Circulating blood metabolite trajectories and risk of rheumatoid arthritis among military personnel in the Department of Defense Biorepository.

OBJECTIVES: We sought to identify metabolic changes potentially related to rheumatoid arthritis (RA) pathogenesis occurring in the blood prior to its diagnosis. METHODS: In a US military biorepository, serum samples collected at two timepoints prior to a diagnosis of RA were identified. These were matched to controls who did not develop RA by subject age, race and time between sample collections and RA diagnosis time to stored serum samples. Relative abundances of 380 metabolites were measured using liquid chromatography-tandem mass spectrometry. We determined whether pre-RA case versus control status predicted metabolite concentration differences and differences over time (trajectories) using linear mixed models, assessing for interactions between time, pre-RA status and metabolite concentrations. We separately examined pre-RA and pre-seropositive RA cases versus matched controls and adjusted for smoking. Multiple comparison adjustment set the false discovery rate to 0.05. RESULTS: 291 pre-RA cases (80.8% pre seropositive RA) were matched to 292 controls, all with two serum samples (2.7±1.6 years; 1.0±0.9 years before RA/matched date). 52.0% were women; 52.8% were White, 26.8% Black and 20.4% other race. Mean age was 31.2 (±8.1) years at earliest blood draw. Fourteen metabolites had statistically significant trajectory differences among pre-RA subjects versus controls, including sex steroids, amino acid/lipid metabolism and xenobiotics. Results were similar when limited to pre seropositive RA and after adjusting for smoking. CONCLUSIONS: In this military case-control study, metabolite concentration trajectory differences in pre-RA cases versus controls implicated steroidogenesis, lipid/amino acid metabolism and xenobiotics in RA pathogenesis. Metabolites may have potential as biomarkers and/or therapeutic targets preceding RA diagnosis.

Circulating plasma metabolites and risk of rheumatoid arthritis in the Nurses' Health Study.

OBJECTIVES: RA develops slowly over years. We tested for metabolic changes prior to RA onset using a large non-targeted metabolomics platform to identify novel pathways and advance understanding of RA development. METHODS: Two hundred and fifty-four incident RA cases with plasma samples drawn pre-RA onset in the Nurses' Health Study (NHS) cohorts were matched 1:2 to 501 controls on age, race, menopause/post-menopausal hormone use and blood collection features. Relative abundances of 360 unique, known metabolites were measured. Conditional logistic regression analyses assessed associations between metabolites and incidence of RA, adjusted for age, smoking and BMI, accounting for multiple comparisons. Subgroup analyses investigated seropositive (sero+) RA and RA within 5 years of sample collection. Significant metabolites were then tested in a female military pre-RA case-control study (n = 290). RESULTS: In the NHS, metabolites associated with RA and sero+RA in multivariable models included 4-acetamidobutanoate (odds ratio (OR) = 0.80/S.d., 95% CI: 0.66, 0.95), N-acetylputrescine (OR = 0.82, 95% CI: 0.69, 0.96), C5 carnitine (OR = 0.84, 95% CI: 0.71, 0.99) and C5:1 carnitine (OR = 0.81, 95% CI: 0.68, 0.95). These were involved primarily in polyamine and leucine, isoleucine and valine metabolism. Several metabolites associated with sero+RA within 5 years of diagnosis were replicated in the independent military cohort: C5 carnitine (OR = 0.55, 95% CI: 0.33, 0.92), C5:1 carnitine (OR = 0.62, 95% CI: 0.39, 0.99) and C3 carnitine (OR = 0.57, 95% CI: 0.36, 0.91). CONCLUSION: Several metabolites were inversely associated with incidence of RA among women. Three short-chain acylcarnitines replicated in a smaller dataset and may reflect inflammation in the 5-year period prior to sero+RA diagnosis.

Combination of anti-citrullinated protein antibodies and rheumatoid factor is associated with increased systemic inflammatory mediators and more rapid progression from preclinical to clinical rheumatoid arthritis.

