Brooke E. Gilliam

Factors influencing fracture risk, T score, and management of osteoporosis in patients with rheumatoid arthritis in the Consortium of Rheumatology Researchers of North America (CORRONA) registry.

Objectives:This study examined a wide array of clinical factors to evaluate their influence on fracture risk and T scores in women with rheumatoid arthritis (RA) and determine if women with RA who are at risk for osteoporosis (OP) are adequately treated with OP medications. Methods:Data from 8419 female RA patients participating in the Consortium of Rheumatology Researchers of North America registry from March 02, 2006 to August 15, 2006 was evaluated. Covariates included medication subgroups, demographic, and clinical parameters. Lumbar spine and hip T scores and fracture rates were studied in relation to the variables. Use of OP medications in patients with OP risk factors was also evaluated. Results:Postmenopausal status and higher modified health assessment questionnaire score (mHAQ) had a negative effect on lumbar spine score, while marriage, education, and body mass index had a positive effect. A similar trend was found with hip T scores. Increase in overall fracture risk correlated with postmenopausal status, mHAQ, and prednisone use, while tumor necrosis factor monotherapy was associated with decreased overall fracture risk. mHAQ was also associated with nonhip/nonspine fractures. Eighty percent of patients had at least 1 risk factor for OP, but only 32% were on OP medications. Only 54% of patients with 3 risk factors were on OP medication. Conclusions:In RA, postmenopausal status, mHAQ, and prednisone use were associated with a higher overall fracture risk. Women with RA who were at risk for OP may have been inadequately treated with OP medications.

Evidence of fibrinogen as a target of citrullination in IgM rheumatoid factor-positive polyarticular juvenile idiopathic arthritis

Background Several studies have noted the significance of measuring anti-cyclic citrullinated peptide (CCP) antibodies in juvenile idiopathic arthritis (JIA) as an important indicator for destructive disease, as is the case in rheumatoid arthritis (RA). While the role of anti-CCP antibodies in RA and JIA has become better understood, the identity of the target proteins of this modification has remained elusive. In this study, we evaluated serum from patients with various subtypes of JIA to investigate the presence of anti-deiminated (citrullinated) fibrinogen and anti-citrullinated α-enolase antibodies, and their association with RF and anti-CCP antibody isotypes.

Measurement of autoantibodies in pediatric-onset systemic lupus erythematosus and their relationship with disease-associated manifestations.

OBJECTIVE To evaluate an autoantibody profile in pediatric-onset systemic lupus erythematosus (SLE) patients to determine clinical and statistical associations with disease-associated manifestations. METHODS Sera from 53 SLE patients and 22 healthy individuals were collected. Antibodies to C1q, histone, chromatin, ribosomal P, dsDNA, and high-avidity dsDNA were measured by enzyme-linked immunosorbent assays. Patient records were evaluated for clinical and laboratory associations. RESULTS The most prevalent autoantibodies found in the SLE cohort were anti-C1q antibodies (n = 32, 60%), which correlated significantly with proteinuria and decreased complement levels (P < 0.05). Anti-C1q and antihistone antibodies were significantly elevated in patients with class III/IV nephritis compared with class I/II/V nephritis (P = 0.041). SLE patients with active nephritis at the time of sample collection demonstrated significantly elevated levels of anti-C1q antibodies compared with those without active nephritis, also exhibiting 100% sensitivity for active nephritis, proteinuria, and urinary casts. Antibodies to C1q, dsDNA, histone, and chromatin were significantly elevated in patients with active disease (P < 0.01). Chart-documented anti-dsDNA antibodies were positive in 28 SLE patients, INOVA anti-dsDNA antibodies in 25 patients, and high-avidity anti-dsDNA antibodies in 8 patients. Antihistone correlated significantly with leukopenia and hemolytic anemia (P < 0.05). CONCLUSIONS This study indicates the importance of measuring anti-C1q antibodies in pediatric-onset SLE patients because elevated anti-C1q antibodies may be more indicative of renal disease activity, showing significant correlation with proteinuria, urinary casts, and active nephritis. Antibodies to C1q, histone, chromatin, and dsDNA exhibited the strongest association with clinical features, indicating the importance of measuring all of these antibodies in pediatric-onset SLE patients.

