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1.
Arthritis Rheumatol ; 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31793250

RESUMO

OBJECTIVE: IgG4-related disease (IgG4-RD) can cause fibroinflammatory lesions in nearly any organ. Correlation among clinical, serologic, radiologic, and pathologic data is required for diagnosis. This work was undertaken to develop and validate an international set of classification criteria for IgG4-RD. METHODS: An international multispecialty group of 86 physicians was assembled by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR). Investigators used consensus exercises, existing literature, derivation and validation cohorts of 1,879 subjects (1,086 cases, 793 mimickers), and multicriterion decision analysis to identify, weight, and test potential classification criteria. Two independent validation cohorts were included. RESULTS: A 3-step classification process was developed. First, it must be demonstrated that a potential IgG4-RD case has involvement of at least 1 of 11 possible organs in a manner consistent with IgG4-RD. Second, exclusion criteria consisting of a total of 32 clinical, serologic, radiologic, and pathologic items must be applied; the presence of any of these criteria eliminates the patient from IgG4-RD classification. Third, 8 weighted inclusion criteria domains, addressing clinical findings, serologic results, radiology assessments, and pathology interpretations, are applied. In the first validation cohort, a threshold of 20 points had a specificity of 99.2% (95% confidence interval [95% CI] 97.2-99.8%) and a sensitivity of 85.5% (95% CI 81.9-88.5%). In the second, the specificity was 97.8% (95% CI 93.7-99.2%) and the sensitivity was 82.0% (95% CI 77.0-86.1%). The criteria were shown to have robust test characteristics over a wide range of thresholds. CONCLUSION: ACR/EULAR classification criteria for IgG4-RD have been developed and validated in a large cohort of patients. These criteria demonstrate excellent test performance and should contribute substantially to future clinical, epidemiologic, and basic science investigations.

2.
Ann Rheum Dis ; 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31796497

RESUMO

IgG4-related disease (IgG4-RD) can cause fibroinflammatory lesions in nearly any organ. Correlation among clinical, serological, radiological and pathological data is required for diagnosis. This work was undertaken to develop and validate an international set of classification criteria for IgG4-RD. An international multispecialty group of 86 physicians was assembled by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR). Investigators used consensus exercises; existing literature; derivation and validation cohorts of 1879 subjects (1086 cases, 793 mimickers); and multicriterion decision analysis to identify, weight and test potential classification criteria. Two independent validation cohorts were included. A three-step classification process was developed. First, it must be demonstrated that a potential IgG4-RD case has involvement of at least one of 11 possible organs in a manner consistent with IgG4-RD. Second, exclusion criteria consisting of a total of 32 clinical, serological, radiological and pathological items must be applied; the presence of any of these criteria eliminates the patient from IgG4-RD classification. Third, eight weighted inclusion criteria domains, addressing clinical findings, serological results, radiological assessments and pathological interpretations, are applied. In the first validation cohort, a threshold of 20 points had a specificity of 99.2% (95% CI 97.2% to 99.8%) and a sensitivity of 85.5% (95% CI 81.9% to 88.5%). In the second, the specificity was 97.8% (95% CI 93.7% to 99.2%) and the sensitivity was 82.0% (95% CI 77.0% to 86.1%). The criteria were shown to have robust test characteristics over a wide range of thresholds. ACR/EULAR classification criteria for IgG4-RD have been developed and validated in a large cohort of patients. These criteria demonstrate excellent test performance and should contribute substantially to future clinical, epidemiological and basic science investigations.

3.
Front Immunol ; 10: 2855, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31867013

RESUMO

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a small- to medium-vessel necrotizing vasculitis responsible for excess morbidity and mortality (1). The AAVs, which include granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA), are among the most difficult types of vasculitis to treat. Although clinicopathologic disease definitions have been used traditionally to categorize patients into one of these three diagnoses, more recently ANCA specificity for either proteinase 3 (PR3) or myeloperoxidase (MPO) has been advocated for the purpose of disease classification (2). This is because differences in genetics, pathogenesis, risk factors, treatment responses, and outcomes align more closely with PR3- or MPO-ANCA type than with the clinocopathologic diagnosis. Moreover, classifying patients as GPA or MPA can be challenging because biopsies are not obtained routinely in most cases and existing classification systems can provide discrepant classification for the same patient (3). In this review, we address the recent literature supporting the use of ANCA specificity to study and personalize the care of AAV patients (Table 1). We focus particularly on patients with GPA or MPA.

