Objective
Riedel's thyroiditis is a chronic fibrosing disorder of unknown etiology often associated with “multifocal fibrosclerosis.” IgG4‐related systemic disease is characterized by IgG4+ plasma ...cell infiltration and fibrosis throughout many organs. We hypothesized that Riedel's thyroiditis is part of the IgG4‐related systemic disease spectrum.
Methods
We searched our institution's pathology database using the terms “Riedel's,” “struma,” “thyroid,” and “fibrosis,” and identified 3 cases of Riedel's thyroiditis. Riedel's thyroiditis was diagnosed if there was a fibroinflammatory process involving all or a portion of the thyroid gland, with evidence of extension of the process into surrounding tissues. Immunohistochemical stains for IgG4 and IgG were performed. The histopathologic and immunohistochemical features of each involved organ were evaluated. The clinical features of one patient with multiple organ system disease were described.
Results
All 3 thyroidectomy samples stained positively for IgG4‐bearing plasma cells. One patient had extensive extrathyroidal involvement diagnostic of IgG4‐related systemic disease, including cholangitis, pseudotumors of both the lung and lacrimal gland, and a lymph node contiguous to the thyroid that stained intensely for IgG4+ plasma cells. The histologic features of all organs involved were consistent with IgG4‐related systemic disease. Patient 3 had 10 IgG4+ plasma cells per high‐power field initially, but rebiopsy 2 years later demonstrated no IgG4+ plasma cells. That patient's second biopsy, characterized by fibrosis and minimal residual inflammation, further solidifies the link between IgG4‐bearing plasma cells in tissue and the histologic evolution to Riedel's thyroiditis.
Conclusion
Riedel's thyroiditis is part of the IgG4‐related systemic disease spectrum. In many cases, multifocal fibrosclerosis and IgG4‐related systemic disease are probably the same entity.
Objective
IgG4‐related disease (IgG4‐RD) can cause fibroinflammatory lesions in nearly any organ, leading to organ dysfunction and failure. The IgG4‐RD Responder Index (RI) was developed to help ...investigators assess the efficacy of treatment in a structured manner. The aim of this study was to validate the RI in a multinational investigation.
Methods
The RI guides investigators through assessments of disease activity and damage in 25 domains, incorporating higher weights for disease manifestations that require urgent treatment or that worsen despite treatment. After a training exercise, investigators reviewed 12 written IgG4‐RD vignettes based on real patients. Investigators calculated both an RI score as well as a physician's global assessment (PhGA) score for each vignette. In a longitudinal assessment, 3 investigators used the RI in 15 patients with newly active disease who were followed up over serial visits after treatment. We assessed interrater and intrarater reliability, precision, validity, and responsiveness.
Results
The 26 physician investigators included representatives from 6 specialties and 9 countries. The interrater and intrarater reliability of the RI was strong (0.89 and 0.69, respectively). Correlations (construct validity) between the RI and PhGA were high (Spearman's r = 0.9, P < 0.0001). The RI was sensitive to change (discriminant validity). Following treatment, there was significant improvement in the RI score (mean change 10.5 95% confidence interval (95% CI) 5.4–12, P < 0.001), which correlated with the change in the PhGA. Urgent disease and damage were captured effectively.
Discussion
In this international, multispecialty study, we observed that the RI is a valid and reliable disease activity assessment tool that can be used to measure response to therapy.
Hypertrophic pachymeningitis (HP) is an inflammatory condition in which the dura mater of the cranium or spine becomes thickened, leading to symptoms that result from mass effect, nerve compression, ...or vascular compromise. The differential diagnosis of HP includes immune-mediated conditions such as rheumatoid arthritis and vasculitis, malignancies, and infections. Many times, no diagnosis is reached; in such cases, the disease has been described as idiopathic HP. IgG4-related disease (IgG4-RD) is a recently described inflammatory condition known to cause tumefactive lesions at myriad anatomical locations. Both IgG4-RD and idiopathic HP share similar demographics, histopathology, and natural history. We hypothesized that IgG4-RD is a common cause of idiopathic HP.To investigate this hypothesis, we identified all pathology specimens diagnosed as noninfectious HP during 25 years at our institution. Fourteen cases had stained slides and paraffin blocks to permit review of the original hematoxylin and eosin stained slides as well as immunostaining of cell blocks. Recently published consensus guidelines describing characteristic histopathology and the necessary quantity of IgG4+ plasma cell infiltrate were used to diagnose IgG4-RD.Four cases (66.6%) that had been regarded previously as representing idiopathic HP were diagnosed as IgG4-RD; of all the reviewed cases, IgG4-RD represented 29% of cases. Of the remaining cases, 3 cases were associated with granulomatosis with polyangiitis (GPA), 2 with lymphoma, and 1 each with rheumatoid arthritis, giant cell arteritis, and sarcoidosis. Two of the cases could not be diagnosed more precisely and were classified as undifferentiated HP. Clinical history, serologic tests, cerebrospinal fluid studies, and radiology alone could not identify the cause of HP. Rather, biopsy with histopathology and immunostaining was necessary to reach an accurate diagnosis. Significant IgG4+ plasma cell infiltrates were observed in rheumatoid arthritis, granulomatosis with polyangiitis, and lymphoma, underscoring the importance of histopathology in making the diagnosis of IgG4-RD.This case series demonstrates that IgG4-RD may be the most common etiology of noninfectious HP and highlights the necessity of biopsy for accurate diagnosis.
