome 3q was found, and low PIK3CA mutation fractions in many tumors suggest that PI3K mutation can be a late event in tumor progression. Conclusions: PI3K pathway mutation is important to cervical carcinogenesis in Latin America. Therapeutic agents that directly target PI3K could play a role in the therapy of this common malignancy. Clin Cancer Res; 21(23); 5360–70. ©2015 AACR.

Objective.To explore the relationship between fatigue and work productivity loss (WPL) in people with psoriatic arthritis (PsA).Methods.Data were collected from participants in the Utah Psoriasis Initiative Arthritis registry between January 2010 and May 2013. WPL was measured with the 8-item Work Limitations Questionnaire. Fatigue was assessed with question 1 from the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI#1), “How would you describe the overall level of fatigue/tiredness you have experienced?” and with question 1 from the Psoriatic Arthritis Quality of Life Questionnaire (PsAQOL#1) “I feel tired whatever I do.” Psoriatic activity was evaluated with tender joint count (TJC), swollen joint count (SJC), dactylitis count, enthesitis count, inflammatory back pain (IBP), physician global assessment, body surface area, and psoriasis pain and itch.Results.Among 107 participants, work productivity was reduced by 6.7%, compared to benchmark employees without limitations. Fatigue was reported by 54 patients (50.5%) on PsAQOL#1, and 64 (60.0%) were classified as high fatigue by BASDAI#1. TJC, SJC, enthesitis count, IBP, and depressed mood were highest or most frequent in participants reporting fatigue. After adjustments for psoriatic activity and depressed mood, WPL was associated with fatigue, as measured by PsAQOL#1 (p = 0.01) and BASDAI#1 (p = 0.002).Conclusion.WPL was associated with fatigue, and the association was not entirely explained by the evaluated musculoskeletal, cutaneous, or psychiatric manifestations of PsA.

The catastrophic antiphospholipid antibody syndrome (CAPS) is an uncommon disorder characterized by widespread micro and macrovascular changes due to intravascular thrombosis. This complication of the antiphospholipid antibody syndrome is often fatal and recurrences are very rare. The differential diagnosis of CAPS includes thrombotic thrombocytopenic purpura (TTP) and this distinction may be difficult, but essential, for appropriate therapy. Plasmapheresis is effective in both conditions, but anticoagulation, a mainstay in the treatment of CAPS, could be disastrous in TTP. We present the case of an elderly woman who survived two episodes of CAPS four years apart and whose clinical findings were also suggestive of TTP. The characteristics of TTP and CAPS are compared and the importance of accurate diagnosis is emphasized.

In over 10 years since the definition of superantigens, much has been learned about host cell-superantigen interactions. The initial simple set of rules used to define these interactions has given way to a more complex system, in which the activation of multiple cell types can occur as a consequence of superantigen-cell interactions or as a result of bystander effects based on the induction of a specific cytokine milieu. As a consequence, our ideas concerning the ways in which superantigens might be involved in disease are also expanding rapidly. This review highlights some of the many different pathways of superantigen-associated pathogenesis currently under investigation.

Abatacept is a biologic agent used in the treatment of rheumatoid arthritis, for which underlying chronic obstructive lung disease is listed as a precaution to its use due to concern for increased risk of respiratory adverse events. We describe two cases of severe respiratory complications affecting rheumatoid arthritis patients undergoing treatment with abatacept who had been previously diagnosed with underlying lung disease.

Objective To identify novel non-major histocompatibility complex (non-MHC) genetic loci controlling the severity of homologous rat type II collagen-induced arthritis (CIA). Methods We conducted a genome-wide scan to identify CIA regulatory quantitative trait loci (QTL) in an F2 cross between DA (CIA highly susceptible) and ACI (CIA resistant) inbred rats immunized with homologous rat type II collagen (RII). These strains share the MHC/RT1av1 haplotype required for susceptibility to RII-induced CIA. Results F2 females had higher median arthritis scores than did males. Relative resistance in the males was determined by inheriting either a DA or an ACI Y chromosome and was independent of the source of the X chromosome. In addition, a major QTL was localized on chromosome 2 (Cia7, logarithm of odds score 4.6). Cia7 is in a region that shows linkage conservation with chromosomal regions that regulate autoimmune diabetes and experimental autoimmune encephalomyelitis in mice and multiple sclerosis in humans. Conclusion Sex chromosomes and Cia7 play an important role in regulating CIA in response to RII. This rat model should facilitate positional cloning and functional characterization of regulatory genes that may play a role in several forms of autoimmune disease, including rheumatoid arthritis.

