Stabilization of kidney function and reduction in heart failure events with sodium-glucose co-transporter 2 inhibitors: A meta-analysis and meta-regression analysis.

AIMS: Sodium-glucose co-transporter 2 (SGLT2) inhibitors reduce the risk of heart failure (HF) events regardless of diabetes status. However, factors associated with their efficacy in HF reduction remain unknown. This study aims to identify clinically relevant markers for the efficacy of SGLT2 inhibitors in HF risk reduction. MATERIALS AND METHODS: We searched PubMed/MEDLINE and EMBASE for randomized placebo-controlled trials of SGLT2 inhibitors reporting a composite of HF hospitalization or cardiovascular death in participants with or without type 2 diabetes published until 28 February 2023. Random-effects meta-analysis and mixed-effects meta-regression were conducted to evaluate the association between the outcomes and clinical variables, including changes in glycated haemoglobin, body weight, systolic blood pressure, haematocrit and overall/chronic estimated glomerular filtration rate (eGFR) slope. RESULTS: Thirteen trials with 90 413 participants were included. SGLT2 inhibitors reduced the hazard ratio of the composite of HF hospitalization or cardiovascular death (hazard ratio 0.77; 95% confidence interval, 0.74-0.81; p < .0001). In meta-regression analysis, chronic eGFR slope (eGFR change after the initial dip) was significantly associated with the composite outcome (p = .017), and each 1 ml/min/1.73 m2 /year improvement in chronic eGFR slope led to a 14% reduction in the composite outcome. By contrast, changes in the other parameters showed no significant associations. CONCLUSIONS: Improvement in chronic eGFR slope, which reflects the stabilization of kidney function, is significantly associated with the efficacy of the SGLT2 inhibitor in HF, highlighting the cardiorenal axis role in the beneficial effects on HF. The chronic eGFR slope can be a surrogate marker of the effects of SGLT2 inhibitors on HF reduction.

Mevalonate biosynthesis pathway regulates the development and survival of brown adipocytes.

The high thermogenic activity of brown adipose tissue (BAT) has received considerable attention. Here, we demonstrated the role of the mevalonate (MVA) biosynthesis pathway in the regulation of brown adipocyte development and survival. The inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the rate-limiting enzyme in the MVA pathway and the molecular target of statins, suppressed brown adipocyte differentiation by suppressing protein geranylgeranylation-mediated mitotic clonal expansion. The development of BAT in neonatal mice exposed to statins during the fetal period was severely impaired. Moreover, statin-induced geranylgeranyl pyrophosphate (GGPP) deficiency led to the apoptosis of mature brown adipocytes. Brown adipocyte-specific Hmgcr knockout induced BAT atrophy and disrupted thermogenesis. Importantly, both genetic and pharmacological inhibition of HMGCR in adult mice induced morphological changes in BAT accompanied by an increase in apoptosis, and statin-treated diabetic mice showed worsened hyperglycemia. These findings revealed that MVA pathway-generated GGPP is indispensable for BAT development and survival.

Efficacy of antihyperglycemic therapies on cardiovascular and heart failure outcomes: an updated meta-analysis and meta-regression analysis of 35 randomized cardiovascular outcome trials.