4.
Artigo em Inglês | MEDLINE | ID: mdl-31846030

RESUMO

OBJECTIVE: The objective of this study was to evaluate causes of death in a contemporary inception cohort of ANCA-associated vasculitis patients, stratifying the analysis according to ANCA type. METHODS: We identified a consecutive inception cohort of patients newly diagnosed with ANCA-associated vasculitis from 2002 to 2017 in the Partners HealthCare System and determined vital status through the National Death Index. We determined cumulative mortality incidence and standardized mortality ratios (SMRs) compared with the general population. We compared MPO- and PR3-ANCA+ cases using Cox regression models. RESULTS: The cohort included 484 patients with a mean diagnosis age of 58 years; 40% were male, 65% were MPO-ANCA+, and 65% had renal involvement. During 3385 person-years (PY) of follow-up, 130 patients died, yielding a mortality rate of 38.4/1000 PY and a SMR of 2.3 (95% CI: 1.9, 2.8). The most common causes of death were cardiovascular disease (CVD; cumulative incidence 7.1%), malignancy (5.9%) and infection (4.1%). The SMR for infection was greatest for both MPO- and PR3-ANCA+ patients (16.4 and 6.5). MPO-ANCA+ patients had an elevated SMR for CVD (3.0), respiratory disease (2.4) and renal disease (4.5). PR3- and MPO-ANCA+ patients had an elevated SMR for malignancy (3.7 and 2.7). Compared with PR3-ANCA+ patients, MPO-ANCA+ patients had a higher risk of CVD death [hazard ratio 5.0 (95% CI: 1.2, 21.2]; P = 0.03]. CONCLUSION: Premature ANCA-associated vasculitis mortality is explained by CVD, infection, malignancy, and renal death. CVD is the most common cause of death, but the largest excess mortality risk in PR3- and MPO-ANCA+ patients is associated with infection. MPO-ANCA+ patients are at higher risk of CVD death than PR3-ANCA+ patients.

5.
Nanomedicine (Lond) ; 14(20): 2679-2696, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31668141

RESUMO

Plastic surgery encompasses a broad spectrum of reconstructive challenges and prides itself upon developing and adopting new innovations. Practice has transitioned from microsurgery to supermicrosurgery with a possible future role in even smaller surgical frontiers. Exploiting materials on a nanoscale has enabled better visualization and enhancement of biological processes toward better wound healing, tumor identification and viability of tissues, all cornerstones of plastic surgery practice. Recent advances in nanomedicine and biomimicry herald further reconstructive progress facilitating soft and hard tissue, nerve and vascular engineering. These lay the foundation for improved biocompatibility and tissue integration by the optimization of engineered implants or tissues. This review will broadly examine each of these technologies, highlighting areas of progress that reconstructive surgeons may not be familiar with, which could see adoption into our armamentarium in the not-so-distant future.

6.
Cell ; 179(5): 1098-1111.e23, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31730852

RESUMO

We report a 100-million atom-scale model of an entire cell organelle, a photosynthetic chromatophore vesicle from a purple bacterium, that reveals the cascade of energy conversion steps culminating in the generation of ATP from sunlight. Molecular dynamics simulations of this vesicle elucidate how the integral membrane complexes influence local curvature to tune photoexcitation of pigments. Brownian dynamics of small molecules within the chromatophore probe the mechanisms of directional charge transport under various pH and salinity conditions. Reproducing phenotypic properties from atomistic details, a kinetic model evinces that low-light adaptations of the bacterium emerge as a spontaneous outcome of optimizing the balance between the chromatophore's structural integrity and robust energy conversion. Parallels are drawn with the more universal mitochondrial bioenergetic machinery, from whence molecular-scale insights into the mechanism of cellular aging are inferred. Together, our integrative method and spectroscopic experiments pave the way to first-principles modeling of whole living cells.

