Safety of Tacrolimus in Autoimmune Disease: Results From Post-marketing Surveillance in South Korea

Objective@#Tacrolimus, a macrolide immunosuppressant, is approved in Korea for the treatment of rheumatoid arthritis (RA), lupus nephritis (LN) and myasthenia gravis (MG). We report three prospective post-marketing surveillance studies of tacrolimus conducted in South Korea in these indications. @*Methods@#Studies were conducted according to South Korean Ministry of Food and Drug Safety requirements. Patients were followed up for the duration of the study (up to 4 years) or until treatment discontinuation. Occurrence and likely relationship with tacrolimus of adverse events (AEs), adverse drug reactions (ADRs; defined as AEs where causal relationship to tacrolimus could not be excluded) and serious AEs were recorded. Association of AEs with demographic and medical factors was evaluated by multivariable analysis. @*Results@#The studies included 740 (RA), 307 (LN) and 104 (MG) patients. The incidence of AEs was 12.7% in RA (64.2% of AEs potentially related to tacrolimus), 20.9% (37.8% potentially related) in LN and 29.8% (56.8% potentially related) in MG. The incidence of ADRs was 8.4%, 9.8% and 20.2%, respectively. Serious AEs were reported in 0.7%, 7.2% and 8.7%, respectively. The most common AEs were abdominal pain (RA), pharyngitis (LN) and diarrhea (MG). Unexpected AEs occurred in 3.5% of patients with RA, 2.9% in LN and 8.7% in MG; no pattern of unexpected AEs was apparent. Multivariable analysis demonstrated that patients with comorbidity had higher probability of experiencing an AE in RA and MG studies. @*Conclusion@#The incidence of AEs and the safety profile of tacrolimus in each indication was consistent with previous reports.

Safety of Tacrolimus in Autoimmune Disease: Results From Post-marketing Surveillance in South Korea

Objective@#Tacrolimus, a macrolide immunosuppressant, is approved in Korea for the treatment of rheumatoid arthritis (RA), lupus nephritis (LN) and myasthenia gravis (MG). We report three prospective post-marketing surveillance studies of tacrolimus conducted in South Korea in these indications. @*Methods@#Studies were conducted according to South Korean Ministry of Food and Drug Safety requirements. Patients were followed up for the duration of the study (up to 4 years) or until treatment discontinuation. Occurrence and likely relationship with tacrolimus of adverse events (AEs), adverse drug reactions (ADRs; defined as AEs where causal relationship to tacrolimus could not be excluded) and serious AEs were recorded. Association of AEs with demographic and medical factors was evaluated by multivariable analysis. @*Results@#The studies included 740 (RA), 307 (LN) and 104 (MG) patients. The incidence of AEs was 12.7% in RA (64.2% of AEs potentially related to tacrolimus), 20.9% (37.8% potentially related) in LN and 29.8% (56.8% potentially related) in MG. The incidence of ADRs was 8.4%, 9.8% and 20.2%, respectively. Serious AEs were reported in 0.7%, 7.2% and 8.7%, respectively. The most common AEs were abdominal pain (RA), pharyngitis (LN) and diarrhea (MG). Unexpected AEs occurred in 3.5% of patients with RA, 2.9% in LN and 8.7% in MG; no pattern of unexpected AEs was apparent. Multivariable analysis demonstrated that patients with comorbidity had higher probability of experiencing an AE in RA and MG studies. @*Conclusion@#The incidence of AEs and the safety profile of tacrolimus in each indication was consistent with previous reports.

Health-related Quality of Life Outcomes of Adalimumab for Patients With Rheumatoid Arthritis in Korea

Objective@#Rheumatoid arthritis (RA) is a chronic, progressive, autoimmune disorder that impairs patients’ overall health-related quality of life (HRQOL). In this study, we evaluated the effect of adalimumab in Korean patients with active RA on HRQOL. @*Methods@#Patients included in the study had moderate to severe active RA that did not respond to conventional drugs with a Disease Activity Score of 28 joints ＞3.2 and were biologics-naïve. All patients received adalimumab 40 mg subcutaneously every other week and were followed for 24 weeks. The primary endpoint was the change in baseline Health Assessment Questionnaire Disability Index (HAQ-DI) score at week 24. Secondary endpoints were changes in the EuroQol 5-dimension 3-Level (EQ-5D-3L) baseline score and Short Form 36-Item Health Survey (SF-36) domain scores at weeks 12 and 24 and change in baseline HAQ-DI score at week 12. @*Results@#In total, 91 Korean patients were included. Ninety-three percent of patients were in high disease activity with a baseline mean DAS28 value of 6.1 within all patients. The mean change from baseline in HAQ-DI scores were −0.46 at week 12 and∼0.67 at week 24 (p＜0.0001). Additionally, EQ-5D-3L score at weeks 12 and 24 had significantly improved (p＜0.0001) compared to baseline. SF-36 at weeks 12 and 24 had significantly improved (p＜0.0001, p=0.0001) compared to baseline. @*Conclusion@#Treatment with adalimumab resulted in significant improvement in HAQ-DI, EQ-5D-3L, and SF-36 scores at 12 and 24 weeks in Korean RA patient.