BACKGROUND: Effects of antihyperglycemic therapies on cardiovascular and heart failure (HF) risks have varied widely across cardiovascular outcome trials (CVOTs), and underlying factors remain incompletely understood. We aimed to determine the relationships of glycated hemoglobin (HbA1c) or bodyweight changes with these outcomes in all CVOTs of antihyperglycemic therapies. METHODS: We searched PubMed and EMBASE up to 25 January 2023 for all randomized controlled CVOTs of antihyperglycemic therapies reporting both major adverse cardiovascular events (MACE) and HF outcomes in patients with type 2 diabetes or prediabetes. We performed meta-regression analyses following random-effects meta-analyses to evaluate the effects of HbA1c or bodyweight reductions on each outcome. RESULTS: Thirty-five trials comprising 256,524 patients were included. Overall, antihyperglycemic therapies reduced MACE by 9% [risk ratio (RR): 0.91; 95% confidence interval (CI) 0.88-0.94; P < 0.001; I2 = 36.5%]. In meta-regression, every 1% greater reduction in HbA1c was associated with a 14% reduction in the RR of MACE (95% CI 4-24; P = 0.010), whereas bodyweight change was not associated with the RR of MACE. The magnitude of the reduction in MACE risk associated with HbA1c reduction was greater in trials with a higher baseline prevalence of atherosclerotic cardiovascular disease. On the other hand, antihyperglycemic therapies showed no overall significant effect on HF (RR: 0.95; 95% CI 0.87-1.04; P = 0.28; I2 = 75.9%). In a subgroup analysis based on intervention type, sodium-glucose cotransporter-2 inhibitors (SGLT2i) conferred the greatest HF risk reduction (RR: 0.68; 95% CI 0.62-0.75; P < 0.001; I2 = 0.0%). In meta-regression, every 1 kg bodyweight reduction, but not HbA1c reduction, was found to reduce the RR of HF by 7% (95% CI 4-10; P < 0.001); however, significant residual heterogeneity (P < 0.001) was observed, and SGLT2i reduced HF more than could be explained by HbA1c or bodyweight reductions. CONCLUSIONS: Antihyperglycemic therapies reduce MACE in an HbA1c-dependent manner. These findings indicate that HbA1c can be a useful marker of MACE risk reduction across a wide range of antihyperglycemic therapies, including drugs with pleiotropic effects. In contrast, HF is reduced not in an HbA1c-dependent but in a bodyweight-dependent manner. Notably, SGLT2i have shown class-specific benefits for HF beyond HbA1c or bodyweight reductions.

Management of sarcopenia in patients with rheumatoid arthritis.

This review summarizes the evidence for the management of sarcopenia in patients with rheumatoid arthritis (RA) in terms of drugs, exercise, and nutrition. Sarcopenia is a decrease in skeletal muscle mass and muscle strength or physical function. The prevalence of sarcopenia in patients with RA is higher than that in the general population. The treatment and management of sarcopenia in patients with RA are clinically important for long-term prognosis. One of the mechanisms of muscle metabolism is the pro-inflammatory cytokine pathway, which involves tumour necrosis factor α and interleukin-6, and is a common pathway in the pathogenesis of RA. Thus, tumour necrosis factor α and interleukin-6 inhibitors may play a potential role in controlling sarcopenia. In exercise therapy, a combination of moderate resistance and aerobic exercise may be effective in improving muscle strength, muscle mass, and physical function; however, intense exercise may exacerbate the inflammatory response in RA. Regarding nutrition, protein intake is generally considered beneficial, but other nutrients such as vitamin D and carotenoids have also been studied. Overall, there remains a lack of concrete evidence on sarcopenia treatment and management in patients with RA from any perspective; more longitudinal and intervention studies are needed in the future.

High plasma homocysteine level is associated with increased prevalence of the non-remission state in rheumatoid arthritis: Findings from the KURAMA cohort.

OBJECTIVES: We aimed to determine the clinical impact of plasma homocysteine levels on disease activity and clinical remission in patients with rheumatoid arthritis (RA). METHODS: A cross-sectional study was conducted using KURAMA (Kyoto University Rheumatoid Arthritis Management Alliance) database. We enrolled 291 female patients, who were treated in a treat-to-target manner. We measured plasma total homocysteine using a liquid chromatography-tandem mass spectrometry system and collected clinical data including a 28-joint RA disease activity score-erythrocyte sedimentation rate (DAS28-ESR). Clinical remission of disease activity was defined as a DAS28-ESR < 2.6. RESULTS: In a univariable analysis, the plasma homocysteine concentration was significantly and positively associated with DAS-28-ESR and was higher in the non-remission group than in the remission group. The cutoff value of the plasma homocysteine level was calculated to be 7.9 nmol/mL by the test of the receiver operating characteristic curve analysis. In a multivariable analysis, after adjusting for clinically relevant variables, the high homocysteine level remained a significant positive association for DAS28-ESR (estimate 0.27, P = .0019) and a positive factor for the presence of RA non-remission (odds ratio 2.39, P = .0071). CONCLUSIONS: Increased plasma homocysteine levels showed a significant positive association with current disease activity and the non-remission state in female patients with RA under treat-to-target treatment. The findings suggest the potential utility of plasma homocysteine as a disease state marker reflecting conditions that are treatment failure and difficult to remission and may provide clinical evidence on the interplay between homocysteine and inflammatory activation in RA.