The development of rheumatoid factor (RF) and/or anti-citrullinated protein antibodies (ACPAs) can be observed years prior to clinical diagnosis of rheumatoid arthritis (RA). Nevertheless, the interaction between these two autoantibodies and their combined effect on development of RA is unclear. We measured RF, cytokines, and ACPA subtypes in serial pre-clinical serum samples collected from 83 US veterans who all developed RA. Levels of cytokines and ACPAs were compared between the following groups: anti-cyclic citrullinated peptide (anti-CCP)-/RF- (double negative), anti-CCP+/RF-, anti-CCP-/RF+, or anti-CCP+/RF+ (double-positive). The double-positive subgroup had significantly higher levels of 20 inflammatory cytokines and 29 ACPA reactivities, and the shortest interval, 1.3 years, between the preclinical sample timepoint and diagnosis of RA. Thus, the combined presence of ACPAs and RF is associated with a more rapid progression to RA, suggesting that anti-CCP+/RF+ individuals have a more advanced preclinical disease state and that the onset of RA may be imminent.

Inhibition of Sphingosine-1-phosphate receptors in ischemia reperfusion injured autoimmunity-prone mice.

B6.MRL/lpr mice, an autoimmune strain, have an accelerated injury time course, increased intensity of tissue damage, and increased CD4+ T cell infiltration in the mesenteric ischemia/reperfusion injury model. In this study, the mechanism by which CD4+ T cells were recruited into injured tissue was addressed. Fingolimod (FTY720) was utilized to assess the role of infiltrating CD4+ T cells. FTY720 treatment was more effective in attenuating injury in B6.MRL/lpr mice then in control mice. Reduced CD4+ cell infiltration and tissue injury correlated with decreased neutrophil infiltration and pro-inflammatory cytokine generation. Inhibiting downstream Sphingosine-1-phosphate (S1P) receptor signaling, specifically GαI mediated signaling, did not inhibit injury, suggesting differential utilization of the S1P receptors between control and MRL/lpr strains. Analysis of S1P receptor expression exposed a predominance of S1P2 in the B6.MRL/lpr strain. Reliance on alternate S1P receptors in the autoimmune strain will alter the progress of inflammation and tissue injury.

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.

Multi-Autoantibody Testing Identifies Expansion of Reactivity to Targeted Antigens Before a Diagnosis of Rheumatoid Arthritis.

OBJECTIVE: Rheumatoid arthritis (RA) has a "pre-RA" period in which multiple autoantibodies, including antibodies to citrullinated (cit) proteins (ACPA), rheumatoid factor (RF), anti-peptidyl arginine deiminase (anti-PAD), among others, have been described; however, few studies have tested all autoantibodies in a single pre-RA cohort. This study aims to evaluate the prevalence of multiple autoantibodies in pre-RA and potentially identify an autoantibody profile in pre-RA that indicates imminent onset of clinical RA. METHODS: We evaluated 148 individuals with two pre- and one post-RA diagnosis samples available from the Department of Defense Serum Repository and matched controls. Samples were tested for immuglobulin (Ig) G anti-cyclic cit peptide-3 (anti-CCP3), five ACPA fine specificities, five anti-PAD isoforms, as well as RF IgA and RF IgM using commercial platforms; cutoffs were determined using levels present in <1% of controls. RESULTS: Positivity of anti-CCP3, RF IgA and RF IgM, anti-PAD1, anti-cit-vimentin 2, anti-cit-fibrinogen, and anti-cit-histone 1 increased over time in pre-RA, although anti-PAD and ACPA fine specificities were predominately present within anti-CCP3-positive individuals. Within anti-CCP3-positive samples from the pre-RA period, positivity for RFs as well as anti-PAD and ACPA fine specificities classified samples as being closer to the time of RA diagnosis. CONCLUSION: Multiple autoantibodies are present in pre-RA and increase in positivity as the time of RA diagnosis approaches. These results confirm previous findings predicting imminent RA and provide a pathway using commercial-grade assays to assess the risk for and timing of development of clinical RA.

Association of Race and Risk of Future Scleroderma Renal Crisis at Systemic Sclerosis Diagnosis.

