Jason R. Kolfenbach

Brief report: airways abnormalities and rheumatoid arthritis-related autoantibodies in subjects without arthritis: early injury or initiating site of autoimmunity?

OBJECTIVE To evaluate the presence of pulmonary abnormalities in rheumatoid arthritis (RA)-related autoantibody-positive subjects without inflammatory arthritis. METHODS Forty-two subjects who did not have inflammatory arthritis but were positive for anti-cyclic citrullinated peptide antibodies and/or ≥2 rheumatoid factor isotypes (a profile that is 96% specific for RA), 15 autoantibody-negative controls, and 12 patients with established seropositive early RA (<1-year duration) underwent spirometry and high-resolution computed tomography (HRCT) lung imaging. RESULTS The median age of autoantibody-positive subjects was 54 years, 52% were female, and 38% were ever-smokers; these characteristics were not significantly different from those of autoantibody-negative control subjects. No autoantibody-positive subject had inflammatory arthritis based on joint examination. HRCT revealed that 76% of autoantibody-positive subjects had airways abnormalities including bronchial wall thickening, bronchiectasis, centrilobular opacities, and air trapping, compared with 33% of autoantibody-negative controls (P = 0.005). The prevalence and type of lung abnormalities among autoantibody-positive subjects were similar to those among patients with early RA. In 2 autoantibody-positive subjects with airways disease, inflammatory arthritis classifiable as articular RA developed ∼13 months after the lung evaluation. CONCLUSION Airways abnormalities that are consistent with inflammation are common in autoantibody-positive subjects without inflammatory arthritis and are similar to airways abnormalities seen in patients with early RA. These findings suggest that the lung may be an early site of autoimmune-related injury and potentially a site of generation of RA-related autoimmunity. Further studies are needed to define the mechanistic role of lung inflammation in the development of RA.

A prospective approach to investigating the natural history of preclinical rheumatoid arthritis (RA) using first-degree relatives of probands with RA

OBJECTIVE To describe a large, multicenter prospective cohort study of first-degree relatives (FDRs) of probands with rheumatoid arthritis (RA), and outline the use of such a study in investigating the natural history of RA development. METHODS A total of 1,058 FDRs, none of whom met the American College of Rheumatology criteria for RA, were enrolled in a prospective study investigating genetic and environmental influences on the development of RA-related autoimmunity. Demographic, epidemiologic, genetic, autoantibody, and physical examination data from the initial study enrollment visit were described for these FDRs, and the relationship was examined between genetic factors, autoantibodies, inflammation, and joint disease. RESULTS Fifty-five percent of the FDRs had > or =1 copy of the shared epitope, 20% had > or =1 copy of the PTPN22 polymorphism, and approximately 16% were positive for rheumatoid factor (RF; including isotypes) and/or anti-cyclic citrullinated peptide antibody. IgM-RF positivity is associated with > or =1 tender joint on examination (odds ratio [OR] 2.50, 95% confidence interval [95% CI] 1.27-4.89; P < 0.01) and elevated C-reactive protein (CRP) levels (OR 5.31, 95% CI 1.45-19.52; P = 0.01). CONCLUSION FDRs without RA demonstrate high prevalences of genetic risk factors and RA-related autoantibodies. Additionally, an RF association with tender joints and elevated CRP levels suggests that autoantibodies are a valid intermediate marker of RA-related autoimmunity in this cohort. This prospective FDR cohort will be a valuable resource for evaluating the relationship between genetic and epidemiologic factors and the development of RA-related autoimmunity.