Partial C4 deficiency in juvenile idiopathic arthritis patients.

Objectives:C4 is encoded by 2 distinct but closely linked loci within the major histocompatibility complex locus on human chromosome 6. C4A deficiencies have been associated with autoimmune disease and C4B with increased frequency of infection. C4 deficiencies have rarely been associated with juvenile idiopathic arthritis (JIA). Our aim was to investigate the prevalence of deficiencies in C4 allotypes in JIA patients. Methods:We evaluated 61 patients [35 JIA patients, 15 systemic lupus erythematosus patients, 9 rheumatoid arthritis patients, and 2 mixed connective tissue disease (CTD) patients] for C4 deficiency. Genomic DNA was isolated from whole blood and subjected to polymerase chain reaction using sequence-specific primers for C4 allotypes. Results:We found 5 JIA patients with C4 deficiencies. Two IgM rheumatoid factor-positive JIA polyarthritis patients had C4 deficiencies, one with complete C4A deficiency and another with partial C4A and complete C4B deficiency. Two oligoarthritis patients displayed partial C4B deficiencies, and complete C4B deficiency was revealed in 1 IgM rheumatoid factor-negative polyarthritis patient. Three patients had histories of recurrent infections and 2 demonstrated a more severe disease course. Disease controls showed 8 systemic lupus erythematosus patients had partial C4 deficiencies, whereas no deficiencies were revealed in the rheumatoid arthritis or mixed CTD patients. Conclusions:Defects in the complement system have been implicated in the pathogenesis of CTD. However, the specific role of C4 in JIA is not clear. We demonstrate partial C4 deficiencies in 5 JIA patients. Our findings suggest an association between C4 deficiency and another CTD, JIA, as well as with disease severity and recurrent infections.

Evaluation of anti-citrullinated type II collagen and anti-citrullinated vimentin antibodies in patients with juvenile idiopathic arthritis

BackgroundTo determine the prevalence and significance of anti-citrullinated vimentin and anti-citrullinated type II collagen antibodies and elucidate their role in the disease process of juvenile idiopathic arthritis (JIA).MethodsSera were obtained from 95 patients with various subtypes of JIA, 19 systemic lupus erythematosus (SLE) patients, and 10 healthy children. Antibodies were measured in the sera against citrullinated and native type II collagen and vimentin (vim1-16 and vim 59-74) by enzyme-linked immunosorbent assay. Samples were compared to anti-cyclic citrullinated peptide (anti-CCP) antibody and rheumatoid factor (RF) isotypes, and our previously measured anti-citrullinated fibrinogen and α-enolase antibodies on the same patient population, in addition to erythrocyte sedimentation rate and C-reactive protein. The relationship between the anti-citrullinated antibody profile and disease activity and joint damage were also investigated.ResultsTwenty-three JIA patients (24%) demonstrated reactivity to anti-citrullinated type II collagen. Ten JIA patients (10.5%) demonstrated reactivity to anti-citrullinated vimentin 1–16 antibodies and 7 (7.4%) to anti-citrullinated vimentin 59–74 antibodies. One IgM RF-positive polyarticular patient was positive for all 5 of the citrullinated autoantibodies tested. Thirty-seven different subsets of patients were identified based on their anti-citrullinated autoantibody and RF isotype profile. No significant associations were noted with anti-citrullinated type II collagen and anti-citrullinated vimentin antibodies with joint damage or disease activity. Anti-citrullinated vimentin 59–74 antibodies demonstrated the highest overall specificity at 89.7%, with anti-citrullinated vimentin 1–16 and anti-citrullinated type II collagen antibodies at 86.2%.ConclusionThis study demonstrates that antibodies to multiple citrullinated epitopes are present in the sera of patients with various subtypes of JIA. It also demonstrates the frequent occurrence of anti-citrullinated type II collagen and anti-citrullinated fibrinogen antibodies. The presence of autoantibodies to citrullinated antigens in JIA patients is highly diverse.

