Associations between Adiponectin and the Development of Diabetes in Rheumatoid Arthritis.

PURPOSE: We evaluated associations between adiponectin and the risk of diabetes among patients with rheumatoid arthritis (RA), a systemic inflammatory disease associated with metabolic disturbance. METHODS: This prospective cohort study included adults with RA from the Veteran's Affairs Rheumatoid Arthritis Registry. Adiponectin and inflammatory cytokines/chemokines were measured at enrollment on stored serum samples. Adiponectin levels were categorized and clinical variables were described across categories (<10 µg/mL; 10-40 µg/mL; > 40 µg/mL. Multivariable Cox proportional hazard models evaluated associations between adiponectin and incident diabetes adjusting for age, sex, race, smoking status, body mass index (BMI), disease-modifying therapy use, calendar year, and comorbidity. Testing for modification of effect in the context of elevated cytokines/chemokines was performed. RESULTS: Among 2595 patients included in the analysis, those with adiponectin levels >40 µg/mL (N = 379; 15%) were older and had lower BMI. There were 125 new cases of diabetes among 1,689 patients without prevalent disease at enrollment. There was an inverse association between adiponectin and incident diabetes, however, the association was positive among patients with adiponectin levels >40 µg/mL. Patients with levels >40 µg/mL were at higher risk compared to those with levels 10-40 µg/mL [HR: 1.70 (1.34,2.16) p < 0.001]. Those with adiponectin levels >40 µg/mL had significantly higher levels of inflammatory cytokines with evidence of a modified effect of adiponectin on diabetes risk in the setting of inflammation. CONCLUSIONS: The relationship between adiponectin and incident diabetes risk is U-shaped in RA. Patients with very high adiponectin levels have greater systemic inflammation and an altered relationship between adiponectin and diabetes risk.

Adipocytokines and achievement of low disease activity in rheumatoid arthritis.

PURPOSE: To determine if adipocytokines are independently associated with the achievement of low disease activity (LDA) over long-term follow-up in a large rheumatoid arthritis (RA) registry. METHODS: This cohort study evaluated adults with RA from the Veteran's Affairs RA Registry. Adipocytokines (adiponectin, leptin, and fibroblast growth factor [FGF]-21) and inflammatory cytokines were measured as part of a multi-analyte panel on banked serum from enrollment. Covariates were derived from medical record, biorepository, and registry databases. Multivariable Cox proportional hazard models evaluated associations between adipocytokines and rates of 1) DAS28 LDA and remission, 2) individual Boolean remission criteria and 3) initiation of a new bDMARD or tsDMARD. RESULTS: There were 1,276 participants with a DAS28 >3.2 at enrollment. Of these, 827 achieved LDA and 598 achieved remission over 2,287 and 4,096 person-years, respectively. Patients in the highest quartile of adiponectin had lower rates LDA before and after adjustment [aHR Q4: 0.68 (0.53,0.87) p<0.001]. Those in the highest quartile of leptin and FGF-21 also had lower rates of LDA. Higher quartiles of adipocytokines were also associated with lower rates of achieving a low patient/evaluator global scores and low tender joint counts. Among 1,236 biologic-naïve participants, values above the median for adiponectin [HR: 1.67 (1.23,1.26) p = 0.001] and FGF-21 [HR: 1.27 (1.09,1.47) p = 0.002] were associated with a greater likelihood of initiating a b/tsDMARD. CONCLUSIONS: Adipocytokines may serve as prognostic biomarkers of a more severe RA disease course. Additional study is needed to determine whether adipocytokines are phenotypic markers or whether they actively promote disease progression.

The Role of Clinical Features and Serum Biomarkers in Identifying Patients with Incomplete Lupus Erythematosus at Higher Risk of Transitioning to Systemic Lupus Erythematosus: Current Perspectives.