Objective
In this pilot study, we used untargeted metabolomics to identify biochemical mechanisms or biomarkers potentially underlying SLE-related fatigue.
Methods
Metabolon conducted untargeted ...metabolomic plasma profiling using ultrahigh performance liquid chromatography/tandem mass spectrometry on plasma samples of 23 Black females with systemic lupus erythematosus (SLE) and 21 no SLE controls. Fatigue phenotypes of general fatigue, physical fatigue, mental fatigue, reduced activity, and reduced motivation were measured with the reliable and valid Multidimensional Fatigue Inventory (MFI).
Results
A total of 290 metabolites were significantly different between the SLE and no SLE groups, encompassing metabolites related to glycolysis, TCA cycle activity, heme catabolism, branched chain amino acids, fatty acid metabolism, and steroids. Within the SLE group, controlling for age and co-morbidities, TCA cycle metabolites of alpha-ketoglutarate (AKG) and succinate were statistically significantly associated (p < .05) with physical and general fatigue.
Conclusion
While pervasive perturbations in the entire TCA cycle have been implicated as a potential mechanism for fatigue, our results suggest individual metabolites of AKG and succinate may be potential biomarkers or targets of intervention for fatigue symptom management in SLE. Additionally, perturbations in heme metabolism in the SLE group provide additional insights into mechanisms that promote systemic inflammation.
Abstract IgG4-related systemic disease (IgG4-RD) is an inflammatory condition of unknown etiology that has been identified as the cause of tumefactive lesions in a number of tissues and organs. The ...role of the IgG4 remains to be clarified fully, but the histopathologic diagnosis hinges upon the finding of IgG4-bearing plasma cells in addition to characteristic morphologic features, with or without elevated seum IgG4. We present a 56-year-old man with orbital pseudotumor in whom, after 30 years of intractable disease, biopsy showed IgG4-RD involving the lacrimal gland, extraocular muscles, intraconal fat, and trigeminal nerve. Six months after initiating treatment with rituximab, his disease remained dormant, with improvement in his proptosis and normalization of serum IgG4 levels. We review the differential of idiopathic orbital inflammatory disease, including IgG4-RD, and emphasize the need for biopsy for accurate diagnosis and to guide appropriate treatment.
Development of an IgG4-RD Responder Index Carruthers, Mollie N.; Stone, John H.; Deshpande, Vikram ...
International Journal of Rheumatology,
01/2012, Volume:
2012
Journal Article
Peer reviewed
Open access
IgG4-related disease (IgG4-RD) is a multiorgan inflammatory disease in which diverse organ manifestations are linked by common histopathological and immunohistochemical features. Prospective studies ...of IgG4-RD patients are required to clarify the natural history, long-term prognosis, and treatment approaches in this recently recognized condition. Patients with IgG4-RD have different organ manifestations and are followed by multiple specialties. Divergent approaches to the assessment of patients can complicate the interpretation of studies, emphasizing the critical need for validated outcome measures, particularly assessments of disease activity and response to treatment. We developed a prototype IgG4-RD Responder Index (IgG4-RD RI) based on the approach used in the development of the Birmingham Vasculitis Activity Score for Wegener’s granulomatosis (BVAS/WG). The IgG4-RD RI was refined by members of the International IgG4-RD Symposium Organizing Committee in a paper case exercise. The revised instrument was applied retrospectively to fifteen IgG4-RD patients at our institution. Those scores were compared to physician’s global assessment scale for the same visits. This paper describes the philosophy and goals of the IgG4-RD RI, the steps in the development of this instrument to date, and future plans for validation of this instrument as an outcome measure.
Eosinophilic angiocentric fibrosis (EAF) is an uncommon tumefactive lesion of the orbit and upper respiratory tract of unknown etiology. The condition is characterized histologically by concentric ...layers of fibrosis around small-caliber arteries and a mixed inflammatory infiltrate dominated by eosinophils. After the serendipitous observation of an elevated serum concentration of IgG4 in 1 patient with EAF, we investigated the hypothesis that EAF is an IgG4-related systemic disease.
We retrospectively identified 5 EAF cases from our files. Demographic, clinical, and serological data were reviewed, and the histologic features and tissue IgG4 staining patterns were examined on biopsies from each case.