Liver autophagy-induced valine and leucine in plasma reflect the metabolic effect of sodium glucose co-transporter 2 inhibitor dapagliflozin.

BACKGROUND: Sodium glucose co-transporter 2 (SGLT2) inhibitors are anti-diabetic drugs for type 2 diabetes that lower blood glucose levels and body weight. It is of special interest that SGLT2 inhibitors also improve liver metabolism and fatty liver. Liver is an important organ in regulation of energy metabolism, but the metabolic action of SGLT inhibitors in liver remains unclear. METHODS: We investigated the factors associated with the beneficial effects of dapagliflozin, a SGLT2 inhibitor, in the liver after confirming its glucose-lowering and weight loss effects using an obesity and diabetes mouse model. We also performed clinical study of patients with type 2 diabetes to explore candidate biomarkers that reflect the beneficial action of dapagliflozin in the liver. FINDINGS: In animal study, dapagliflozin induced autophagy in the liver (LC3-II to LC3-I expression ratio: P < 0·05 vs. control), and valine and leucine levels were increased in plasma (P < 0·01 vs. control) as well as in liver (P < 0·05 vs. control). Thus, increased plasma valine and leucine levels are potential biomarkers for improved liver metabolism. Clinical study found that valine and leucine levels were markedly higher in patients treated with dapagliflozin (valine: P < 0·05 vs. control, leucine: P < 0·01 vs. control) than those not treated after one week intervention. INTERPRETATION: Dapagliflozin improves liver metabolism via hepatic autophagy, and plasma valine and leucine levels may reflect its metabolic effect. FUNDING: AstraZeneca K.K., Ono Pharmaceutical Co., Ltd., Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan Society for the Promotion of Science (JSPS), Japan Agency for Medical Research and Development (AMED), Novo Nordisk Pharma Ltd., and Japan Foundation for Applied Enzymology, and MSD Life Science Foundation International.

Comment on "The effect of disease-modifying anti-rheumatic drugs on skeletal muscle mass in rheumatoid arthritis patients: a systematic review with meta-analysis".

We read with great interest the article by Hein et al., which described the meta-analysis study on the impact of disease-modifying anti-rheumatic drugs (DMARDs) therapy on skeletal muscle mass in rheumatoid arthritis (RA) patients. While the data presented are impressive, we add some remarks about methodological issues that should be considered. First, this meta-analysis does not include several necessary studies that have provided data on the relationship between anti-tumor necrosis factor (anti-TNF) therapy and body composition. To make the meta-analysis more comprehensive, it could be necessary to incorporate these studies into this analysis. Second, this study did not employ a representative measure of skeletal muscle mass that was adjusted for body size, such as skeletal muscle mass index (SMI). It is well recognized that skeletal muscle mass varies with body size, particularly height and body mass index. Given the heterogeneity background of body size in the studies included in this meta-analysis, it may be worthwhile to conduct an additional analysis regarding the associations between DMARDs and the adjusted measure of skeletal muscle mass such as SMI, which is recommended in several guidelines when determining and contrasting the quantity of skeletal muscle mass. Third, when determining body composition, several reports show variances between bioelectrical impedance analysis (BIA) and dual-energy X-ray absorptiometry (DEXA) in RA as well as in general. In this regard, it may not be appropriate to simultaneously perform a meta-analysis of skeletal muscle mass determined by DEXA and BIA. With the issues described above, we conclude by recommending additional investigations to strengthen the arguments presented by this valuable meta-analysis.

Causal associations between body fat accumulation and COVID-19 severity: A Mendelian randomization study.