Discovery of antinuclear antibodies (ANA) enabled earlier diagnosis of systemic lupus erythematosus (SLE) and other ANA+ connective tissue diseases (CTD). Rheumatologists increasingly encounter high referral volume of ANA+ patients. It has been estimated that only a small percentage of these patients will eventually transition to either SLE or other specified CTD. Incomplete lupus erythematosus (ILE) has been defined as a subset of patients who have some SLE-specific clinical manifestations but do not meet currently accepted classification criteria for SLE. Several studies have been performed with the goal of identifying clinical features, serum and tissue biomarkers that can distinguish those patients with ILE at risk of transitioning to SLE from those who will not. Increased autoantibody diversity, presence of anti-double-stranded DNA (dsDNA) antibodies, high expression of type I and type II interferon (IFN)-gene products, increased serum levels of B-cell-activating factor of the TNF family (BAFF), and certain serum cytokines and complement products have been identified as markers with positive predictive value, particularly when combined together. Once this patient population is better characterized biochemically, clinical trials should be considered with the primary objective to completely halt or slow down the transition from ILE to SLE. Hydroxychloroquine (HCQ) appears to be a promising agent due to its good tolerability and low toxicity profile and open-label studies in ILE patients have already shown its ability to delay the onset of SLE. Other therapeutics, like those targeting abnormal type I and type II IFN-signatures, B-cell specific signaling pathways, complement activation pathways and high BAFF levels should also be evaluated, but the risk to benefit ratio must be carefully determined before they can be considered.

A patient-centered gout information value chain: a scoping review.

OBJECTIVE: To examine and identify the scope of research addressing health information requirements for gout patients using value chain analysis. METHODS: Five electronic databases (PubMed, CINAHL, ERIC, PsycINFO, Embase, and Scopus) and grey literature (WorldCat) were searched in accordance with a published protocol. Only English language articles were included, with no limitations for date of publication. The findings of the 33 studies included for final analysis were subsequently divided into 6 groups according to the stages of the care delivery value chain their research most closely pertained to: screening/preventing (n = 2), diagnosing (n = 1), preparing (n = 7), intervening (n = 11), recovering/rehabilitating (n = 5), and monitoring/managing (n = 13). RESULTS: The 33 studies focused on one or more of the following information phenotypes: 1) pathophysiology; 2) medical treatment; and 3) nonpharmaceutical interventions. Long term treatment adherence was a popular topic amongst studies that focused on gout patient education. CONCLUSION: Based on the identified studies, gout patients are being told what to do, but are not being adequately educated regarding why recommended interventions are important or how to accomplish them. PRACTICE IMPLICATIONS: This review provides a foundation to develop and evaluate personalized education materials using value chain analysis.

Establishing core domain sets for Chronic Nonbacterial Osteomyelitis (CNO) and Synovitis, Acne, Pustulosis, Hyperostosis, Osteitis (SAPHO): A report from the OMERACT 2020 special interest group.

OBJECTIVE: A working group was established to develop a core domain set (CDS) for Chronic Nonbacterial Osteomyelitis (CNO) and Synovitis, Acne, Pustulosis, Hyperostosis, Osteitis (SAPHO) following the OMERACT filter 2.1. METHODS: A scoping review to identify disease-related manifestations was performed, followed by a special interest group (SIG) session at OMERACT2020 to begin the CNO/SAPHO CDS framework. RESULTS: Candidate items were identified from the scoping review and most fell under Life Impact and Pathophysiology Manifestation core areas. A SIG agreed on the need to develop a CDS for CNO and SAPHO (100%) and for children and adults (91%). CONCLUSION: Based on candidate items identified, qualitative research and Delphi surveys will be performed as next steps.

Accuracy of US Administrative Claims Codes for the Diagnosis of Autoinflammatory Syndromes.