7.
Ann Intern Med ; 2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31590183
8.
Arthritis Rheumatol ; 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31612628

RESUMO

OBJECTIVE: Four autoantigens have been described recently in IgG4-related disease (IgG4-RD): prohibitin, annexin A11, laminin 511-E8, and galectin-3. However, no external validation has been performed and the possibility that some individuals break tolerance to more than one autoantigen has not been explored. METHODS: Autoantibody responses against prohibitin, annexin A11 and laminin 511-E8 were measured by ELISA among a clinically diverse cohort of IgG4-RD patients (n=100). Autoantibody responses were correlated with disease severity and organ distribution. RESULTS: The frequencies of IgG4 autoantibody responses against prohibitin (10%), annexin A11 (12%), and laminin 511-E8 (7%) were not significantly different from those of controls. A portion of the cohort (n = 86) had been analyzed previously at our center for anti-galectin-3 antibody responses with 25 (29%) having IgG4 anti-galectin-3 antibodies. Among these 86 subjects, 32 (37%) had IgG4 antibodies to at least one of the 4 auto-antigens and 12 (14%) showed reactivity to ≥2 of the tested antigens. The subset of patients with ≥2 autoantibodies had higher total IgG1, IgG2, IgG4, and C-reactive protein levels; were more commonly hypocomplementemic; and were more likely to have visceral organ involvement. CONCLUSION: Antibodies against prohibitin, annexin A11, and laminin 511-E8 were found in only a small portion of patients with IgG4-RD. A subset of IgG4-RD patients, however, had IgG4 antibodies against ≥2 autoantigens. Patients with antibodies against ≥2 autoantigens present with robust IgG subclass elevations, complement consumption, and visceral organ involvement. This broader break in immunological tolerance in IgG4-RD was associated with more severe disease.

9.
J Chem Inf Model ; 59(10): 4328-4338, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31525965

RESUMO

Compartmentalization is a central theme in biology. Cells are composed of numerous membrane-enclosed structures, evolved to facilitate specific biochemical processes; viruses act as containers of genetic material, optimized to drive infection. Molecular dynamics simulations provide a mechanism to study biomolecular containers and the influence they exert on their environments; however, trajectory analysis software generally lacks knowledge of container interior versus exterior. Further, many relevant container analyses involve large-scale particle tracking endeavors, which may become computationally prohibitive with increasing system size. Here, a novel method based on 3-D ray casting is presented, which rapidly classifies the space surrounding biomolecular containers of arbitrary shape, enabling fast determination of the identities and counts of particles (e.g., solvent molecules) found inside and outside. The method is broadly applicable to the study of containers and enables high-performance characterization of properties such as solvent density, small-molecule transport, transbilayer lipid diffusion, and topology of protein cavities. The method is implemented in VMD, a widely used simulation analysis tool that supports personal computers, clouds, and parallel supercomputers, including ORNL's Summit and Titan and NCSA's Blue Waters, where the method can be employed to efficiently analyze trajectories encompassing millions of particles. The ability to rapidly characterize the spatial relationships of particles relative to a biomolecular container over many trajectory frames, irrespective of large particle counts, enables analysis of containers on a scale that was previously unfeasible, at a level of accuracy that was previously unattainable.