Previous studies reported associations between obesity measured by body mass index (BMI) and coronavirus disease 2019 (COVID-19). However, BMI is calculated only with height and weight and cannot distinguish between body fat mass and fat-free mass. Thus, it is not clear if one or both of these measures are mediating the relationship between obesity and COVID-19. Here, we used Mendelian randomization (MR) to compare the independent causal relationships of body fat mass and fat-free mass with COVID-19 severity. We identified single nucleotide polymorphisms associated with body fat mass and fat-free mass in 454,137 and 454,850 individuals of European ancestry from the UK Biobank, respectively. We then performed two-sample MR to ascertain their effects on severe COVID-19 (cases: 4,792; controls: 1,054,664) from the COVID-19 Host Genetics Initiative. We found that an increase in body fat mass by one standard deviation was associated with severe COVID-19 (odds ratio (OR)body fat mass = 1.61, 95% confidence interval [CI]: 1.28-2.04, P = 5.51 × 10-5; ORbody fat-free mass = 1.31, 95% CI: 0.99-1.74, P = 5.77 × 10-2). Considering that body fat mass and fat-free mass were genetically correlated with each other (r = 0.64), we further evaluated independent causal effects of body fat mass and fat-free mass using multivariable MR and revealed that only body fat mass was independently associated with severe COVID-19 (ORbody fat mass = 2.91, 95% CI: 1.71-4.96, P = 8.85 × 10-5 and ORbody fat-free mass = 1.02, 95%CI: 0.61-1.67, P = 0.945). In summary, this study demonstrates the causal effects of body fat accumulation on COVID-19 severity and indicates that the biological pathways influencing the relationship between COVID-19 and obesity are likely mediated through body fat mass.

Effects of glucagon-like peptide-1 receptor agonists on cardiovascular and renal outcomes: A meta-analysis and meta-regression analysis.

AIM: To evaluate the cardiovascular and renal outcomes of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and the associations between these outcomes and HbA1c or weight reduction. MATERIALS AND METHODS: We searched PubMed/MEDLINE, EMBASE, and CENTRAL databases for randomized, placebo-controlled trials of GLP-1 RAs reporting major adverse cardiovascular events (MACE; a composite of cardiovascular mortality, stroke, and myocardial infarction) as the primary outcome. We conducted a meta-regression analysis of primary and secondary outcomes with HbA1c or weight reduction following a meta-analysis with a random-effects model for these outcomes. RESULTS: We extracted data of 60 800 individuals from eight eligible studies (ELIXA, LEADER, SUSTAIN-6, EXSCEL, HARMONY, PIONEER 6, REWIND, and AMPLITUDE-O). GLP-1 RAs reduced MACE (hazard ratio [HR] 0.86; 95% CI: 0.80-0.93; P < .001) and secondary outcomes including the composite renal outcome (0.80; 0.73-0.87; P < .001). In meta-regression analysis, every 1% reduction in HbA1c was associated with 26% and 35% decreases in the logarithm of HR of MACE (P = .044; R2  = 0.65) and the composite renal outcome (P = .040; R2  = 0.85), respectively. On the contrary, weight reduction was not associated with any outcome, including MACE (P = .390). CONCLUSIONS: The reduction in HbA1c, but not body weight, is associated with cardiovascular and renal outcomes. The magnitude of HbA1c reduction can be a surrogate for the cardiovascular and renal benefits of treatment with GLP-1 RAs.

Serum vitamin D status inversely associates with a prevalence of severe sarcopenia among female patients with rheumatoid arthritis.

Sarcopenia is an age-related disease with an increased risk of mortality. It is emerging that low serum 25-hydroxyvitamin D [25(OH)D] affects the sarcopenic state in general, but in rheumatoid arthritis (RA), these associations are not understood although the prevalence of vitamin D insufficiency is high in RA. We conducted a cross-sectional study of older female outpatients from our cohort (KURAMA) database. We measured skeletal muscle mass, handgrip strength, and gait-speed to diagnose severe sarcopenia. The serum 25(OH)D concentration was measured using electrochemiluminescence immunoassay. A total of 156 female patients with RA (sarcopenia:44.9%, severe sarcopenia: 29.5%, and without sarcopenia: 25.6%) were enrolled. Classification of vitamin D status at a cutoff point of median 25(OH)D concentration revealed that low 25(OH)D status was associated with a high prevalence of severe sarcopenia and with low measured values of muscle mass, handgrip, and gait speed. Furthermore, multivariable logistic regression analysis identified that low 25(OH)D status was associated with a high prevalence of severe sarcopenia (OR 6.00; 95% CI 1.99-18.08).The same association was observed when the cut-off value was set at 20 ng/ml. In components of sarcopenia, both low physical performance and muscle mass were associated with low 25(OH)D status. In conclusion, vitamin D status was inversely associated with severe sarcopenia, low physical performance, and low skeletal muscle mass. Modification of vitamin D status including vitamin D supplementation should be investigated as a therapeutic strategy for sarcopenic patients with RA.