Multiple cytokines and chemokines are associated with rheumatoid arthritis-related autoimmunity in first-degree relatives without rheumatoid arthritis: Studies of the Aetiology of Rheumatoid Arthritis (SERA)

Objective We investigated whether rheumatoid arthritis (RA)-related autoantibodies were associated with systemic inflammation in a prospective cohort of first-degree relatives (FDRs) of RA probands, a population without RA but at increased risk for its future development. Methods We studied 44 autoantibody positive FDRs, of whom 29 were rheumatoid factor (RF) positive, 25 were positive for the high risk autoantibody profile (HRP), that is, positive for anti-cyclic citrullinated peptide and/or for at least two RF IgM, IgG or IgA isotypes, and nine FDRs who were positive for both; and 62 FDRs who were never autoantibody positive. Twenty-five cytokines/chemokines were measured using a bead-based assay in serum. As a comprehensive measure of inflammation, we calculated a Cytokine Score by summing all cytokine/chemokine levels, weighted by their regression coefficients for RA-autoantibody association. We compared C-reactive protein, individual cytokines/chemokines and Cytokine Score to the outcomes: positivity for RF and for the HRP using logistic regression. Results Adjusting for age, sex, ethnicity and ever smoking, the Cytokine Score and levels of IL-6 and IL-9 were associated with both RF and HRP. IL-2, granulocyte macrophage-colony stimulating factor (GM-CSF), and interferon (IFN)-γ were associated with HRP only. Associations between the Cytokine Score and RF and HRP positivity were replicated in an independent military personnel cohort. Conclusions In first-degree relatives of patients with RA, RA-related autoimmunity is associated with inflammation, as evidenced by associations with multiple cytokines and chemokines.

Anti-carbamylated Protein Antibodies Are Present Prior to Rheumatoid Arthritis and Are Associated with Its Future Diagnosis

Objective. Anti-carbamylated protein (anti-CarP) antibodies could further elucidate early rheumatoid arthritis (RA) pathogenesis and predict clinical disease. We compared the diagnostic accuracy of anti-CarP antibodies for future RA to other RA-related antibodies in military personnel. Methods. Stored pre-RA diagnosis serum samples from 76 RA cases were tested for anti-CarP fetal calf serum (FCS), anti-CarP fibrinogen (Fib), anticyclic citrullinated peptide antibodies version 2 (anti-CCP2), rheumatoid factor-nephelometry (RF-Neph), and RF isotypes [immunoglobulin M (IgM), IgG, and IgA]. Positivity for all antibodies was determined as ≥ 2 SD of log-transformed means from controls. Relationships between autoantibodies and future RA were assessed in prediagnosis serum for all RA cases compared to controls using sensitivity, specificity, and logistic regression. Differences in diagnostic accuracy between antibody combinations were assessed using comparisons of area under the curves (AUC). Results. Anti-CarP-FCS was 26% sensitive and 95% specific for future RA, whereas anti-CarP-Fib was 16% sensitive and 95% specific for future RA. Anti-CarP-FCS positivity was associated with future RA, while anti-CarP-Fib trended toward association. The antibody combination of anti-CCP2 and/or ≥ 2 RF (RF-Neph and/or RF-isotypes) resulted in an AUC of 0.72 for future RA, where the AUC was 0.71 with the addition of anti-CarP-FCS to this prior combination. Conclusion. Adding anti-CarP-FCS to antibody combinations did not improve AUC. However, anti-CarP-FCS was associated with future onset of RA, and was present in prediagnosis serum in ∼10% of RA cases negative for anti-CCP2 but positive for RF.

Autoimmunity to Peptidyl Arginine Deiminase Type 4 Precedes Clinical Onset of Rheumatoid Arthritis