OBJECTIVE: Scleroderma renal crisis (SRC) is a rare and severe manifestation of systemic sclerosis (SSc). Although it is well documented that Black patients with SSc have worse morbidity and mortality than non-Black patients, racial predilection for SRC is underreported. We examine the association of race and future development of SRC in an SSc cohort. METHODS: Using the electronic health record of the US Military Health System, we conducted a comprehensive chart review of each patient with SSc from 2005 to 2016. The final study cohort was comprised of 31 SRC cases and 322 SSc without SRC controls. We conducted logistic regression of SRC as the outcome variable and race (Black versus non-Black) as the primary predictor variable, adjusted for age, estimated glomerular filtration rate, hypertension, and proteinuria at SSc diagnosis. RESULTS: Of 353 patients, 294 had identifiable race (79 Black, 215 non-Black). Thirteen of 79 Black patients (16.5%) versus 16 of 215 (7.4%) non-Black patients developed SRC (P = 0.02). On adjusted analysis, Black patients had a significantly higher risk of developing SRC than non-Black patients (odds ratio 6.4 [95% confidence interval 1.3-31.2], P = 0.02). Anti-Ro antibody was present in a higher proportion of Black SRC patients versus Black patients without SRC (45% versus 14%, P = 0.01). Conversely, older age, thrombocytopenia, and anti-RNA polymerase III antibody at SSc diagnosis were significantly associated with future SRC in the non-Black cohort. CONCLUSION: Black race was independently associated with a higher risk of future SRC. Further studies are needed to elucidate the mechanisms that underlie this important association.

Serum antibodies to periodontal pathogens prior to rheumatoid arthritis diagnosis: A case-control study.

OBJECTIVES: 1) To quantify the association between anti-Porphyromonas gingivalis serum antibody concentrations and the risk of developing rheumatoid arthritis (RA), and 2) to quantify the associations among RA cases between anti-P. gingivalis serum antibody concentrations and RA-specific autoantibodies. Additional anti-bacterial antibodies evaluated included anti-Fusobacterium nucleatum and anti-Prevotella intermedia. METHODS: Serum samples were acquired pre- and post- RA diagnosis from the U.S. Department of Defense Serum Repository (n = 214 cases, 210 matched controls). Using separate mixed-models, the timing of elevations of anti-P. gingivalis, anti-P. intermedia, and anti-F. nucleatum antibody concentrations relative to RA diagnosis were compared in RA cases versus controls. Associations were determined between serum anti-CCP2, ACPA fine specificities (vimentin, histone, and alpha-enolase), and IgA, IgG, and IgM RF in pre-RA diagnosis samples and anti-bacterial antibodies using mixed-effects linear regression models. RESULTS: No compelling evidence of case-control divergence in serum anti-P. gingivalis, anti-F. nucleatum, and anti-P. intermedia was observed. Among RA cases, including all pre-diagnosis serum samples, anti-P. intermedia was significantly positively associated with anti-CCP2, ACPA fine specificities targeting vimentin, histone, alpha-enolase, and IgA RF (p<0.001), IgG RF (p = 0.049), and IgM RF (p = 0.004), while anti-P. gingivalis and anti-F. nucleatum were not. CONCLUSIONS: No longitudinal elevations of anti-bacterial serum antibody concentrations were observed in RA patients prior to RA diagnosis compared to controls. However, anti-P. intermedia displayed significant associations with RA autoantibody concentrations prior to RA diagnosis, suggesting a potential role of this organism in progression towards clinically-detectable RA.

Antibodies to Citrullinated Protein Antigens, Rheumatoid Factor Isotypes and the Shared Epitope and the Near-Term Development of Clinically-Apparent Rheumatoid Arthritis.

Background/Purpose: In rheumatoid arthritis (RA) autoantibodies including antibodies to citrullinated protein antigens (ACPA) and rheumatoid factor (RF) can be predictive of incident clinical RA. However, there is limited understanding of how antibody changes over time impact prediction of the likelihood and timing of future clinical RA. Materials and Methods: We evaluated relationships between ACPA, the shared epitope (SE), RF isotypes and incident RA in a prospective cohort of 90 ACPA(+) individuals without baseline arthritis identified through health-fair testing (i.e. Healthfair). We also evaluated ACPA and RF isotypes and time-to-diagnosis of RA in a retrospective cohort of 215 individuals with RA from the Department of Defense Serum Repository (DoDSR). Results: Twenty-six of 90 (29%) of ACPA(+) Healthfair participants developed incident RA. Baseline or incident dual RF-IgA and RF-IgM positivity was associated with increased risk for incident RA (HR 3.09; 95% CI 1.15 to 8.29) although RFs were negative in ~50% of individuals with incident RA. SE was associated with increased risk of RA (HR 2.87, 95% CI 1.22-6.76). In the DoDSR cohort, triple positivity for ACPA, RF-IgA and RF-IgM was present a median of 1-2 years prior to RA diagnosis, with some sex-specific differences. Conclusion: These findings can be used to counsel individuals at-risk for future RA and to design clinical trials for RA prevention. The findings also suggest that RF could be a surrogate outcome as a success of an immunologic intervention in RA prevention. Additional studies are needed to understand the biologic of different patterns of autoantibody elevations in RA evolution.