Influence of dietary habits on depression among patients with rheumatoid arthritis: A cross-sectional study using KURAMA cohort database.

OBJECTIVE: Although mental disorder is one of the most common comorbidities of rheumatoid arthritis (RA) and is known as a critical influence on RA remission rates, there is little knowledge regarding a possible therapeutic strategy for depression or anxiety in a RA population. Most recently, clinical evidence of dietary improvement for depression has emerged in a general population, but the relationship between dietary habits and mental disorder has not been investigated in RA. The purpose of this study is to elucidate clinical associations between mental disorder (depression/anxiety), dietary habits and disease activity/physical function in patients with RA. METHODS: A cross-sectional study was performed with 267 female outpatients from the KURAMA database. Using the Hospital Anxiety and Depression Scale (HADS), we classified the participants into three groups by depression state, and their characteristics were compared. Using the 20-items on the self-reported food frequency questionnaire, we investigated the relationship between dietary habits and depression or anxiety, adopting a trend test and a multivariate standardized linear regression analysis for the HADS score of depression or that of anxiety as a dependent variable. RESULTS: According to the classified stage of depression, current disease activity (DAS28-CRP: 28-Joint RA Disease Activity Score-C-reactive protein) and the health assessment questionnaire disability Index (HAQ-DI) were significantly increased. Trend analyses revealed that the depression score was inversely associated with the consumption of three food (fish, vegetables and fruit) out of twenty as was the anxiety score with only fish intake. Furthermore, multiple linear regression analysis revealed that the depression score was negatively associated with frequent fish intake (≥ 3 times per week) (Estimate -0.53, p = 0.033), HAQ-DI score within normal range (Estimate -0.88, p ≤ 0.001) and MTX use (Estimate -0.60, p ≤ 0.023). For the anxiety score, multivariate analysis showed similar but not significant associations with variables except for HAQ-DI score. CONCLUSIONS: In a RA population, both depression and anxiety had a significant and negative association with HAQ-DI score, and depression rather than anxiety had negative association with frequent fish intake. Modification of dietary habits such as increased fish consumption may have a beneficial effect on the depression state in RA patients.

Habitual fish intake negatively correlates with prevalence of frailty among patients with rheumatoid arthritis.

Frailty is a geriatric syndrome characterized by anabolic-catabolic imbalance and multisystem dysregulation resulting in increased adverse health outcomes, and is closely related with dietary habits in the general population. Although chronic inflammatory diseases are thought to accelerate development of frailty, correlations between rheumatoid arthritis (RA), frailty and dietary habits have not been examined. We performed a cross-sectional study using our cohort database (KURAMA cohort), and classified 306 participants into three groups (robust, prefrail and frail) according to the Study of Osteoporotic Fracture (SOF) criteria. Multivariate logistic analysis revealed that the presence of frailty/prefrailty was significantly correlated with the disease activity score (DAS28-ESR) (OR 1.70 (1.30-2.22), p < 0.0001). Additional analyses of frailty and food intake showed that 5 foods (fish, meat, milk, vegetables and fruits) of 20 groups on the questionnaire were inversely associated with the prevalence of frail/prefrail categories. In multivariate analysis with the five nutrients, fish intake (> two times a week) was an independent covariate negatively correlated with frailty/prefrailty (OR 0.35 (0.19-0.63), p = 0.00060). In conclusion, habitual fish intake may play a key role in nutritional intervention to prevent progression of frailty and RA.

Urinary sodium-to-potassium ratio associates with hypertension and current disease activity in patients with rheumatoid arthritis: a cross-sectional study.

BACKGROUND: Excessive salt intake is thought to exacerbate both development of hypertension and autoimmune diseases in animal models, but the clinical impact of excessive salt in rheumatoid arthritis (RA) patients is still unknown. We performed a cross-sectional study to clarify the associations between salt load index (urinary sodium-to-potassium ratio (Na/K ratio)), current disease activity, and hypertension in an RA population. METHODS: Three hundred thirty-six participants from our cohort database (KURAMA) were enrolled. We used the spot urine Na/K ratio as a simplified index of salt loading and used the 28-Joint RA Disease Activity Score (DAS28-ESR) as an indicator of current RA disease activity. Using these indicators, we evaluated statistical associations between urinary Na/K ratio, DAS28-ESR, and prevalence of hypertension. RESULTS: Urinary Na/K ratio was positively associated with measured systolic and diastolic blood pressure and also with prevalence of hypertension even after covariate adjustment (OR 1.34, p <  0.001). In addition, increased urinary Na/K ratio was significantly and positively correlated with DAS28-ESR in multiple regression analysis (estimate 0.12, p <  0.001), as was also the case in gender-separated and prednisolone-separated sub-analyses. CONCLUSION: Urinary Na/K ratio was independently associated with current disease activity as well as with prevalence of hypertension in RA patients. Thus, dietary modifications such as salt restriction and potassium supplementation should be investigated as a potential candidate for attenuating both disease activity and hypertension in RA patients.