The role of anti-cyclic citrullinated peptide (CCP) antibodies in early detection of rheumatoid arthritis: an overview of the INOVA Diagnostics, Inc. QUANTA Lite CCP assays

INTRODUCTION Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation and the presence of self-reactive autoantibodies. Since the discovery of anti-cyclic citrullinated peptide (anti-CCP) antibodies, several assays have been developed to measure these autoantibodies in RA patients. The first-generation kit offered high specificity, but sensitivity was low. The second-generation IgG anti-CCP antibody assay (CCP2) offered the same high specificity, with greatly improved sensitivity for RA. INOVA Diagnostics, Inc. offers, in addition to CCP2, a third-generation assay with higher sensitivity compared with CCP2 and also a combined IgG/IgA anti-CCP antibody assay. AREAS COVERED The review covers the use of INOVA Diagnostics, Inc. multiple anti-CCP antibody assays in early detection of RA, while also comparing these assays with other commercially available methods of measuring anti-CCP antibodies. While most of the review focuses on the significance of these autoantibodies in adult RA patients, their role in juvenile idiopathic arthritis is also discussed. EXPERT OPINION Detection of anti-CCP antibodies has emerged as one of the most important disease markers in RA patients. Several methods are available to measure anti-CCP antibodies, and isotyping and identification of citrullination targets are now the next step in further characterizing these autoantibodies.

Rheumatic manifestations of parvovirus B19 in children

It is well known that parvovirus B19 causes erythema infectiosum, a common febrile exanthema of childhood. Studies have also shown that parvovirus B19 can cause chronic arthropathy in children, and some children may meet classification criteria for juvenile idiopathic arthritis. A childs anti-B19 antibodies may cross-react with other antigens leading to autoantibody formation and immune complex deposition. This process can cause a similar clinical picture to systemic lupus erythematosus, and in some cases has been implicated in initiation of disease. Parvovirus B19 has also been linked to the presence of antiphospholipid antibodies, juvenile dermatomyositis, vasculitides, immune thrombocytopenic purpura, and hemophagocytic lymphohistiocytosis. This review provides an extensive evaluation of the literature on parvovirus B19 and its role in rheumatic diseases in children.

Rheumatic manifestations of Epstein-Barr virus in children

Epstein-Barr virus (EBV) is known to cause infectious mononucleosis; in addition, it is strongly associated with malignancies. Studies have also demonstrated that EBV infection may trigger the development of systemic lupus erythematosus. EBV infection has been implicated in complicating treatment of juvenile idiopathic arthritis, in addition to triggering cytokine production. Awareness of a past or present EBV infection has been highlighted as an important factor in determining treatment options in several diseases. Repeated associations have been described between EBV infection and various rheumatic diseases and complications of rheumatic disease, including Kawasaki disease, immune thrombocytopenic purpura, and hemophagocytic lymphohistiocytosis. We present a review of recent literature demonstrating the significance of EBV infection in rheumatic diseases, and complications of rheumatic disease, in children.