Objective To define which regions of the type II collagen (CII) molecule result in anticollagen antibody production and the subsequent development of autoantibodies in a collagen-induced arthritis (CIA) nonhuman primate model. Methods Male and female cynomolgus monkeys (2-6 of each sex per group) were immunized with either chicken (Ch), human, or monkey (Mk) CII, or with cyanogen bromide (CB)-generated peptide fragments of ChCII emulsified in Freund's complete adjuvant. Monkeys were observed for the development of arthritis, and sera were collected and analyzed for anticollagen antibody specificity by enzyme-linked immunosorbent assay. Results Overt arthritis developed in all groups of monkeys immunized with intact CII and with all major CB peptide fragments of ChCII except CB8. Onset and severity of arthritis correlated best with serum anti-MkCII antibody levels. The levels of IgG autoantibody to MkCII were a result of the cross-reactivity rate of anti-heterologous CII antibodies with MkCII, which was based on the genetic background of individual monkeys rather than on sex differences. Conclusion CII from several species and disparate regions of the CII molecule were able to induce autoantibody-mediated arthritis in outbred cynomolgus monkeys. The strong anti-MkCII response suggests that epitope spreading or induction of broad-based CII cross-reactivity occurred in these animals. Autoantibody levels to MkCII were higher in CIA-susceptible monkeys than in resistant monkeys, despite comparable antibody levels in response to the various immunizations of CII. These results closely parallel the type of anticollagen responses found in sera from rheumatoid arthritis patients. Perhaps this can be accounted for by similar major histocompatibility complex heterogenicity associated with an outbred population, or maybe this is a primate-specific pattern of reactivity to CII.

In 460 B.C., Hippocrates described a syndrome of thickened skin. It wasn’t until 1752 that this condition was described in more detail by Carlo Curzio. The term “scleroderma” was first used by Giovambattista Fantonetti in 1836. There was little interest in this disease again until the mid-late 1900’s and now it is a clearly defined disease with ongoing research into pathophysiology and treatment options. Scleroderma is broken down into three main categories: localized, systemic and sine. The first, localized sclerosis is limited to the skin. It has deep and extensive involvement of the skin but spares any internal organ involvement. Systemic Scleroderma (SSc) is divided into limited and diffuse based on the extent of skin involvement. Limited cutaneous (lcSSc) can involve the forearms, hands, legs, feet and face. Diffuse cutaneous (dcSSc) can involve any body area. Both will involve internal organs, differentiating them from the localized form. The last major category, Sine (ssSSc), is rare and involves only internal organs, sparing the skin.

Breast cancer is the most common cancer among American women. Any woman can be affected by breast cancer, with risk for the disease increasing with age. Risk for breast cancer is also exacerbated in women who have certain genetic alterations. Mutations in the BRCA1 and BRCA2 genes predispose women to breast and ovarian cancer, and are increasingly recognized in prostate and pancreatic cancers (1-3). In Caucasian and Asian ethnicities BRCA mutations are associated with basal-type/triple-negative disease. However this association between BRCA gene mutations and basal/triple-negative disease has been understudied in other ethnicities (4-6). The incidence and mortality of breast cancer of Hispanics and Native Americans are lower than other ethnicities; however they are underrepresented in epidemiological and clinical studies. Further, it is known that common recurrent mutations in BRCA1 and BRCA2 genes exist in Hispanic/Latino communities which account for 35-45% of mutation carriers (7, 8). The objective of our study is thus to investigate triple-negative disease and BRCA gene mutations in Hispanic women.