OBJECTIVE: To determine the accuracy of case definitions for autoinflammatory syndromes (AISs) based on administrative claims codes compared with rheumatology records in the electronic medical record (EMR). METHODS: An AIS screening filter of administrative codes was applied to a large tertiary care EMR database to extract all possible AIS cases. We manually chart reviewed all patients who were evaluated by a rheumatologist to determine their reference standard diagnosis of adult onset Still's disease (AOSD), Behçet's disease (BD), and familial Mediterranean fever (FMF). We calculated sensitivity, specificity, positive predictive values, negative predictive values, and area under the receiver operating characteristic curve of specific codes for diagnosing AIS subtypes. RESULTS: We identified 273 individuals with possible AIS, of which 72 (26.4%) had a true AIS diagnosis, including 24 with AOSD, 32 with BD, and 9 with FMF. For all 3 AIS subtypes, the estimates of specificities and negative predictive values for specific administrative codes were excellent (>95%). Sensitivity estimates were excellent (>89%) for BD and FMF codes and lower for AOSD (46%-50%). Positive predictive values were excellent for BD (>99%) and AOSD (>86%) and lower for FMF (>53%). Area under the receiver operating characteristic curve estimates were excellent for BD (97%-98%) and FMF (93%) and very good for AOSD (75%). CONCLUSIONS: This is the first study to characterize the accuracy of specific administrative codes for the diagnosis of AOSD, BD, and FMF in a large tertiary care EMR. Validation in external EMRs and linked EMR-administrative databases is needed to enable future clinical outcomes research of AIS.

Atypical Large Vessel Vasculitis Presenting With Cholestatic Liver Abnormalities: Case-Based Review.

ABSTRACT: Clinicians usually easily recognize cranial manifestations of giant cell arteritis (GCA) such as new-onset headache, jaw claudication, scalp tenderness, and abrupt changes in visual acuity or blindness; however, when presented with an aberrant clinical course, the diagnosis becomes more elusive. In addition to temporal arteries and other extracranial branches of the carotid arteries, large vessel vasculitis (LVV) can also affect other blood vessels including coronary arteries, aorta with its major branches, intracranial blood vessels, and hepatic arteries.Over time, the scope of the symptoms typically associated with LVV has broadened and includes cases of fever of unknown origin accompanied with other constitutional symptoms that can mimic a range of neoplastic and infectious diseases. In up to half of patients with atypical LVV, liver enzyme level elevations with a cholestatic pattern have been observed. Alkaline phosphatase level and γ-glutamyl transferase level elevations tend to be more prevalent in those LVV patients with vigorous inflammatory responses, particularly in those with fever and other nonspecific constitutional symptoms. These patients also have more profound anemia and thrombocytosis. With the exception of rare instances of vasculitides and granulomas affecting the liver tissue, liver biopsy is generally of little help and primarily shows nonspecific changes of fatty liver.In this article, we review 3 patients who were eventually diagnosed with atypical LVV. The diagnosis was confirmed with temporal artery biopsy in 2 patients and with positron emission tomography/computed tomography in 1 patient. The common hepatic abnormality observed in all patients was the elevation of alkaline phosphatase level, which tended to respond rapidly to initiation of immunosuppressive treatment.

Comparing children and adults with chronic nonbacterial osteomyelitis.

PURPOSE OF REVIEW: To describe the main clinical differences of children and adults with chronic nonbacterial osteomyelitis (CNO). RECENT FINDINGS: CNO is a severe systemic autoinflammatory syndrome characterized by multiple bone lesions because of inflammatory osteitis. Delay to diagnosis of CNO can lead to functional impairment, fractures, and chronic pain. Key clinical aspects and disease patterns differ in children and adults, including onset and time to diagnosis, symptom localization, associated comorbidities (i.e. skin, joints), bone lesion distribution pattern, and treatment approach. Novel biomarkers, such as urine N-terminal telopeptide in children and serum IgG4 in adults, are being studied for possible future use in improving diagnosis and guiding treatment. Despite recent advances in our understanding of CNO, many children and adults have a high disease burden and poor long-term outcomes. Recent findings suggest that adults with CNO tend to have a more chronic disease course and are less likely to achieve remission in follow-up. SUMMARY: The clinical presentation of CNO differs in children and adults, highlighting the importance of these key features for the accurate diagnosis and early treatment in CNO.