10.
Artigo em Inglês | MEDLINE | ID: mdl-31507077

RESUMO

BACKGROUND: Prior authorizations (PA) are commonly used by health payers as cost-containment strategies for expensive medications, including infused biologics. There is scarce data about the effect of PA requirements on patient-oriented outcomes. METHODS: We included subjects for whom an infusible medication was prescribed for a rheumatologic condition. The exposures of interest were a PA requirement and whether or not the PA was denied. The primary outcome was the difference in days from medication request to infusion. Secondary outcomes included the proportion of denied PAs and differences in glucocorticoid exposure following PA request. RESULTS: Of the 225 subjects, 160 (71%) required a PA. PAs were associated with a greater median (IQR) number of days to infusion compared to cases in which no authorization was required (31 days [15, 60] vs 27 days [13, 41], p=0.045), especially among the 33 (21%) subjects whose PA was denied initially (50 days [31, 76] vs 27 days [13, 41], p<0.001). PA denials were associated with greater median (IQR) prednisone-equivalent glucocorticoid exposure in the 3 months following the request than when a PA was not required (605mg [0, 1575] vs 160mg [0, 675], p=0.01). Twenty-seven (82%) of the 33 PA requests initially denied were eventually approved. Thus, 96% of all PAs were ultimately approved. CONCLUSION: PA requirements are associated with treatment delays and denials are associated with greater glucocorticoid exposure. Because the great majority of PA requests are ultimately approved, the value of PA requirements and their impact on patient safety should be re-evaluated.

11.
Clin Chest Med ; 40(3): 583-597, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31376893

RESUMO

Immunoglobulin G4 (IgG4)-Related Disease (IgG4-RD) can cause fibroinflammatory lesions in nearly any organ and lead to organ dysfunction and irreversible damage. In addition to frequent involvement of the salivary glands, lacrimal glands, and/or pancreas, IgG4-RD often affects the chest. Thoracic manifestations include lung nodules and consolidations, pleural thickening, aortitis, and lymphadenopathy. The diagnosis is made after careful clinicopathologic correlation because there is no single diagnostic test with excellent sensitivity or specificity. Biopsy of pulmonary lesions can be useful for distinguishing IgG4-RD from common mimickers. Immunosuppressive regimens, such as glucocorticoids and/or glucocorticoid-sparing agents, form the cornerstone of treatment.

12.
Arthritis Rheumatol ; 2019 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-31403264
13.
Artigo em Inglês | MEDLINE | ID: mdl-31319101

RESUMO

BACKGROUND: IgG4-related disease (IgG4-RD) is a fibroinflammatory condition marked by rapid clinical improvement after selective depletion of B lymphocytes with rituximab. This feature suggests that B cells might participate in fibrogenesis and wound healing. OBJECTIVE: In the present work we aimed to demonstrate that B lymphocytes contribute directly to tissue fibrosis in patients with IgG4-RD. METHODS: Total circulating CD19+ B lymphocytes, naive B cells, memory B cells, or plasmablasts from patients with IgG4-RD were cultivated with human fibroblasts. Profibrotic soluble factors and collagen production in cocultures were assessed by using ELISAs and Luminex assays. RNA sequencing and quantitative RT-PCR were used to assess fibroblast activation in the presence of B cells, as well as induction of profibrotic pathways in B-cell subsets. Relevant profibrotic and inflammatory molecules were confirmed in vitro by using functional experiments and on IgG4-RD tissue sections by using multicolor immunofluorescence studies. RESULTS: B cells from patients with IgG4-RD (1) produced the profibrotic molecule platelet-derived growth factor B and stimulated collagen production by fibroblasts; (2) expressed enzymes implicated in extracellular matrix remodeling, such as lysyl oxidase homolog 2; (3) produced the chemotactic factors CCL4, CCL5, and CCL11; and (4) induced production of these same chemokines by activated fibroblasts. Plasmablasts expressed sets of genes implicated in fibroblast activation and proliferation and therefore represent cells with intrinsic profibrotic properties. CONCLUSION: We have demonstrated that B cells contribute directly to tissue fibrosis in patients with IgG4-RD. These unanticipated profibrotic properties of B lymphocytes, particularly plasmablasts, might be relevant for fibrogenesis in patients with other fibroinflammatory disorders and for wound-healing processes in physiologic conditions.