Patients (2 male, 3 female) ranged in age from 31 to 82 years (mean, 56 y). The extent of disease varied from isolated involvement of the nasal cavity or the lacrimal gland to multicentric disease affecting the sinuses, nasal tract, and lower respiratory tract. The duration of symptoms ranged from 6 months to >20 years. The demographic features of the patients and disease extent were consistent with previously published reports of EAF, except for involvement of the lower respiratory tract in 1 case. Four of the 5 cases showed concentric perivascular fibrosis surrounding small-caliber vascular channels, embedded in an inflammatory infiltrate composed of lymphocytes, plasma cells, and eosinophils. One lacrimal gland biopsy showed a periductal inflammatory infiltrate, and 2 cases showed a storiform pattern of fibrosis. The index case had a serum IgG4 concentration of 1490 mg/dL (normal, 8 to 140 mg/dL). IgG4-positive plasma cells were identified in biopsies from 4 of the 5 cases. The numbers of IgG4-positive plasma cells ranged from 43 to 118 per high-power field, and the IgG4:IgG ratios ranged from 0.68 to 0.97. Neither IgG4-bearing nor IgG-bearing plasma cells were identified in 1 patient, whose longstanding disease was characterized principally by concentric perivascular fibrosis.
Our data suggest that EAF is part of the spectrum of IgG4-related systemic disease.
There are few reports of COVID-19 in pediatric patients with rheumatic diseases. This study describes the clinical presentation and outcomes of COVID-19 in this population.
We analyzed a ...single-center case series of pediatric patients with rheumatic diseases and laboratory-confirmed COVID-19. Demographic, baseline and COVID-19 associated clinical features were compared between ambulatory and hospitalized patients using univariate analysis.
Fifty-five cases were identified: 45 (81.8%) in the ambulatory group and 10 (18.2%) hospitalized. African American race (OR 7.78; 95% CI 1.46-55.38; p = 0.006) and cardiovascular disease (OR 19.40; 95% CI 2.45-254.14; p = 0.001) predominated in hospitalized patients. Active rheumatic disease (OR 11.83; 95% CI 1.43-558.37; p = 0.01), medium/high-dose corticosteroid use (OR 14.12; 95% CI 2.31-106.04; p = 0.001), mycophenolate use (OR 8.84; 95% CI 1.64-63.88; p = 0.004), rituximab use (OR 19.40; 95% CI 2.45-254.14; p = 0.001) and severe immunosuppression (OR 34.80; 95% CI 3.94-1704.26; p = < 0.001) were associated with increased odds of hospitalization. Fever (OR 7.78; 95% CI 1.46-55.38; p = 0.006), dyspnea (OR 26.28; 95% CI 2.17-1459.25; p = 0.003), chest pain (OR 13.20; 95% CI 1.53-175.79; p = 0.007), and rash (OR 26.28; 95% CI 2.17-1459.25; p = 0.003) were more commonly observed in hospitalized patients. Rheumatic disease flares were almost exclusive to hospitalized patients (OR 55.95; 95% CI 5.16-3023.74; p < 0.001).. One patient did not survive.
Medium/high-dose corticosteroid, mycophenolate and rituximab use, and severe immunosuppression were risk factors for hospitalization. Fever, dyspnea, chest pain, and rash were high-risk symptoms for hospitalization. Rheumatic disease activity and flare could contribute to the need for hospitalization.
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multiple autoantibody types, some of which are produced by long-lived plasma cells (LLPC). Active SLE generates increased ...circulating antibody-secreting cells (ASC). Here, we examine the phenotypic, molecular, structural, and functional features of ASC in SLE. Relative to post-vaccination ASC in healthy controls, circulating blood ASC from patients with active SLE are enriched with newly generated mature CD19
CD138
ASC, similar to bone marrow LLPC. ASC from patients with SLE displayed morphological features of premature maturation and a transcriptome epigenetically initiated in SLE B cells. ASC from patients with SLE exhibited elevated protein levels of CXCR4, CXCR3 and CD138, along with molecular programs that promote survival. Furthermore, they demonstrate autocrine production of APRIL and IL-10, which contributed to their prolonged in vitro survival. Our work provides insight into the mechanisms of generation, expansion, maturation and survival of SLE ASC.
Fetal survival during gestation implies that tolerance mechanisms suppress the maternal immune response to paternally inherited alloantigens. Here we show that the inhibitory T cell costimulatory ...molecule, programmed death ligand 1 (PDL1), has an important role in conferring fetomaternal tolerance in an allogeneic pregnancy model. Blockade of PDL1 signaling during murine pregnancy resulted in increased rejection rates of allogeneic concepti but not syngeneic concepti. Fetal rejection was T cell- but not B cell-dependent because PDL1-specific antibody treatment caused fetal rejection in B cell-deficient but not in RAG-1-deficient females. Blockade of PDL1 also resulted in a significant increase in the frequency of IFN-gamma-producing lymphocytes in response to alloantigen in an ELISPOT assay and higher IFN-gamma levels in placental homogenates by ELISA. Finally, PDL1-deficient females exhibited decreased allogeneic fetal survival rates as compared with littermate and heterozygote controls and showed evidence of expansion of T helper type 1 immune responses in vivo. These results provide the first evidence that PDL1 is involved in fetomaternal tolerance.
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