Purpose We previously identified a genetic copy number polymorphism (CNP147) that was statistically associated with age-related macular degeneration (AMD) and that resides downstream of the complement factor H ( CFH ) gene. Factor H protein is polymorphic at amino acid 402, in which the resulting histidine containing moiety has been established to impart significant risk of AMD. We present a method to precisely determine the exact copy number of CNP147 and examine in more detail the association with AMD. Design Case-control study. Participants A total of 421 Age-Related Eye Disease Study (AREDS) subjects, of whom approximately 35% were diagnosed with neovascular disease, 19% were diagnosed with geographic atrophy, 16% were diagnosed with both, 30% were diagnosed with large drusen, and 215 were controls. Methods By using copy number assays available from Applied Biosystems Inc. (Carlsbad, CA), we examined 4 loci spanning CNP147 and neighboring CNP148 in an AREDS matched case-control sample set. We analyzed these data by copy number while controlling for 2 high-risk CFH variants, rs1061170 (Y402H) and rs1410996. We phased the high-risk CFH variants with CNP147 and analyzed haplotype frequencies in cases and controls. To further validate copy numbers, 6 Utah Centre D'etude du Polymorphism Humaine (CEPH) families were typed for CNP147, and the segregation was assessed. Main Outcome Measures Increased or decreased risk of AMD from genetic loci. Results Having fewer than 2 copies of CNP147 was associated with an estimated 43% reduction in odds of having AMD in this sample set (adjusted odds ratio [OR] = 0.57, P =0.006). CNP148 variation is rare in Caucasians and was not statistically significant. Common haplotypes reveal that the risk alleles for rs1061170 and rs1410996 most frequently segregate with higher copy numbers for CNP147, but not exclusively, and that 1 haplotype that carried a deletion of CNP147 was highly protective (OR = 0.25 P =1.3×10 −13 ) when compared with the reference. Conclusions In this matched subset of AREDS subjects, after adjusting for 2 known risk variants in CFH , CNP147 deletion statistically associates with diminished risk for AMD. Financial Disclosure(s) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Pruritus is a common symptom in systemic sclerosis (SSc), an autoimmune disease which causes fibrosis and vasculopathy in skin, lung, and gastrointestinal tract (GIT). Unfortunately, pruritus has limited treatment options in this disease. Pilot trials of low-dose naltrexone hydrochloride (LDN) for pruritus, pain, and quality of life (QOL) in other GIT diseases have been successful. In this case series we report three patients that had significant improvement in pruritus and total GIT symptoms as measured by the 10-point faces scale and the University of California Los Angeles Scleroderma Clinical Trials Consortium Gastrointestinal Tract 2.0 (UCLA SCTC GIT 2.0) questionnaire. This small case series suggests LDN may be an effective, highly tolerable, and inexpensive treatment for pruritus and GIT symptoms in SSc.

Background Knee osteoarthritis (OA) is a major cause of pain and functional limitation in older adults, yet longer-term studies of medical treatment of OA are limited. Objective To evaluate the efficacy and safety of glucosamine and chondroitin sulphate (CS), alone or in combination, as well as celecoxib and placebo on painful knee OA over 2 years. Methods A 24-month, double-blind, placebo-controlled study, conducted at nine sites in the US ancillary to the Glucosamine/chondroitin Arthritis Intervention Trial, enrolled 662 patients with knee OA who satisfied radiographic criteria (Kellgren/Lawrence grade 2 or 3 changes and baseline joint space width of at least 2 mm). This subset continued to receive their randomised treatment: glucosamine 500 mg three times daily, CS 400 mg three times daily, the combination of glucosamine and CS, celecoxib 200 mg daily, or placebo over 24 months. The primary outcome was a 20% reduction in Western Ontario and McMaster University Osteoarthritis Index (WOMAC) pain over 24 months. Secondary outcomes included an Outcome Measures in Rheumatology/Osteoarthritis Research Society International response and change from baseline in WOMAC pain and function. Results Compared with placebo, the odds of achieving a 20% reduction in WOMAC pain were celecoxib: 1.21, glucosamine: 1.16, combination glucosamine/CS: 0.83 and CS alone: 0.69, and were not statistically significant. Conclusions Over 2 years, no treatment achieved a clinically important difference in WOMAC pain or function as compared with placebo. However, glucosamine and celecoxib showed beneficial but not significant trends. Adverse reactions were similar among treatment groups and serious adverse events were rare for all treatments.