2020 American College of Rheumatology Guideline for the Management of Gout

To provide guidance for the management of gout, including indications for and optimal use of urate- lowering therapy (ULT), treatment of gout ares, and lifestyle and other medication recommendation Fifty- seven population, intervention, comparator, and outcomes questions were developed, followed by a systematic literature review, including network meta- analyses with ratings of the available evidence according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, and patient input. A group consensus process was used to compose the nal recommendations and grade their strength as strong or conditional.Results. Forty- two recommendations (including 16 strong recommendations) were generated. Strong recommen-dations included initiation of ULT for all patients with tophaceous gout, radiographic damage due to gout, or frequent gout ares; allopurinol as the preferred rst- line ULT, including for those with moderate- to- severe chronic kidney disease (CKD; stage >3); using a low starting dose of allopurinol (≤100 mg/day, and lower in CKD) or febuxostat (<40 mg/day); and a treat- to- target management strategy with ULT dose titration guided by serial serum urate (SU) measurements, with an SU target of <6 mg/dl. When initiating ULT, concomitant antiinammatory prophylaxis therapy for a duration of at least 3­6 months was strongly recommended. For management of gout ares, colchicine, nonsteroidal antiinammatory drugs, or glucocorticoids (oral, intraarticular, or intramuscular) were strongly recommended.Conclusion. Using GRADE methodology and informed by a consensus process based on evidence from the current literature and patient preferences, this guideline provides direction for clinicians and patients making decisions on the management of gout.

2020 American College of Rheumatology Guideline for the Management of Gout.

OBJECTIVE: To provide guidance for the management of gout, including indications for and optimal use of urate-lowering therapy (ULT), treatment of gout flares, and lifestyle and other medication recommendations. METHODS: Fifty-seven population, intervention, comparator, and outcomes questions were developed, followed by a systematic literature review, including network meta-analyses with ratings of the available evidence according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, and patient input. A group consensus process was used to compose the final recommendations and grade their strength as strong or conditional. RESULTS: Forty-two recommendations (including 16 strong recommendations) were generated. Strong recommendations included initiation of ULT for all patients with tophaceous gout, radiographic damage due to gout, or frequent gout flares; allopurinol as the preferred first-line ULT, including for those with moderate-to-severe chronic kidney disease (CKD; stage >3); using a low starting dose of allopurinol (≤100 mg/day, and lower in CKD) or febuxostat (<40 mg/day); and a treat-to-target management strategy with ULT dose titration guided by serial serum urate (SU) measurements, with an SU target of <6 mg/dl. When initiating ULT, concomitant antiinflammatory prophylaxis therapy for a duration of at least 3-6 months was strongly recommended. For management of gout flares, colchicine, nonsteroidal antiinflammatory drugs, or glucocorticoids (oral, intraarticular, or intramuscular) were strongly recommended. CONCLUSION: Using GRADE methodology and informed by a consensus process based on evidence from the current literature and patient preferences, this guideline provides direction for clinicians and patients making decisions on the management of gout.

2020 American College of Rheumatology Guideline for the Management of Gout.

OBJECTIVE: To provide guidance for the management of gout, including indications for and optimal use of urate-lowering therapy (ULT), treatment of gout flares, and lifestyle and other medication recommendations. METHODS: Fifty-seven population, intervention, comparator, and outcomes questions were developed, followed by a systematic literature review, including network meta-analyses with ratings of the available evidence according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, and patient input. A group consensus process was used to compose the final recommendations and grade their strength as strong or conditional. RESULTS: Forty-two recommendations (including 16 strong recommendations) were generated. Strong recommendations included initiation of ULT for all patients with tophaceous gout, radiographic damage due to gout, or frequent gout flares; allopurinol as the preferred first-line ULT, including for those with moderate-to-severe chronic kidney disease (CKD; stage >3); using a low starting dose of allopurinol (≤100 mg/day, and lower in CKD) or febuxostat (<40 mg/day); and a treat-to-target management strategy with ULT dose titration guided by serial serum urate (SU) measurements, with an SU target of <6 mg/dl. When initiating ULT, concomitant antiinflammatory prophylaxis therapy for a duration of at least 3-6 months was strongly recommended. For management of gout flares, colchicine, nonsteroidal antiinflammatory drugs, or glucocorticoids (oral, intraarticular, or intramuscular) were strongly recommended. CONCLUSION: Using GRADE methodology and informed by a consensus process based on evidence from the current literature and patient preferences, this guideline provides direction for clinicians and patients making decisions on the management of gout.

Clinical characteristics and comorbidities in adult-onset Still's disease using a large US administrative claims database.