14.
J Autoimmun ; 105: 102302, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31320177

RESUMO

OBJECTIVE: To investigate serum IL-6 (sIL-6) levels during active disease, complete remission (CR), and relapse in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), and to explore the association of changes in sIL-6 with clinical outcomes. METHODS: sIL-6 levels were measured at baseline and longitudinally over 18 months, in 78 patients with AAV enrolled in a randomized controlled trial comparing treatment with either rituximab (RTX) or cyclophosphamide (CYC)/azathioprine (AZA). Outcome variables included baseline clinical features, ANCA specificity, disease activity (active disease versus CR), time to relapse events, B cell repopulation, and ANCA titer increases. RESULTS: At baseline, sIL6 levels were detectable in 81% of patients; 73% (n = 57) of subjects were proteinase 3 (PR3)-ANCA positive, sIL-6 levels were higher in subjects with PR3-ANCAs and positively correlated with their levels (rs = 0.36,p < 0.01), but not with levels of myeloperoxidase (MPO)-ANCA (rs = -0.17,p = 0.47). Higher baseline sIL-6 levels were associated with PR3-ANCA positivity, fever, pulmonary nodules/cavities, conductive deafness, and absence of urinary red blood cell casts (p < 0.05). Baseline sIL6 levels did not predict CR at month 6 (p = 0.71), and the median sIL-6 level declined from baseline with induction therapy, regardless of CR achievement. An increase in sIL-6 during CR was a predictor for subsequent severe relapse in RTX-treated patients (hazard ratio (HR):7.24,p = 0.01), but not in CYC/AZA-treated patients (HR:0.62,p = 0.50). In contrast, a sIL-6 increase did not predict B cell repopulation or ANCA titer increase in either treatment arm (p > 0.05). CONCLUSION: At baseline, sIL-6 concentrations correlate with PR3-ANCA titers and are associated with specific clinical manifestations of AAV. Baseline sIL6 concentrations do not predict CR at 6 months, but the increase in sIL-6 concentrations during CR is associated with subsequent severe relapse among RTX-treated patients. Further investigation into the mechanistic role of IL6 in AAV might lead to identifying this pathway as a potential therapeutic target in this disease.

15.
Arthritis Rheumatol ; 71(11): 1888-1893, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31216123

RESUMO

OBJECTIVE: To assess the frequency of venous thromboembolism (VTE) events in the Rituximab in Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis (RAVE) trial and identify novel potential risk factors. METHODS: VTE events in 197 patients enrolled in the RAVE trial were analyzed. Baseline demographic and clinical characteristics were recorded, and univariate and multivariate analyses were performed to identify factors associated with VTE in ANCA-associated vasculitis (AAV). RESULTS: VTE occurred in 16 patients (8.1%) with an overall average time to event of 1.5 months (range 1.0-2.75). In univariate analyses with calculation of hazard ratios (HRs) and 95% confidence intervals (95% CIs), heart involvement (HR 17.408 [95% CI 2.247-134.842]; P = 0.006), positive proteinase 3 (PR3)-ANCA (HR 7.731 [95% CI 1.021-58.545]; P = 0.048), pulmonary hemorrhage (HR 3.889 [95% CI 1.448-10.448]; P = 0.008), and the presence of red blood cell casts (HR 15.617 [95% CI 3.491-69.854]; P < 0.001) were associated with the onset of VTE. In multivariate models adjusted for age and sex, the significant associations between VTE events and heart involvement (HR 21.836 [95% CI 2.566-185.805]; P = 0.005), PR3-ANCA (HR 9.12 [95% CI 1.158-71.839]; P = 0.036), pulmonary hemorrhage (HR 3.91 [95% CI 1.453-10.522]; P = 0.007), and urinary red blood cell casts (HR 16.455 [95% CI 3.607-75.075]; P < 0.001) remained. CONCLUSION: Patients diagnosed as having AAV with pulmonary hemorrhage, positive PR3-ANCA, heart involvement, and the presence of red blood cell casts are at an increased risk to develop VTE. Further studies are needed to confirm and expand these findings and to explore the mechanisms of hypercoagulability in these patients with the aim of informing potential targets for therapeutic intervention.