Objective To investigate the familiality of systemic sclerosis (SSc) in relation to Raynaud's phenomenon (RP) (a marker of vasculopathy), other autoimmune inflammatory disease, and fibrotic interstitial lung disease (ILD). Methods A genealogic resource, the Utah Population Database (UPDB), was used to test heritability of RP, other autoimmune disease, and ILD. Diseases were defined by International Classification of Diseases, Ninth Revision codes and identified from statewide discharge data, the University of Utah Health Science Center Enterprise Data Warehouse, and death certificates and were linked to the UPDB for analysis. Familial standardized incidence ratio (FSIR), relative risks (RRs) to first-, second-, third-, and fourth-degree relatives for SSc, RP, other autoimmune disease, and ILD (with 95% confidence intervals [95% CIs]), and population attributable risk (PAR) were calculated. Results A software kinship analysis tool was used to analyze 1,037 unique SSc patients. Fifty SSc families had significant FSIRs, ranging from 2.07 to 17.60. The adjusted PAR was ∼8%. The RRs were significant for other autoimmune disease in the first-degree relatives (2.49 [95% CI 1.99–3.41], P = 2.42 × 10−15) and second-degree relatives (1.48 [95% CI 1.34–2.39], P = 0.002), for RP in first-degree relatives (6.38 [95% CI 3.44–11.83], P = 4.04 × 10−9) and second-degree relatives (2.39 [95% CI 1.21–4.74], P = 0.012), and for ILD in first-degree relatives (1.53 [95% CI 1.04–2.26], P = 0.03), third-degree relatives (1.47 [95% CI 1.18–1.82], P = 0.0004), and fourth-degree relatives (1.2 [95% CI 1.06–1.35], P = 0.004). Conclusion These data suggest that SSc pedigrees include more RP, autoimmune inflammatory disease, and ILD than would be expected by chance. In SSc pedigrees, genetic predisposition to vasculopathy is the most frequent risk among first-degree relatives.

Background: Age-related macular degeneration (AMD) is the leading cause of irreversible visual loss in the developed countries and is caused by both environmental and genetic factors. A recent study (Tuo et al., PNAS) reported an association between AMD and a single nucleotide polymorphism (SNP) (rs3793784) in the ERCC6 (NM_000124) gene. The risk allele also increased ERCC6 expression. ERCC6 is involved in DNA repair and mutations in ERCC6 cause Cockayne syndrome (CS). Amongst others, photosensitivity and pigmentary retinopathy are hallmarks of CS. Methodology/Principal Findings: Separate and combined data from three large AMD case-control studies and a prospective population-based study (The Rotterdam Study) were used to analyse the genetic association between ERCC6 and AMD (2682 AMD cases and 3152 controls). We also measured ERCC6 mRNA levels in retinal pigment epithelium (RPE) cells of healthy and early AMD affected human donor eyes. Rs3793784 conferred a small increase in risk for late AMD in the Dutch population (The Rotterdam and AMRO-NL study), but this was not replicated in two non-European studies (AREDS, Columbia University). In addition, the AMRO-NL study revealed no significant association for 9 other variants spanning ERCC6. Finally, we determined that ERCC6 expression in the human RPE did not depend on rs3793784 genotype, but, interestingly, on AMD status: Early AMD-affected donor eyes had a 50% lower ERCC6 expression than healthy donor eyes (P = 0.018). Conclusions/Significance: Our meta-analysis of four Caucasian cohorts does not replicate the reported association between SNPs in ERCC6 and AMD. Nevertheless, our findings on ERCC6 expression in the RPE suggest that ERCC6 may be functionally involved in AMD. Combining our data with those of the literature, we hypothesize that the AMD-related reduced transcriptional activity of ERCC6 may be caused by diverse, small and heterogeneous genetic and/or environmental determinants.

The role of the vascular microenvironment in the pathogenesis Systemic Sclerosis (SSc) is appreciated clinically as Raynaud's syndrome with capillary nail bed change. This manifestation of vasculopathy is used diagnostically in both limited and diffuse cutaneous subsets of SSc, and is thought to precede fibrosis. The degree of subsequent fibrosis may also be determined by the vascular microenvironment. This paper describes why the vascular microenvironment might determine the degree of end-organ damage that occurs in SSc, with a focus on vascular cell senescence, endothelial progenitor cells (EPC) including multipotential mesenchymal stem cells (MSC), pericytes, and angiogenic monocytes. An explanation of the role of EPC, pericytes, and angiogenic monocytes is important to an understanding of SSc pathogenesis. An evolving understanding of the vascular microenvironment in SSc may allow directed treatment.

Osteoarthritis is a major cause for pain worldwide and is increasingly so as the number of elderly people continues to grow. Finding treatments that are effective and safe for this pain has been challenging primarily because gastrointestinal risks increase with aging as well. One step in the direction of improvement was the development of selective COX-2 inhibitors, which as a group have lower gastrointestinal adverse reaction rates than traditional non-steroidal anti-inflammatory drugs. However, increases in cardiovascular adverse events with some of these have dampened initial enthusiasm for this approach. One of these inhibitors, celecoxib remains available in most areas of the world for use in pain associated with osteoarthritis. This review illustrates how best to consider it's role in the current treatment of pain associated with arthritis with an emphasis on osteoarthritis.