OBJECTIVES: We aimed to describe clinical characteristics, treatment patterns and major comorbidities of a US-based adult-onset Still's disease (AOSD) cohort. METHODS: Administrative claims data from Truven MarketScan were collected from 2009 to 2015. An AOSD case was defined as ≥1 M06.1 International Classification of Diseases 10th revision (ICD-10) medical claim code. We extracted data for the AOSD cohort (n = 106) and 1:5 matched controls (n = 530) without AOSD. Outcomes of interest and a novel claims-based set of Yamaguchi criteria were identified by relevant ICD 9th revision (ICD-9) and ICD-10 codes. Bivariate descriptive analyses were conducted on all variables. Comorbidity rates and rate ratios were calculated in AOSD cases and matched controls. Statistical significance of cohort differences was determined to compare AOSD cases and matched controls. RESULTS: The AOSD cohort, with a mean age of 43.08 (standard deviation, s.d. 13.9) years and with female predominance (68.9%) was observed over a mean of 750.12 (637.6) days. A total of 35.9% of AOSD patients fulfilled claims-based Yamaguchi criteria compared with 0.4% matched controls (P< 0.05). We identified severe AOSD-related complications, including macrophage activation syndrome (4.7%) and acute respiratory distress syndrome (12.3%). Treatment commonly involved systemic glucocorticoids (62.2%), MTX (51%) and anakinra (24.5%). Compared with matched controls, serious infections were significantly increased (rate ratio 2.58, 95% CI: 1.53, 4.37, P = 0.0004), while hyperlipidaemia (0.54, 95% CI: 0.35, 0.85; P = 0.008) and obesity (0.30, 95% CI: 0.15, 0.62; P = 0.001) were significantly decreased in AOSD patients. CONCLUSION: We characterized a first US-based AOSD cohort using a large national administrative claims database, and identified key complications, treatments and comorbidities.

Diagnostic Dilemma of Disseminated Histoplasmosis Mimicking Hemophagocytosis Lymphohistiocytosis in Patient with Rheumatoid Arthritis on Anti-TNF Therapy: Case Report and Review of the Literature.

Tumor necrosis factor inhibitors (TNFi) have become the cornerstone for the treatment of rheumatoid arthritis and other systemic autoimmune conditions. However, these biologic DMARDs can lead to various opportunistic infections such as viral infection, tuberculosis, and histoplasmosis. Furthermore, these biologics can also cause severe systemic inflammatory reactions known as hemophagocytosis lymphohistiocytosis (HLH) that can lead to multiorgan failure and high mortality. Due to overlapping clinical features and time-intensive microbiological culture methods, distinguishing between HLH and opportunistic infections can be challenging early in the disease course. We present a similar situation with our patient where the patient met the diagnostic criteria for HLH however was found to have disseminated histoplasmosis. This case uniquely evaluates the utility of the HLH diagnostic criteria and hemophagocytosis for accurate diagnosis of HLH.

Spotlight on blisibimod and its potential in the treatment of systemic lupus erythematosus: evidence to date.

B cells in general and BAFF (B cell activating factor of the tumor necrosis factor [TNF] family) in particular have been primary targets of recent clinical trials in systemic lupus erythematosus (SLE). In 2011, belimumab, a monoclonal antibody against BAFF, became the first biologic agent approved for the treatment of SLE. Follow-up studies have shown excellent long-term safety and tolerability of belimumab. In this review, we critically analyze blisibimod, a novel BAFF-neutralizing agent. In contrast to belimumab that only blocks soluble BAFF trimer but not soluble 60-mer or membrane BAFF, blisibimod blocks with high affinity all three forms of BAFF. Furthermore, blisibimod has a unique structure built on four high-affinity BAFF-binding peptides fused to the IgG1-Fc carrier. It was tested in phase I and II trials in SLE where it showed safety and tolerability. While it failed to reach the primary endpoint in a recent phase II trial, post hoc analysis demonstrated its efficacy in SLE patients with higher disease activity. Based on these results, blisibimod is currently undergoing phase III trials targeting this responder subpopulation of SLE patients. The advantage of blisibimod, compared to its competitors, lies in its higher avidity for BAFF, but a possible drawback may come from its immunogenic potential and the anticipated loss of efficacy over time.