Antibody Responses to Epstein-Barr Virus in the Preclinical Period of Rheumatoid Arthritis Suggest the Presence of Increased Viral Reactivation Cycles.

OBJECTIVE: Patients with established rheumatoid arthritis (RA) demonstrate altered immune responses to Epstein-Barr virus (EBV), but the presence and roles of EBV have not been fully explored during the pre-clinical disease period. This study was undertaken to determine if EBV infection, as evidenced by an altered anti-EBV antibody response, either plays an important role in driving the development of RA or is a result of expanded RA-related autoimmunity. METHODS: A total of 83 subjects with RA according to the 1987 American College of Rheumatology (ACR) criteria and 83 age-, sex-, and race-matched control subjects without RA were included in our study. We collected sera from RA subjects and matched controls during the pre-RA and post-RA diagnosis periods and tested the sera for the presence of 5 anti-EBV antibodies (anti-EBV nuclear antigen 1 IgG isotype, anti-viral capsid antigen [anti-VCA] isotypes IgG and IgA, and anti-early antigen [EA] isotypes IgG and IgA), 7 RA-related autoantibodies (rheumatoid factor measured by nephelometry [RF-Neph] as well as isotype-specific IgA-RF, IgM-RF, and IgG-RF, and anti-cyclic citrullinated peptide [anti-CCP] antibodies, including anti-CCP2, anti-CCP3, and anti-CCP3.1), 22 cytokines/chemokines, 36 individual anti-citrullinated protein antibodies, and IgG-cytomegalovirus (CMV) antibodies. Random forest classification, mixed modeling, and joint mixed modeling were used to determine differences in anti-EBV antibody levels between RA subjects and controls. RESULTS: Random forest analysis identified the presence of preclinical EBV antibodies in the serum that differentiated RA subjects from controls without RA. Specifically, IgG-EA antibody levels were higher in RA subjects (mean ± SD 0.82 ± 0.72 international standardized ratio [ISR]) compared to controls (mean ± SD 0.49 ± 0.28 ISR). In subjects with RA, elevated serum IgG-EA levels in the preclinical period before seroconversion were significantly correlated with increased serum IgM-RF levels (P = 0.007), whereas this correlation was not seen in control subjects without RA (P = 0.15). IgG-CMV antibody levels did not differ between groups. CONCLUSION: Subjects whose serum IgG-EA antibody levels are elevated in the preclinical period will eventually develop RA, which suggests that EBV reactivation cycles are increased during the preclinical period of RA. A combination of RF and EBV reactivation may play an important role in the development of RA.

The number of elevated cytokines and chemokines in preclinical seropositive rheumatoid arthritis predicts time to diagnosis in an age-dependent manner.

OBJECTIVE: To evaluate levels of biomarkers in preclinical rheumatoid arthritis (RA) and to use elevated biomarkers to develop a model for the prediction of time to future diagnosis of seropositive RA. METHODS: Stored samples obtained from 73 military cases with seropositive RA prior to RA diagnosis and from controls (mean 2.9 samples per case; samples collected a mean of 6.6 years prior to diagnosis) were tested for rheumatoid factor (RF) isotypes, anti-cyclic citrullinated peptide (anti-CCP) antibodies, 14 cytokines and chemokines (by bead-based assay), and C-reactive protein (CRP). RESULTS: Preclinical positivity for anti-CCP and/or ≥2 RF isotypes was >96% specific for future RA. In preclinical RA, levels of the following were positive in a significantly greater proportion of RA cases versus controls: interleukin-1α (IL-1α), IL-1ß, IL-6, IL-10, IL-12p40, IL-12p70, IL-15, fibroblast growth factor 2, flt-3 ligand, tumor necrosis factor α, interferon-γ-inducible 10-kd protein, granulocyte-macrophage colony-stimulating factor, and CRP. Also, increasing numbers of elevated cytokines/chemokines were present in cases nearer to the time of diagnosis. RA patients who were ≥40 years old at diagnosis had a higher proportion of samples positive for cytokines/chemokines 5-10 years prior to diagnosis than did patients who were <40 years old at diagnosis (P < 0.01). In regression modeling using only case samples positive for autoantibodies highly specific for future RA, increasing numbers of cytokines/chemokines were predictive of decreased time to diagnosis, and the predicted time to diagnosis based on cytokines/chemokines was longer in older compared with younger cases. CONCLUSION: Levels of autoantibodies, cytokines/chemokines, and CRP are elevated in the preclinical period of RA development. In preclinical autoantibody-positive cases, the number of elevated cytokines/chemokines is predictive of the time of diagnosis of future RA in an age-dependent manner.