Objective Osteoarthritis (OA) of the knee causes significant morbidity and current medical treatment is limited to symptom relief, while therapies able to slow structural damage remain elusive. This study was undertaken to evaluate the effect of glucosamine and chondroitin sulfate (CS), alone or in combination, as well as celecoxib and placebo on progressive loss of joint space width (JSW) in patients with knee OA. Methods A 24-month, double-blind, placebo-controlled study, conducted at 9 sites in the United States as part of the Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT), enrolled 572 patients with knee OA who satisfied radiographic criteria (Kellgren/Lawrence [K/L] grade 2 or grade 3 changes and JSW of at least 2 mm at baseline). Patients with primarily lateral compartment narrowing at any time point were excluded. Patients who had been randomized to 1 of the 5 groups in the GAIT continued to receive glucosamine 500 mg 3 times daily, CS 400 mg 3 times daily, the combination of glucosamine and CS, celecoxib 200 mg daily, or placebo over 24 months. The minimum medial tibiofemoral JSW was measured at baseline, 12 months, and 24 months. The primary outcome measure was the mean change in JSW from baseline. Results The mean JSW loss at 2 years in knees with OA in the placebo group, adjusted for design and clinical factors, was 0.166 mm. No statistically significant difference in mean JSW loss was observed in any treatment group compared with the placebo group. Treatment effects on K/L grade 2 knees, but not on K/L grade 3 knees, showed a trend toward improvement relative to the placebo group. The power of the study was diminished by the limited sample size, variance of JSW measurement, and a smaller than expected loss in JSW. Conclusion At 2 years, no treatment achieved a predefined threshold of clinically important difference in JSW loss as compared with placebo. However, knees with K/L grade 2 radiographic OA appeared to have the greatest potential for modification by these treatments.

Background Coll2-1 is a peptide located in the triple helical part of type II collagen and Coll2-1NO2 is the nitrated form. Fib3-2 is a fragment of fibulin-3, an extracellular glycoprotein highly expressed in OA.The levels of these biomarkers have been found to be elevated in serum of OA patients and to vary with severity. Objectives To investigate soluble osteoarthritis (OA) biomarkers in the per-protocol (PP) population of the double-blind Multicentre Osteoarthritis interVEntion trial with Sysadoa (MOVES) comparing the efficacy and safety of Chondroitin Sulfate (CS) plus Glucosamine Hydrochloride (GH) versus CElecoxib (CE) in patients with knee OA. Methods Coll2-1, Coll2-1NO2 and Fib3-2 were directly measured by immunassays (ARTIALIS SA, Liege, Belgium) in the serum of the PP population of the MOVES trial including 606 patients with knee OA receiving 400 mg of CS+500 mg of GH three times daily or 200 mg of CE once daily for 6 months.This PP population included 418 subjects (215 receiving CS+GH and 203 receiving CE) with at least one biomarker value at three time points (D0, D120 and D180). Results Serum biomarkers values at baseline or at follow-up D120 and D180 were not associasted with age, sex, race, weight, height of BMI. In overall PP population, there were no statistically significant differences between CE and CS + GH groups for any of the three biomarkers at any time. However, there was a trend in favor of CS+GH in reducing Coll2-1 at D180 (p=0.069) and a trend in favor of CE to reduce Fib3-2 (p=0.055). When population was stratified according the radiological OA severity, the occurrence of synovitis, the WOMAC score or the sympromatic response to treatment some significant differences in biomarkers serum levels were observed between treatment groups. At D 180, CS +GH induced a significantly greater decrease of Coll2-1 in the subgroups of patients with the more severe radiographic disease (K&L III), with synovitis (at least one joint swelling or effusion event), in OMERACT-OARSI responders or in patients with WOMAC pain at baseline ≤369 compared to CE (p 369 (p=0.042). Conclusions CS + GH was more efficient than CE in reducing serum Coll2-1 particularly in a subgroup of patients with severe OA. This data indicates that CS + GH may down-regulate cartilage catabolism and are in accordance with the symptomatic benefits observed in the clinical trials with these therapies. Disclosure of Interest None declared