Detecting novel micro RNAs in rheumatoid arthritis with gene-based association testing.

OBJECTIVES: To identify novel risk genes by gene-based association analysis in rheumatoid arthritis (RA). METHODS: We performed gene-based association testing with GATES (Gene-based Association Test using Extended Simes procedure) to augment the power of genomewide-association study (GWAS) results from the largest meta-GWAS by Okada et al. in 14,361 RA cases and 43,923 controls of European ancestry using 8,694,488 SNPs. RESULTS: We identified 115 genes significantly associated with RA by gene-based association testing corresponding to 43 RA risk loci; 23 risk loci contained a single top risk gene, while 20 risk loci contained two or more risk genes. We replicated 39 of the genomewide significant risk loci identified by Okada et al. in Europeans with RA; we found identical top genes for 26 loci. Our gene-based testing identified 6 new top gene hits for each of the following 6 RA risk loci: RPP14 (for DNASE1L3-ABHD6-PXK), PXT1 (for ETV7), MIR5708 (for TPD52), DDX6 (for CXCR5), SUOX (for CDK2), and PCAT29 (for LOC145837). We also identified a potential novel RA risk locus (11q23.3, start position 118528941 bp) which contains the following 3 genes: TREH-PHLDB1-MIR6716; the locus was not identified previously but may be a proxy for CXCR5. CONCLUSIONS: Through novel comprehensive gene-based association testing in >50,000 Europeans with RA using ~8 million SNPs, we confirmed prior RA risk loci and identified novel risk genes including non-coding regulatory miRNAs, providing further insight into the complex genetics of RA.

Tapering biologics in rheumatoid arthritis: a pragmatic approach for clinical practice.

Optimal rheumatoid arthritis (RA) therapy in daily clinical practice is based on the treat-to-target strategy. Quicker escalation of therapy and earlier introduction of biological disease-modifying anti-rheumatic drugs have led to improved outcomes in RA. However, chronic immunosuppressive therapy is associated with adverse events and higher costs. In addition, our patients frequently express a desire for lower dosing and drug holidays. Current clinical practice guidelines from the American College of Rheumatology and European League Against Rheumatism suggest that rheumatologists consider tapering treatment after achieving remission. However, the optimal approach for tapering therapy in RA, specifically de-escalation of biologics, remains unknown. This clinical review discusses biologic tapering strategies in RA. We draw our recommendations for everyday clinical practice from the most recent observational, pragmatic, and controlled clinical trials on de-escalation of biologics in RA. For each biologic, we highlight clinically relevant outcomes, such as flare rates, recapture of the disease control with retreatment, radiographic progression, side effects, and functional impact. We discuss the use of musculoskeletal ultrasound to select patients for successful tapering. In conclusion, we provide the reader with a practical guide for tapering biologics in the rheumatology clinic.

Macrophage activation syndrome complicating adult onset Still's disease: A single center case series and comparison with literature.

OBJECTIVES: Macrophage activation syndrome (MAS) is a life-threatening condition that can complicate adult onset Still's disease (AOSD). Due to its rarity, there is no clear consensus concerning treatment recommendations and outcomes. We studied the clinical manifestations and outcomes of a relatively large cohort of patients with MAS and AOSD, and compared the data with the literature reports. METHODS: We performed a retrospective review of 7 adult patients with MAS complicating AOSD at the Cleveland Clinic (CCF) over 7 years. All patients underwent bone marrow biopsies. Through MEDLINE and PubMed literature searches, we identified 48 cases of MAS/AOSD. We compared the data of the CCF and literature cohorts. RESULTS: We identified 7 patients with MAS complicating AOSD (6 females and 1 males) for our CCF cohort, with 4 cases simultaneously presenting with MAS and AOSD. The mean age at diagnosis of MAS was 41.9 ± 20.2 years and mean follow-up time was 18.6 ± 16.0 months. All patients had fever, arthralgias, and typical rash; 6 had leukocytosis, 4 had sore throat, and 3 had lymphadenopathy. These patients with AOSD also had MAS, with renal insufficiency and disseminated intravascular coagulation in 4, lung involvement in 3, and serositis and shock in 2. There was significant hepatic dysfunction in all patients and 6 had bi-cytopenias. At onset of MAS, all 7 patients had active AOSD. In addition to systemic glucocorticoids, 5 patients received anakinra, with 3 patients receiving combination therapy with cyclosporine. We also identified 48 cases (35 females and 13 males) for the literature cohort with the mean age at diagnosis of MAS of 40.2 ± 16.0 years and mean follow-up time of 17.5 ± 32.3 months. While the 2 cohorts were similar clinically, in the CCF cohort, more patients had renal insufficiency (p < 0.001), higher soluble IL-2 receptor level (p = 0.01), and lower ESR (p = 0.02) as compared with the literature cohort. All of our patients survived with a better outcome than the literature cohort. CONCLUSION: MAS can be a serious complication of active AOSD. Our study of a relatively large cohort in conjunction with literature suggests that prompt recognition and treatment with early addition of anakinra, systemic glucocorticoids, and cyclosporine as a triple regimen may improve clinical outcomes.