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.

Interstitial Lung Disease and Myositis in a Patient With Antisynthetase Syndrome and PL12 and Ro52 Co-positivity in a Retired Medical Officer.

Antisynthetase syndrome (ASS) is an idiopathic inflammatory myopathy characterized by myositis, arthritis, interstitial lung disease (ILD), Raynaud's phenomenon, and distinctive cutaneous manifestations. Anti-PL12 is a rare myositis-specific autoantibody classically associated with an amyopathic presentation and rapidly progressive ILD. Anti-Ro52 is a myositis-associated antibody that has been postulated to be directly pathogenic in inflammatory myopathy patients. The disease phenotype, course, and response to treatment associated with anti-PL12 and anti-Ro52 co-positivity is not well described.A 58-year-old man with anti-PL12 and anti-Ro52 ASS presented with rapidly progressive ILD and myositis refractory to high-dose prednisone. He ultimately required a dexamethasone burst with intravenous immunoglobulin and mycophenolate mofetil for disease control.Severe and rapidly progressive myositis is infrequently reported in anti-PL12 ASS. This case suggests that concurrent anti-Ro52 positivity predicts a more aggressive disease phenotype and may require more initial immunosuppression. If rapid progression of this disease were to occur in an active duty service member, it would have significant implications for readiness and potentially catastrophic outcomes in the deployed setting. Early identification and treatment of the disease are imperative. The question must also be raised of an occupational exposure from military service.

Comparing Rheumatology Consultation Patterns Across Telehealth Platforms and Face-to-Face Clinic in the Military Health System.

OBJECTIVE: To compare patterns of rheumatology consultations and outcomes across four different platforms in the Military Health System (MHS): face-to-face, synchronous telehealth, and two asynchronous telehealth platforms. METHODS: We conducted a retrospective review comparing face-to-face rheumatology consults during 2019 with teleconsultations from three virtual systems in the MHS: an asynchronous email-based system from May 2006 to Feb 2018, a web-based platform from 2014 to 2018, and synchronous telehealth consults from March 2020 to March 2021. Consults were reviewed for diagnosis, and if medical evacuation was required for consults originating OCONUS or if face-to-face follow-up was required for synchronous teleconsults. Diagnoses of interest included inflammatory arthritis, noninflammatory arthritis, crystalline arthritis, myositis, lupus, vasculitis, fibromyalgia, antibody positivity without diagnosis, symptoms without specified diagnosis, and a composite of other rheumatic diseases. RESULTS: Leading diagnoses across platforms were inflammatory arthritis, noninflammatory arthritis, and a composite of other diagnoses. Consultation modality influenced the type of cases seen. Inflammatory arthritis accounted for significantly more consults in the synchronous telehealth (38.4%) and email-based (40.9%) models than in the web-based (23.7%) and face-to-face (32.0%) models. The composite of other diagnoses was the leading diagnosis for the asynchronous web-based model (32.9%), which was significantly more than the synchronous telehealth and face-to-face consults. Synchronous models saw significantly more cases of crystalline arthritis, vasculitis, and fibromyalgia.Email-based consultations resulted in medical evacuation in 25 cases and prevented evacuation in 5. Web-based consultations prompted medical evacuation in 100 cases. In the synchronous model, face-to-face follow-up was recommended in 142 (15%) cases. CONCLUSIONS: Modality of consultation influences the type of cases seen. Both synchronous and asynchronous telerheumatology models were able to answer the consult question without referral for face-to-face evaluation in 79.9-85.0% of consults, suggesting teleconsultation is a viable method to increase access to high-quality rheumatology care.