BACKGROUND: Glucosamine and chondroitin sulfate are used to treat osteoarthritis. The multicenter, double-blind, placebo- and celecoxib-controlled Glucosamine/chondroitin Arthritis Intervention Trial (GAIT) evaluated their efficacy and safety as a treatment for knee pain from osteoarthritis. METHODS: We randomly assigned 1583 patients with symptomatic knee osteoarthritis to receive 1500 mg of glucosamine daily, 1200 mg of chondroitin sulfate daily, both glucosamine and chondroitin sulfate, 200 mg of celecoxib daily, or placebo for 24 weeks. Up to 4000 mg of acetaminophen daily was allowed as rescue analgesia. Assignment was stratified according to the severity of knee pain (mild [N=1229] vs. moderate to severe [N=354]). The primary outcome measure was a 20 percent decrease in knee pain from baseline to week 24. RESULTS: The mean age of the patients was 59 years, and 64 percent were women. Overall, glucosamine and chondroitin sulfate were not significantly better than placebo in reducing knee pain by 20 percent. As compared with the rate of response to placebo (60.1 percent), the rate of response to glucosamine was 3.9 percentage points higher (P=0.30), the rate of response to chondroitin sulfate was 5.3 percentage points higher (P=0.17), and the rate of response to combined treatment was 6.5 percentage points higher (P=0.09). The rate of response in the celecoxib control group was 10.0 percentage points higher than that in the placebo control group (P=0.008). For patients with moderate-to-severe pain at baseline, the rate of response was significantly higher with combined therapy than with placebo (79.2 percent vs. 54.3 percent, P=0.002). Adverse events were mild, infrequent, and evenly distributed among the groups. CONCLUSIONS: Glucosamine and chondroitin sulfate alone or in combination did not reduce pain effectively in the overall group of patients with osteoarthritis of the knee. Exploratory analyses suggest that the combination of glucosamine and chondroitin sulfate may be effective in the subgroup of patients with moderate-to-severe knee pain.

Background Combined glucosamine hydrochloride (GH) and chondroitin sulfate (CS) was found to be efficacious compared with placebo in subjects with knee osteoarthritis (OA) with severe pain in the GAIT trial 1 . The proportion of OA patients who achieved after 6 months a 20% improvement in pain was similar between GH+CS and Celecoxib (CE) 200mg. Objectives To extend the findings of GAIT, a clinical trial was designed to assess whether GH+CS has comparable efficacy to CE to reduce severe pain in knee OA patients after 6 months of treatment. Secondary objectives included comparison of other outcomes related to signs and symptoms of knee OA and to tolerability and safety. Methods MOVES was an international multicentric, phase IV, double-blind, non-inferiority, randomized trial to compare efficacy and safety of combined GH+CS (Droglican®, Bioiberica) vs CE in patients with knee OA with severe pain. Patients received either 2 capsules of Droglican (GH250mg and CS200mg) TID or CE200mg and 5 placebo capsules. Patients were eligible if ≥40years, fulfilled the ACR criteria for knee OA, had KL grade 2 or 3 and WOMAC pain>301 (0-500scale). Patients with gastrointestinal or cardiovascular risk were excluded. The primary outcome was the mean decrease in WOMAC Pain after 6 months. Results 763 patients were screened, 606 randomized to receive GH+CS (N=304) or CE (N=302), 522 (86.1%) completed the trial and included in the PP non-inferiority analysis. There was no difference in proportion completing between groups. Mean (SD) age was 62.7 (8.9) years, 438(83.9%) were women; KL grade 2 was present in 327 (62.6%). The mean WOMAC pain at randomization was 372.0 (41.8) in GH+CS and 370.6 (41.4) in CE. At 6 months, pain decreased ∼50% in both groups to 185.8 (7.4) in GH+CS and 184.7 (7.6) in CE, SEM difference of 1.11 (10.63) units (95%CI-21.99,19.76) (p=0.917) respecting non-inferiority margin. These results were robust in sensitivity analyses using the ITT population and BOCF imputation in PP and ITT populations. There was no difference in secondary outcomes after the 6-month treatment with WOMAC stiffness of 69.1 (3.0) and 65.8 (3.0) (p=0.434), WOMAC function of 617.0 (23.5) and 595.8 (24.1) (p=0.53), VAS pain of 37.9 and 37.6 (p=0.924) and OMERACT-OARSI responders of 79.7% and 79.2% (p=0.908) in GH+CS and CE groups respectively. Both arms elicited a reduction>50% in joint swelling (p=0.53) and effusion (p=0.61). Overall, there was similar rescue medication consumption in both arms. There was no significant difference in the proportion of patients with treatment-emergent AEs between groups (50.7% overall); no deaths occurred. All the results are consistent with those from the GAIT. Conclusions The MOVES demonstrated clinical efficacy of a combination of GH and CS and good safety profile in the symptomatic treatment of patients with severe knee OA. References N Engl J Med 2006Feb23;354(8):795-808 Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.4950