Current and emerging treatment options for ANCA-associated vasculitis: potential role of belimumab and other BAFF/APRIL targeting agents.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) comprises several clinical entities with diverse clinical presentations, outcomes, and nonunifying pathogenesis. AAV has a clear potential for relapses, and shows unpredictable response to treatment. Cyclophosphamide-based therapies have remained the hallmark of induction therapy protocols for more than four decades. Recently, B-cell depleting therapy with the anti-CD20 antibody rituximab has proved beneficial in AAV, leading to Food and Drug Administration approval of rituximab in combination with corticosteroids for the treatment of AAV in adults. Rituximab for ANCA-associated vasculitis and other clinical trials provided clear evidence that rituximab was not inferior to cyclophosphamide for remission induction, and rituximab appeared even more beneficial in patients with relapsing disease. This raised hopes that other B-cell-targeted therapies directed either against CD19, CD20, CD22, or B-cell survival factors, B-cell activating factor of the tumor necrosis factor family (BAFF) and a proliferation-inducing ligand could also be beneficial for the management of AAV. BAFF neutralization with the fully humanized monoclonal antibody belimumab has already shown success in human systemic lupus erythematosus and, along with another anti-BAFF reagent blisibimod, is currently undergoing Phase II and III clinical trials in AAV. Local production of BAFF in granulomatous lesions and elevated levels of serum BAFF in AAV provide a rationale for BAFF-targeted therapies not only in AAV but also in other forms of vasculitis such as Behcet's disease, large-vessel vasculitis, or cryoglobulinemic vasculitis secondary to chronic hepatitis C infection. BAFF-targeted therapies have a very solid safety profile, and may have an additional benefit of preferentially targeting newly arising autoreactive B cells over non-self-reactive B cells.

Modulating toll-like receptor 7 and 9 responses as therapy for allergy and autoimmunity.

Type I allergic diseases, such as allergic rhinitis and asthma, depend on allergen-induced T-helper type 2 (Th2) cells and IgE-secreting plasma cells. Fortunately, this harmful immune response can be modified by engaging Toll-like receptor (TLR)7 and TLR9, offering hopes to allergy sufferers. While clinical trials employing synthetic ligands for TLR7 or TLR9 are under way, one can wonder whether TLR7 or TLR9 engagements may trigger inadvertent autoreactivity and/or Th1-/Th17-mediated tissue pathology. To neutralize such danger, we have pioneered the development of potent TLR9 pathway antagonists, inhibitory oligonucleotides (INH-ODNs), which work in a sequence-specific manner. Interestingly, INH-ODNs also have TLR7-inhibitory properties; however, these effects appear to be sequence independent and phosphorothioate backbone dependent. In B cells, co-engagement of the B-cell receptor for antigen and TLR7 or TLR9 may influence how INH-ODNs impose their regulatory effects. INH-ODNs block TLR9 activation by competitively antagonizing ligand binding to proteolytically cleaved C-terminal TLR9 fragment. One may envision future use of INH-ODNs in systemic autoimmune diseases, DNA-mediated sepsis, or other situations in which chronic inflammation results from abnormal TLR7- and/or TLR9-mediated immune activation.