16.
Arthritis Rheumatol ; 71(11): 1879-1887, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31162829

RESUMO

OBJECTIVE: Patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) have an elevated risk of cardiovascular disease (CVD). This study was undertaken to develop a clearer understanding of the association between changes in disease activity and lipid levels in AAV, which may inform CVD risk stratification in this population. METHODS: Lipid levels were assessed in stored serum samples (obtained at baseline and month 6) from the Rituximab for ANCA-Associated Vasculitis (RAVE) trial, which randomized patients to receive either rituximab or cyclophosphamide followed by azathioprine. Paired t-tests and multivariable linear regression were used to assess changes in lipid levels. RESULTS: Of the 142 patients with serum samples available, the mean ± SD age was 52.3 ± 14.7 years, 72 (51%) were male, 95 (67%) were proteinase 3 (PR3)-ANCA positive, 72 (51%) had received a new diagnosis of AAV, and 75 (53%) were treated with rituximab. Several lipid levels increased between baseline and month 6, including total cholesterol (+12.4 mg/dl [95% confidence interval (95% CI) +7.1, +21.0]), low-density lipoprotein (+10.3 mg/dl [95% CI +6.1, +17.1]), and apolipoprotein B (+3.5 mg/dl [95% CI +1.0, +8.3]). These changes were observed among newly diagnosed and PR3-ANCA-positive patients but not among those with relapsing disease or myeloperoxidase-ANCA-positive patients. There was no difference in change in lipid levels between rituximab-treated patients and cyclophosphamide-treated patients. Changes in lipid levels correlated with changes in erythrocyte sedimentation rate but not with other inflammatory markers or glucocorticoid exposure. CONCLUSION: Lipid levels increased during remission induction among patients with newly diagnosed AAV and those who were PR3-ANCA positive. Disease activity and ANCA type should be considered when assessing lipid profiles to stratify CVD risk in patients with AAV.

17.
AMA J Ethics ; 21(6): E493-498, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31204989

RESUMO

This article analyzes a child psychiatrist's referral approach when the patient's care must be transferred to an adult psychiatrist and the otherwise best adult psychiatrist has "accented" language, which is associated with the patient's prior trauma. The analysis considers the value of simplicity and a related "simplicity strategy," revealing that many ethical factors lay behind the simplicity approach. The inquiry then addresses simplicity regarding practical wisdom and context. The paper argues that simplicity should mean considering just what's relevant and no more. Applied to the case, simplicity includes respect for persons, openness, honesty, trustworthiness, beneficence, nonmaleficence, ethics of care, professional empathy, group inquiry, epistemic humility, and justice. An objection regarding undue complexity is noted and refuted.

18.
Medicine (Baltimore) ; 98(20): e15616, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31096469

RESUMO

RATIONALE: IgG4-related disease (IgG4-RD) is a multiorgan disease of unestablished prevalence that is characterized histopathologically by a dense lymphoplasmacytic infiltrate enriched with IgG4-expressing plasma cells and associated with storiform fibrosis. Tubulointerstitial nephritis (TIN) is the most common renal manifestation of IgG4-RD, but membranous nephropathy (MN) has also been described and often occurs in the context of concurrent TIN. Patients with IgG4-related MN have been characteristically negative for autoantibodies to the phospholipase A2 receptor (PLA2R). PATIENT CONCERNS: A 45-year-old man presented with abdominal pain and lower extremity edema. DIAGNOSIS: Histopathological evaluation of pancreas and liver biopsies established a diagnosis of IgG4-RD. Renal biopsy confirmed a diagnosis of PLA2R-associated MN without evidence of concurrent TIN. INTERVENTIONS: The patient was treated with rituximab, a short course of low-dose, oral cyclophosphamide, and a rapid glucocorticoid taper. OUTCOMES: The patient achieved remission of MN after 8 months of therapy and maintained remission of IgG4-RD. LESSONS: PLA2R-associated MN may be a rare manifestation of IgG4-RD. Systematic evaluation of larger cohorts of IgG4-RD patients for the presence of PLA2R autoantibodies and the investigation of PLA2R-associated MN cohorts for evidence of IgG4-RD would facilitate the understanding of the nature of the relationship between these observations.