Mycoplasma arthritidismitogen (MAM) is a potent superantigen secreted byM. arthritidis, an agent of murine arthritis. Here we compare the abilities of MAM to induce a panel of cytokines in vitro and in vivo in BALB/c and C3H/HeJ mouse strains that differ in susceptibility to mycoplasmal arthritis. Splenocytes from both mouse strains produced high levels of all cytokines by 24 h following in vitro exposure to MAM. No differences in cytokine profiles were seen irrespective of the MAM dose. However, there were striking differences in cytokine profiles present in supernatants of splenocytes that had been collected from mice after intravenous (i.v.) injection of MAM and subsequently rechallenged with MAM in vitro. Splenocytes collected 24 and 72 h after i.v. injection of MAM and challenged in vitro with MAM showed the most marked divergence in the secreted cytokines. Type 1 cytokines were markedly elevated in C3H/HeJ cell supernatants, whereas they were depressed or remained low in BALB/c cell supernatants. In contrast, the levels of type 2 cytokines were all greatly increased in BALB/c cell cultures but were decreased or remained low in C3H/HeJ supernatants. Interleukin-12 mRNA and protein was also markedly elevated in C3H/HeJ mice, as were the levels of immunoglobulin G2a. The data indicate a major skewing in cytokine profiles to a type 1 inflammatory response in C3H/HeJ mice but to a protective type 2 response in BALB/c mice. These cytokine changes appear to be associated with the severe arthritis in C3H/HeJ mice following injection ofM. arthritidisin comparison to the mild disease seen in injected BALB/c mice.

This report describes 2 patients with longstanding seropositive rheumatoid arthritis (RA) treated with oral methotrexate (MTX) who developed large cell lymphoma of B cell phenotype. In situ hybridization studies showed nuclear staining for Epstein-Barr virus (EBV) within the malignant lymphoid cells. In both cases, the lymphoma was undetectable several weeks after diagnostic biopsy followed by discontinuation of MTX. These observations suggest that, in patients with RA who develop an EBV-associated lymphoproliferative disorder, a trial of discontinuation of immunosuppressive agents may be warranted before chemotherapy is considered. In addition, there is a need for a heightened awareness of the development of lymphoma in this patient population.

New hypotheses for the induction of autoimmunity have emerged based upon the interaction of lymphoid cells with superantigens (SAgs)—a new class of immunostimulants that are produced by viruses, bacteria, and mycoplasmas. SAgs are believed to play a role in the human autoimmune diseases including rheumatoid arthritis (RA) by clonally expanding anti-self T cells and by triggering polyclonal B cell responses. Mycoplasma arthritidis mitogen (MAM)— superantigen produced by an organism—causes chronic proliferative arthritis in rodents, in vivo expansion of collagen-reactive murine Vβ6 and Vβ8 T-cell receptors (TCR), and polyclonal activation of B cells. Furthermore, cytokine responses in injected animals shift toward a pattern that would favor the development of a humoral autoimmune response. Consistent with these properties is the ability of MAM to trigger and accelerate the onset of collagen-induced arthritis (CIA) in mice suboptimally immunized with collagen and to cause rapid flares in arthritis in animals convalescing from a previous episode of CIA.

Collagen-Induced Arthritis (CIA) is an experimentally induced and genetically controlled animal model of chronic joint inflammation. In rats, there are informative strain differences in susceptibility to CIA. DA rats (RT1avl) develop severe CIA after immunization with bovine (BII), chick (CII), or homologous rat (RII) type II collagens. In contrast, the MHC-congenic DA. 1N(BN) and WF.1N(BN) rats (RT1n) are relatively resistant to CIA and develop moderate CIA in response to immunization with CII but not BII or RII. We previously found that simultaneous infection with rat cytomegalovirus (RCMV) greatly exacerbates the severity of arthritis that develops in BII-immunized DA rats. To examine the mechanism of RCMV amplification of CIA, the effect of simultaneous infection with RCMV on arthritis and autoimmunity to type II collagen was determined in WF.1N and DA.1N rats after immunization with BII, CII and RII. RCMV increased the incidence of CIA and the level of autoimmunity to type II collagen (skin-testing and IgG antibody titer) selectively in DA.1N and WF.1N rats immunized with CII, but not in littermates immunized with BII, although the transient reversal of CD4+/CD8+ mononuclear cell ratios in peripheral blood that is associated with RCMV infection occurred equally in both BII- and CII- immunized DA.1N rats. Likewise, RCMV infection moderately increased the levels of anti-RII autoimmunity and arthritis in DA rats sub-optimally immunized with RII but had no consistent effect on either anti-RII immunity or arthritis in RII-immunized DA.1N and WF.1n rats. The data show that RCMV augments arthritis only in rats that are genetically susceptible to CIA and that are appropriately immunized with a species of type II collagen that is arthritogenic for the MHC-haplotype being tested. Two possible mechanisms are suggested by these data: RCMV-associated increases in anti-RII autoimmunity in rats with CIA may result from amino acid sequence homologies between RCMV and type II collagen; alternatively, virus-induced pro-inflammatory cytokines may activate RII-reactive lymphocytes thereby potentiating autoimmunity and arthritis.