OBJECTIVE To determine whether antibodies against peptidyl arginine deiminase type 4 (PAD-4) are present in the preclinical phase of rheumatoid arthritis (RA) and to compare the timing and extent of their appearance with those of other preclinical autoantibodies. METHODS Prediagnosis serum samples from 83 patients with RA were evaluated for the presence of anti-PAD-4 antibody, anti-cyclic citrullinated peptide (anti-CCP) antibody, and rheumatoid factor. In addition, a control cohort (n = 83) matched by age, sex, race, number of serum samples, and duration of serum storage was tested for the presence of anti-PAD-4 antibody to determine its sensitivity and specificity for the subsequent development of RA. RESULTS Fifteen of 83 patients with RA (18.1%) had at least 1 prediagnosis sample positive for anti-PAD-4. One of 83 control subjects (1.2%) had at least 1 positive sample, resulting in a sensitivity and specificity of 18.1% and 98.8%, respectively, of anti-PAD-4 for the future development of RA. The mean duration of anti-PAD-4 positivity prior to clinical diagnosis was 4.67 years. Anti-PAD-4 positivity was associated with anti-CCP positivity (odds ratio 5.13 [95% confidence interval 1.07-24.5]). In subjects with prediagnosis samples that were positive for both antibodies, anti-CCP positivity predated anti-PAD-4 positivity in 9 of 13 cases (69%). CONCLUSION Autoantibodies to PAD-4 are present during the preclinical phase of RA in a subset of patients and are associated with anti-CCP positivity. Further exploration is needed regarding the timing of appearance and disease-related effects of PAD-4 autoimmunity.

Performance of anti-cyclic citrullinated peptide assays differs in subjects at increased risk of rheumatoid arthritis and subjects with established disease

OBJECTIVE To compare the diagnostic accuracy and agreement of commonly available assays for anti-citrullinated protein antibodies in patients with established rheumatoid arthritis (RA) and subjects at increased risk of RA. METHODS Tests for anti-cyclic citrullinated peptide (anti-CCP) antibodies were performed using CCP2 IgG and CCP3.1 IgA/IgG enzyme-linked immunosorbent assays in the following groups: probands with established RA (n = 340) from the Studies of the Etiology of Rheumatoid Arthritis (SERA) cohort and their first-degree relatives (FDRs) without inflammatory arthritis (n = 681), Department of Defense Serum Repository (DoDSR) RA cases with pre-RA diagnosis samples (n = 83; 47 cases also had post-RA diagnosis samples), and blood donor and DoDSR control subjects (n = 283). RESULTS In patients with established RA, the CCP2 assay was more specific (99.2% versus 93.1%; P < 0.01) but less sensitive (58.7% versus 67.4%; P = 0.01) than the CCP3.1 assay; the specificity of the CCP3.1 assay increased to 97.2% when cutoff levels ≥3-fold the standard level were considered. In all subjects, CCP3.1 assay positivity (using standard cutoff levels) was more prevalent. Among DoDSR cases, the CCP2 assay was more specific than the CCP3.1 for predicting a future diagnosis of RA, and higher CCP levels trended toward increasing specificity for the development of RA within 2 years. At standard cutoff levels, assay agreement was good in patients with established RA (κ = 0.76) but poor in FDRs without inflammatory arthritis (κ = 0.25). CONCLUSION Anti-CCP assays differ to an extent that may be meaningful for diagnosing RA in patients with inflammatory arthritis and evaluating the natural history of RA development in subjects at risk of RA. The mechanisms underlying these differences in test performance need further investigation.

Neuromyelitis optica spectrum disorder in patients with connective tissue disease and myelitis.