Assuntos
Glomerulonefrite Membranosa/complicações , Doença Relacionada a Imunoglobulina G4/complicações , Receptores da Fosfolipase A2/imunologia , Glomerulonefrite Membranosa/imunologia , Humanos , Imunoglobulina G/sangue , Doença Relacionada a Imunoglobulina G4/imunologia , Masculino , Pessoa de Meia-Idade
19.
Mol Genet Genomic Med ; 7(6): e686, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30993913

RESUMO

BACKGROUND: Family screening of a 48-year-old male with recently diagnosed IgG4-related disease (IgG4-RD) revealed unanticipated elevations in plasma IgG4 in his two healthy teenaged sons. METHODS: We performed gene sequencing, immune cell studies, HLA typing, and analyses of circulating cytotoxic CD4+ T lymphocytes and plasmablasts to seek clues to pathogenesis. DNA from a separate cohort of 99 patients with known IgG4-RD was also sequenced for the presence of genetic variants in a specific gene, FGFBP2. RESULTS: The three share a previously unreported heterozygous single base deletion in fibroblast growth factor binding protein type 2 (FGFBP2), which causes a frameshift in the coding sequence. The FGFBP2 protein is secreted by cytotoxic T-lymphocytes and binds fibroblast growth factor. The variant sequence in the FGFBP2 protein is predicted to form a disordered random coil rather than a helical-turn-helix structure, unable to adopt a stable conformation. The proband and the two sons had 5-10-fold higher numbers of circulating cytotoxic CD4 + T cells and plasmablasts compared to matched controls. The three members also share a homozygous missense common variant in FGFBP2 found in heterozygous form in ~40% of the population. This common variant was found in 73% of an independent, well characterized IgG4-RD cohort, showing enrichment in idiopathic IgG4-RD. CONCLUSIONS: The presence of a shared deleterious variant and homozygous common variant in FGFBP2 in the proband and sons strongly implicates this cytotoxic T cell product in the pathophysiology of IgG4-RD. The high prevalence of a common FGFBP2 variant in sporadic IgG4-RD supports the likelihood of participation in disease.

20.
Arthritis Rheumatol ; 71(8): 1329-1338, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30835950

RESUMO

OBJECTIVE: This study was undertaken to evaluate glucocorticoid dosages and serologic findings in patients with giant cell arteritis (GCA) flares. METHODS: Patients with GCA were randomly assigned to receive double-blind dosing with either subcutaneous tocilizumab (TCZ) 162 mg weekly plus 26-week prednisone taper (TCZ-QW + Pred-26), every-other-week TCZ plus 26-week prednisone taper (TCZ-Q2W + Pred-26), placebo plus 26-week prednisone taper (PBO + Pred-26), or placebo plus 52-week prednisone taper (PBO + Pred-52). Outcome measures were prednisone dosage, C-reactive protein (CRP) level, and erythrocyte sedimentation rate (ESR) at the time of flare. RESULTS: One hundred patients received TCZ-QW + Pred-26, 49 received TCZ-Q2W + Pred-26, 50 received PBO + Pred-26, and 51 received PBO + Pred-52. Of the 149 TCZ-treated patients, 36 (24%) experienced flare, 23 (64%) of whom were still receiving prednisone (median dosage 2.0 mg/day). Among 101 PBO + Pred-treated patients, 59 (58%) experienced flare, 45 (76%) of whom were receiving prednisone (median dosage 5.0 mg/day). Many flares occurred while patients were taking >10 mg/day prednisone: 9 (25%) in the TCZ groups and 13 (22%) in the placebo groups. Thirty-three flares (92%) in TCZ-treated groups and 20 (34%) in PBO + Pred-treated groups occurred with normal CRP levels. More than half of the PBO + Pred-treated patients had elevated CRP levels without flares. Benefits of the TCZ and prednisone combination over prednisone alone for remission induction were apparent by 8 weeks. CONCLUSION: Most GCA flares occurred while patients were still receiving prednisone. Acute-phase reactant levels were not reliable indicators of flare in patients treated with TCZ plus prednisone or with prednisone alone. The addition of TCZ to prednisone facilitates earlier GCA control.

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