Background: Celiac disease is an autoimmune disorder of the small intestine characterized by intolerance to gluten. Traditionally, diagnosis is made by intestinal biopsy. Testing for immunoglobulin (Ig) A endomysial antibodies in the serum also is used for diagnosis. Biopsy and serology revert to normal with adherence to a gluten-free diet. Often, after an index case is diagnosed, siblings with symptoms adhere to a gluten-free diet without biopsy or serologic confirmation. More than 90% of patients with celiac disease have the human leukocyte antigen (HLA) DQA1 * 0501-DQB1 * 0201 genotype. Non-HLA genes also have been implicated. Methods: One hundred ninety-five individuals with confirmed or suspected celiac disease were identified in 73 families affected by the disease. IgA endomysial antibody testing was performed for all symptomatic family members who did not have biopsy-confirmed diagnoses. DNA samples were genotyped at D6S276 and the HLA class II loci DQA and DQB. Results: At the time sampling was begun in families, 88 of 177 (49.7%) individuals were self-diagnosed and adhering to a gluten-free diet. Ninety percent (91/101) of confirmed cases (biopsy or serology) had at least 1 copy of the DQA1 * 0501-DQB1 * 0201 genotype, whereas only 67% (46/69) of cases self-diagnosed (adherence to gluten-free diet without confirmation) had at least 1 copy. Of confirmed cases, 61% carried two copies of DQB * 0201. It is estimated that the HLA association and other unlinked genes contribute approximately equally to the sibling risk of celiac disease. Conclusions: A dosage effect of DQB 1 * 0201 may be associated with an increased risk of celiac disease. Self-diagnosis of celiac disease is as common as confirmed diagnosis in families in the United States. Diagnosis of celiac disease on the basis of clinical response to gluten restriction is inaccurate. With long-term adherence to a gluten-free diet, serologic test results are likely to be negative. Based on HLA genotype, approximately one third of self-diagnosed individuals are unlikely to have celiac disease. However, it is not possible to determine which individuals consuming a gluten-free diet have the disease. Therefore, before starting a gluten-free diet, serologic screening and biopsy confirmation are necessary.

Background Germline mutations in the BRCA1 and BRCA2 genes account for 20–25 % of inherited breast cancers and about 10 % of all breast cancer cases. Detection of BRCA mutation carriers can lead to therapeutic interventions such as mastectomy, oophorectomy, hormonal prevention therapy, improved screening, and targeted therapies such as PARP-inhibition. We estimate that African Americans and Hispanics are 4–5 times less likely to receive BRCA screening, despite having similar mutation frequencies as non-Jewish Caucasians, who have higher breast cancer mortality. To begin addressing this health disparity, we initiated a nationwide trial of BRCA testing of Latin American women with breast cancer. Patients were recruited through community organizations, clinics, public events, and by mail and Internet. Subjects completed the consent process and questionnaire, and provided a saliva sample by mail or in person. DNA from 120 subjects was used to sequence the entirety of BRCA1 and BRCA2 coding regions and splice sites, and validate pathogenic mutations, with a total material cost of $85/subject. Subjects ranged in age from 23 to 81 years (mean age, 51 years), 6 % had bilateral disease, 57 % were ER/PR+, 23 % HER2+, and 17 % had triple-negative disease. Results A total of seven different predicted deleterious mutations were identified, one newly described and the rest rare. In addition, four variants of unknown effect were found. Conclusions Application of this strategy on a larger scale could lead to improved cancer care of minority and underserved populations. Electronic supplementary material The online version of this article (doi:10.1186/s13742-015-0088-z) contains supplementary material, which is available to authorized users.