Synopsis of the 2020 US Department of Veterans Affairs/US Department of Defense Clinical Practice Guideline: The Non-Surgical Management of Hip and Knee Osteoarthritis.

In July 2020, the US Department of Veterans Affairs (VA) and US Department of Defense (DoD) approved a new joint clinical practice guideline for the non-surgical management of hip and knee osteoarthritis. This synopsis highlights some of the recommendations. In February 2019, the VA/DoD Evidence-Based Practice Work Group convened a joint VA/DoD guideline development effort that included clinical stakeholders and conformed to the National Academy of Medicine's tenets for trustworthy clinical practice guidelines. The guideline panel developed key questions, systematically searched (ie, Cochrane Database of Systematic Reviews, EMBASE, MEDLINE PreMEDLINE, PubMed, and the Agency for Healthcare Research and Quality website) and evaluated the literature, created a simple 1-page algorithm, and advanced 19 recommendations using the Grading of Recommendations Assessment, Development, and Evaluation system. This synopsis summarizes key recommendations in all 6 topics covered in the guideline. These topics are diagnosis, self-management, physical therapy, pharmacotherapy, orthobiologics, and complementary and integrative health.

Combinations of Anticyclic Citrullinated Protein Antibody, Rheumatoid Factor, and Serum Calprotectin Positivity Are Associated With the Diagnosis of Rheumatoid Arthritis Within 3 Years.

OBJECTIVE: To evaluate the prevalence of elevations of anti-cyclic citrullinated peptide-3 (anti-CCP3) antibody, rheumatoid factor IgM (RF-IgM) and serum calprotectin (sCP) in pre-rheumatoid arthritis (RA) as well as the diagnostic accuracies of these biomarkers for the timing of diagnosis of future RA. METHODS: A total of 215 RA cases, each with approximately three pre-RA diagnoses and one post-RA diagnosis serum sample, and controls were identified from the Department of Defense Serum Repository. All case samples and a single sample from each control subject were tested for anti-CCP3 (IgG), RF-IgM, and sCP. The diagnostic accuracies of biomarkers for future RA were evaluated. RESULTS: Anti-CCP3, RF-IgM, and sCP were elevated in pre-RA, with anti-CCP3 and sCP significantly elevated compared with RF-IgM at the earliest time points. Within the cases, the combination of anti-CCP3 and RF-IgM positivity had a positive predictive value (PPV) of 35.6% for a diagnosis of RA in 3 years or less, which is significantly higher than the PPV of 18.7% for anti-CCP3 positivity alone (P < 0.001). A combination of anti-CCP3, RF-IgM, and sCP had the highest PPV (53.0%) for a diagnosis of RA in 3 years or less; however, this was not significantly higher than the PPV for anti-CCP3 and RF-IgM positivity (P = 0.248). CONCLUSION: Anti-CCP3, RF-IgM, and sCP are elevated in pre-RA; furthermore, combinations of elevations of these biomarkers are more commonly seen in the period of less than or equal to 3 years to diagnosis. This may be considered in creating inclusion criteria in prevention trials in RA. In addition, the biologic relationships of these biomarkers in pre-RA need exploration.

Gemcitabine-associated large vessel vasculitis presenting as fever of unknown origin.

Gemcitabine is a nucleoside analogue used for treatment of multiple cancers. Recent reports describe small to medium vessel vasculitis as a rare complication of therapy. We report a case of significant large vessel vasculitis presenting as fever of unknown origin in a patient treated adjuvantly with docetaxel and gemcitabine for uterine leiomyosarcoma.The patient presented after her first and second exposure to chemotherapy with fever of unknown origin and worsening subsequent chest and neck discomfort. Extensive workup revealed radiographic and laboratory evidence of aortic vasculitis. We initiated treatment with high-dose corticosteroids, and the patient's condition resolved without complication over the next several weeks.To our knowledge, this represents the first case of gemcitabine-induced large vessel vasculitis which presented in our case as fever of unknown origin. Awareness of this potential complication is essential as discontinuing the inciting drug and initiating corticosteroid treatment can be life-saving.