Presence of anti-cyclic citrullinated peptide antibody isotypes in juvenile idiopathic arthritis synovial fluid indicates autoantibody production at the site of inflammation

Results Eleven of 47 (23%) JIA SF samples were positive for the different anti-CCP antibody isotypes. IgM anti-CCP antibodies were positive in 9 JIA patients, including 5 oligoarthritis, 3 IgM RF+ and 1 IgM RFpolyarthritis. IgG antiCCP antibodies were positive in 8 JIA patients, including 4 oligoarthritis, 2 IgM RF+, 1 IgM RFpolyarthritis, and 1 enthesitis-related. Two IgM RF+ polyarthritis patients were positive for IgA anti-CCP antibodies, and also positive for all 3 isotypes. Four JIA patients were positive for 2 anti-CCP antibody isotypes, including 1 IgM RFpolyarthritis patient (IgG and IgM) and 3 oligoarthritis patients (2 IgG and IgM, 1 IgA and IgM). Five JIA patients were positive for 1 anti-CCP antibody isotype, including 3 oligoarthritis (2 IgM, 1 IgG), 1 enthesitis-related (IgG), and 1 IgM RF+ polyarthritis patient (IgM). Three JIA patients were positive for the combined IgA/IgG anti-CCP antibody ELISA, including 2 with IgM RF+ polyarthritis and 1 enthesitis-related. Polyarthritis patients demonstrated significantly higher levels of all anti-CCP antibody isotypes compared to the other JIA subtypes (p<0.05). When only evaluating the IgM RF+ polyarthritis patients against the other subtypes, the levels were even more significantly increased (p<0.05). Serum-matched IgG anti-CCP antibody data was available in 27 JIA patients and 5 healthy controls. All 3 IgM RF+ polyarthritis patients were positive for the IgG anti-CCP antibodies in serum and SF. Two JIA patients who were positive for IgG anti-CCP antibodies in SF had a negative result in serum. Date-matched SF and serum IgM and IgA data was available on 12 JIA patients. More JIA patients were positive for IgA anti-CCP antibodies in serum compared to SF, while SF showed increased positivity for IgM anti-CCP antibodies compared to serum.

Measurement of autoantibodies in pediatric- and adolescent-onset systemic lupus erythematosus and their significant relationship with disease-associated manifestations

Purpose Pediatric-onset systemic lupus erythematosus (SLE) patients are prone to develop major organ involvement and a more severe disease course than adult-onset SLE. Early management of the disease is necessary to prevent further complications, which can partly be accomplished by monitoring autoantibody levels and understanding their significance in the disease process. We evaluated an autoantibody profile in pediatric- and adolescentonset systemic lupus erythematosus (SLE) patients to determine the clinical and statistical associations with disease-related manifestations. Methods Sera from 53 SLE patients and 22 healthy individuals were collected. Antibodies to C1q, histone, chromatin, ribosomal P, double stranded (ds) DNA, and high avidity (HA) dsDNA were measured by enzyme-linked immunosorbent assays. Patient records were evaluated for clinical and laboratory associations. Results SLE patients exhibited significantly elevated levels of all measured autoantibodies when compared to healthy individuals (p<0.05). The most prevalent autoantibody measured in the SLE cohort was anti-C1q antibodies, found in 58% of SLE patients. Anti-C1q antibodies correlated significantly with proteinuria, fever, urinary casts, and decreased complement levels (p<0.05). Anti-C1q antibodies were significantly elevated in SLE patients with active disease (127U) compared to patients who were inactive (63U) (p<0.05). Anti-C1q antibodies and antihistone antibodies were significantly elevated in patients with class III/IV nephritis compared to class I/II/V nephritis (p<0.05). SLE patients with active nephritis at the time of sample collection demonstrated significantly elevated levels of anti-C1q antibodies compared to those without active nephritis (191U v. 80U, p<0.05), also exhibiting 100% specificity for active nephritis, proteinuria, and urinary casts. Chart-documented anti-dsDNA antibodies were positive in 28 SLE patients, INOVA antidsDNA antibodies in 21 patients, and HA anti-dsDNA antibodies in 8 patients. However, measuring HA antidsDNA antibodies rather than conventional anti-dsDNA antibodies may prove more accurate by eliminating low avidity, weakly bound antibodies detected by traditional assays. Anti-histone antibodies correlated significantly with leukopenia, hemolytic anemia, and anti-dsDNA and HA anti-dsDNA antibodies (p<0.05).