Introduction Neuromyelitis optica (NMO) is a demyelinating, organspecific, autoimmune disease that preferentially targets the optic nerve and spinal cord. The clinical syndrome was first described by Devic and Gault in 1894, and was considered a variant of multiple sclerosis (MS). A resurgence of interest has followed the recent identification of a disease-specific autoantibody, NMO-IgG, and its target antigen, the aquaporin 4 (AQP-4) receptor (1). NMO is classically defined by the presence of both optic neuritis (ON) and longitudinal myelitis (LM), with contiguous spinal cord involvement spanning 3 or more vertebrae. The clinical course is characterized by disease relapse and significant morbidity in more than 90% of cases (2). Research suggests that by 5 years, more than one-half of the patients will be unable to ambulate without assistance and/or be functionally blind (3). Formal diagnosis requires the presence of transverse myelitis (TM), ON, and 2 of 3 supporting criteria (Figure 1), one of which is the serum NMO-IgG antibody. The sensitivity of this assay ranges from 60– 70%, with a specificity of 90% (1,4). Given the potential for permanent disability following isolated attacks of myelitis or ON, efforts have been made to identify individuals at high risk for disease relapse or progression to full-spectrum NMO. Researchers have shown that patients with a single episode of LM in the setting of NMO-IgG positivity have a 50% risk of myelitis relapse or conversion to full-spectrum NMO over the subsequent 12 months (5). Similar data have shown an increased risk for myelitis in NMO-IgG–positive patients that experience recurrent ON (6). Recognition that incomplete forms of NMO are at an increased risk for progression based on the presence of antibody positivity has resulted in the designation of NMO spectrum disorders (NMOSD) (Figure 1). An association between the NMO-IgG antibody and LM in patients with systemic lupus erythematosus (SLE) and Sjögren’s syndrome (SS) has been reported in the literature (7,8), and has spurred interest in NMO/NMOSD from the field of rheumatology. Herein we describe a cohort of patients with autoimmune myelitis and discuss the implications of coexistent NMO/NMOSD for subsequent clinical management. Our objective was to identify the presence of NMOSD in patients with acute myelitis and suspected connective tissue disease (CTD), and to discuss the utility of this distinction in establishing a diagnostic and therapeutic plan.

Anti-Cyclic Citrullinated Peptide Assays Differ in Subjects at Elevated Risk for Rheumatoid Arthritis and Subjects with Established Disease

OBJECTIVE To compare the diagnostic accuracy and agreement of commonly available assays for anti-citrullinated protein antibodies in patients with established rheumatoid arthritis (RA) and subjects at increased risk of RA. METHODS Tests for anti-cyclic citrullinated peptide (anti-CCP) antibodies were performed using CCP2 IgG and CCP3.1 IgA/IgG enzyme-linked immunosorbent assays in the following groups: probands with established RA (n = 340) from the Studies of the Etiology of Rheumatoid Arthritis (SERA) cohort and their first-degree relatives (FDRs) without inflammatory arthritis (n = 681), Department of Defense Serum Repository (DoDSR) RA cases with pre-RA diagnosis samples (n = 83; 47 cases also had post-RA diagnosis samples), and blood donor and DoDSR control subjects (n = 283). RESULTS In patients with established RA, the CCP2 assay was more specific (99.2% versus 93.1%; P < 0.01) but less sensitive (58.7% versus 67.4%; P = 0.01) than the CCP3.1 assay; the specificity of the CCP3.1 assay increased to 97.2% when cutoff levels ≥3-fold the standard level were considered. In all subjects, CCP3.1 assay positivity (using standard cutoff levels) was more prevalent. Among DoDSR cases, the CCP2 assay was more specific than the CCP3.1 for predicting a future diagnosis of RA, and higher CCP levels trended toward increasing specificity for the development of RA within 2 years. At standard cutoff levels, assay agreement was good in patients with established RA (κ = 0.76) but poor in FDRs without inflammatory arthritis (κ = 0.25). CONCLUSION Anti-CCP assays differ to an extent that may be meaningful for diagnosing RA in patients with inflammatory arthritis and evaluating the natural history of RA development in subjects at risk of RA. The mechanisms underlying these differences in test performance need further investigation.

Lung abnormalities in subjects with elevations of rheumatoid arthritis-related autoantibodies without arthritis by examination and imaging suggest the lung is an early and perhaps initiating site of inflammation in rheumatoid arthritis