Increased circulating adiponectin is an independent disease activity marker in patients with rheumatoid arthritis: A cross-sectional study using the KURAMA database.

OBJECTIVE: To clarify the relationship among serum adiponectin, body composition, current disease activity and therapeutics of rheumatoid arthritis (RA). METHODS: We conducted a cross-sectional study in RA patients under treatment with agents including biological disease-modifying antirheumatic drugs (bDMARDs) and Janus kinase (JAK) inhibitors. A total of 351 subjects from the Kyoto University RA Management Alliance cohort (KURAMA) were enrolled in the analysis. We classified the participants into five body composition groups according to the cut-off points for obesity and visceral fat used in Japan: body mass index (BMI), 18.5 kg/m2 for underweight and 25.0 kg/m2 for obesity, and visceral fat area (VFA), 100 cm2 for visceral adiposity. RESULTS: Classification of body composition revealed that serum adiponectin levels and disease activity score (DAS28-ESR) in the low BMI group were significantly higher than those in the normal and overweight groups. Because both increased serum adiponectin and low BMI were previously reported as poor prognostic factors of RA, we performed multiple regression analysis to determine which factor was correlated with RA disease activity. Serum adiponectin level, but not BMI, was positively associated with DAS28-ESR (estimate = 0.0127, p = 0.0258). Subanalysis also showed that the use of bDMARD or JAK inhibitor did not have an obvious influence on circulating adiponectin. CONCLUSIONS: Classification of body composition and multiple regression analysis revealed a positive and independent correlation between serum adiponectin and DAS28-ESR in Japanese RA patients. Thus, serum adiponectin may be an important marker reflecting high disease activity of RA regardless of current medications.

A novel immunopathological association of IgG4-RD and vasculitis with Hashimoto's thyroiditis.

UNLABELLED: A 73-year-old man with Hashimoto's thyroiditis (HT) suffered from purpura on the lower legs. He was diagnosed with IgG4-related disease (IgG4-RD) with serum IgG4 elevation and dacryo-sialadenitis confirmed histologically. Serum Th2 and Treg cytokines, interleukin 7 (IL7), IL8 and Th2 chemokine levels were elevated, while skewed Th1 balance was seen in fluorescence-activated cell sorting (FACS). Therefore, preferential Th1 balance in HT appeared to be followed by IgG4-RD characterized with Th2 and Treg polarization. The commencement of steroid therapy dramatically exacerbated clinical manifestations including IgG4-RD-associated HT. The measurement of cytokine and chemokine levels as well as FACS analysis in the development of IgG4-RD seemed to be beneficial. In conclusion, an innovative association of HT, IgG4-RD and vasculitis was observed. This report also offers novel diagnostic and therapeutic approaches for IgG4-RD. LEARNING POINTS: Recently, a subtype of HT has been considered to be a thyroid manifestation of IgG4-RD, although the etiology of IgG4-RD is not established yet.Immunologically a close association between HT and vasculitis was reported.Leukocytoclastic vasculitis is a rare skin presentation of IgG4-RD.In the current case, during the course of HT, IgG4-RD and leukocytoclastic vasculitis occurred; thus, innate immunity and acquired immunity seem to be involved in the development of IgG4-RD.The measurement of cytokine and chemokines appeared to be beneficial in the development of IgG4-RD.Remarkably, effectiveness of steroid therapy for HT suggested presence of IgG4-RD-associated HT. Therefore, this report highlights the pathogenesis of IgG4-RD and proposes novel therapeutic mechanisms. Clinicians should pay attention to the development of IgG4-RD and vasculitis during long course of HT.