Background/objectives Elevations of serum autoantibodies (Abs) prior to joint symptoms suggest that rheumatoid arthritis (RA) may be initiated outside of the joints. This site is unknown, although several factors suggest that it may be the lungs including the association of inhaled factors such as smoking with RA. Our purpose herein was to evaluate a hypothesis that the lung is a site of initiation of RA-related autoimmunity by comparing lung findings in RA-related Ab+ subjects at risk for future RA but without current inflammatory arthritis (IA) to Ab- controls and patients with established early RA. Materials/methods 45 Ab+ cases without IA on 68 joint exam were identified from the Studies of the aetiology of RA project, a prospective study of preclinical RA. These cases were positive for Abs >96% specific for future RA: anti cyclic citrullinated peptides (CCP2) (Axis-Shield) or CCP3.1 (INOVA, San Diego, CA, USA), and/or ≥2 rheumatoid factor (RF) isotypes (IgA, M, G) (INOVA) (N=9 CCP2+; N=25 CCP3.1+; N=11 RFs+ only). Additionally, 16 Ab-sera controls (frequency matched to Ab+ cases on age, sex and smoking) and 12 patients with early RF/aCCP2+ RA (<1 year) were selected. All subjects underwent high-resolution CT (HRCT) of the lungs, interpreted in a blinded fashion by two chest radiologists according to established criteria (Fleischner Society; Hansell, et al 2008). To evaluate for synovitis not detected on joint exam, a subset of Ab+ cases underwent contrasted MRI of the metacarpophalangeals, wrists and metatarsophalangeals, scored for synovitis by two joint radiologists using the outcome measures in rheumatoid arthritis clinical trials/rheumatoid arthritis MRI scoring system protocols. Results 45 Ab+ cases were a mean age of 54, 56% female and 33% smokers (no significant differences from Ab-controls). 77% of Ab+ cases had airways disease on HRCT including bronchial wall thickening, bronchiectasis, centrilobular opacities and air trapping, compared to 31% of Ab-controls (p<0.01). Of the 30 Ab+ cases that were never smokers, 70% had airways disease compared to 3/12 (25%) of never smoking controls (p=0.01). No Ab+ case had evidence of IA on joint exam at time of lung evaluation, and additionally, 15 Ab+ cases with abnormal lungs that underwent joint MRI had no synovitis by imaging. One Ab+ subject with airways disease developed RA by 1987 criteria (Arnett, et al 1988) ∼13 mos. after lung study. Finally, 9/12 (75%) of early RA subjects (mean age 50, 58% female, 42% smokers) studied in parallel had radiographically indistinguishable airways abnormalities when compared to the Ab+ cases (p>0.5). Conclusions Airways abnormalities are present in a high proportion of RA-specific Ab+ cases without IA (examination or MRI), and these lung abnormalities are similar to those in patients diagnosed with early RA. This suggests that there is a continuum of lung injury during the development of RA, and that lungs are either a site of RA-related autoimmune-mediated injury during the presymptomatic phase of disease, or more likely a site of initiation of RA-related autoimmunity perhaps due to external factors beyond smoking that generate local inflammation, especially since the airways interact substantially with the environment. Prospective studies are ongoing to evaluate the generation of RA-specific in the lungs, and to follow the evolution of autoimmunity and IA in these subjects.

Specialty Practice and Cost Considerations in the Management of Uveitis Associated With Juvenile Idiopathic Arthritis

PURPOSE To evaluate whether cost, prior insurance authorization concerns, and subspecialty practice influence therapeutic decisions in the treatment of uveitis associated with juvenile idiopathic arthritis. METHODS A total of 2,965 pediatric ophthalmologists, uveitis specialists, retina specialists, and rheumatologists across the United States were surveyed via e-mail regarding their choice in long-term therapy for a hypothetical patient with uveitis associated with juvenile idiopathic arthritis. Outcomes of interest were differences in therapy choice based on cost/prior authorization and specialty practice. RESULTS There were significant differences in the use of methotrexate and biologics among specialists, both with and without consideration for cost and prior authorization. CONCLUSIONS Physicians in four different specialties who treat uveitis associated with juvenile idiopathic arthritis agree on methotrexate as a first-line treatment choice and a biologic immunosuppressive medication as a second choice, but there are significant differences between the specialties in their use of these medications. Cost and insurance considerations did not affect therapy selection. [J Pediatr Ophthalmol Strabismus. 2016;53(4):246-251.].