Treat-to-Target Strategy for Asian Patients with Early Rheumatoid Arthritis: Result of a Multicenter Trial in Korea

BACKGROUND: To evaluate the therapeutic benefits of the treat-to-target (T2T) strategy for Asian patients with early rheumatoid arthritis (RA) in Korea. METHODS: In a 1-year, multicenter, open-label strategy trial, 346 patients with early RA were recruited from 20 institutions across Korea and stratified into 2 groups, depending on whether they were recruited by rheumatologists who have adopted the T2T strategy (T2T group) or by rheumatologists who provided usual care (non-T2T group). Data regarding demographics, rheumatoid factor titer, anti-cyclic citrullinated peptide antibody titer, disease activity score of 28 joints (DAS28), and Korean Health Assessment Questionnaire (KHAQ) score were obtained at baseline and after 1 year of treatment. In the T2T group, the prescription for disease-modifying antirheumatic drugs was tailored to the predefined treatment target in each patient, namely remission (DAS28 < 2.6) or low disease activity (LDA) (2.6 ≤ DAS28 < 3.2). RESULTS: Data were available for 163 T2T patients and 162 non-T2T patients. At the end of the study period, clinical outcomes were better in the T2T group than in the non-T2T group (LDA or remission, 59.5% vs. 35.8%; P < 0.001; remission, 43.6% vs. 19.8%; P < 0.001). Compared with non-T2T, T2T was also associated with higher rate of good European League Against Rheumatism response (63.0% vs. 39.8%; P < 0.001), improved KHAQ scores (−0.38 vs. −0.13; P = 0.008), and higher frequency of follow-up visits (5.0 vs. 2.0 visits/year; P < 0.001). CONCLUSION: In Asian patients with early RA, T2T improves disease activity and physical function. Setting a pre-defined treatment target in terms of DAS28 is recommended.

Productivity Loss of Rheumatoid Arthritis Patients according to the Their Stages of the Disease Activity Score

OBJECTIVE: Productivity loss was compared by 3-stage of disease activity and associations between higher disease activity and high productivity loss were identified. METHODS: Data were extracted from Rheumatoid Arthritis (RA) Patient-reported Outcomes Research, which enrolled 2,000 RA patients (>20-year) on disease-modifying-antirheumatic-drugs (DMARDs) (≥6-month) from December 2012 to June 2013. This included 1,457 RA patients with the disease activity score (DAS-28-ESR) in their medical charts. Productivity loss in time and indirect cost was estimated using The World Health Organization Health and Work Performance Questionnaire (HPQ). Baseline characteristics and productivity loss outcomes were compared according to DAS-28-ESR groups. RESULTS: 84.4% were females, 54.2% had low DAS-28-ESR ( 5.1). Patients with moderate to high DAS-28-ESR had higher lost productivity time (LPT) and monthly costs of LPT than those with low DAS-28-ESR (time in hours: 110.0±58.4 vs. 132.4±57.2 vs. 71.5±52.0, p < 0.0001; monthly costs of LPT in 1,000 Korean won: 1,097±607 vs. 1,302±554 vs. 741±531, p < 0.0001). Multiple regression analyses revealed significant associations with high LPT in high (adjusted odds ratio [OR]=3.87, 95% confidence interval [CI]: 2.18∼6.87) and moderate DAS-28-ESR (adjusted OR=1.88, 95% CI: 1.41∼2.52) compared to low DAS-28-ESR. In addition, positive associations with high monthly costs of LPT were observed in high (adjusted OR=3.45, 95% CI: 1.98∼5.99) and moderate DAS-28-ESR (adjusted OR=1.93, 95% CI: 1.43∼2.54) compared to low DAS-28-ESR. CONCLUSION: Timely therapeutic strategies should be taken into consideration given that the RA patients with moderate to high DAS-28-ESR showed strong associations with high productivity loss for effective management of RA.

Atorvastatin inhibits osteoclast differentiation by suppressing NF-κB and MAPK signaling during IL-1β-induced osteoclastogenesis

BACKGROUND/AIMS: To define the effect of statins on interleukin 1β (IL-1β)-induced osteoclastogenesis and elucidate the underlying mechanisms. METHODS: Bone marrow cells were obtained from 5-week-old male ICR (Institute for Cancer Research) mice, and they were cultured to differentiate them into osteoclasts with macrophage colony-stimulating factor and the receptor activator of nuclear factor (NF)-κB ligand in the presence or absence of IL-1β or atorvastatin. The formation of osteoclasts was evaluated by tartrate-resistant acid phosphatase (TRAP) staining and resorption pit assay with dentine slice. The molecular mechanisms of the effects of atorvastatin on osteoclastogenesis were investigated using reverse transcription polymerase chain reaction and immunoblotting for osteoclast specific molecules. RESULTS: Atorvastatin significantly reduced the number of TRAP-positive multinucleated cells as well as the bone resorption area. Atorvastatin also downregulated the expression of the NF of activated T-cell c1 messenger RNA and inhibited the expression of osteoclast-specific genes. A possible underlying mechanism may be that atorvastatin suppresses the degradation of the inhibitors of NF-κB and blocks the activation of the c-Jun N-terminal kinase, extracellular signal-regulated kinase, and p38; thus, implicating the NF-κB and mitogen-activated protein kinases pathway in this process. CONCLUSIONS: Atorvastatin is a strong inhibitor of inflammation-induced osteoclastogenesis in inflammatory joint diseases.

Hypereosinophilic Syndrome Associated with the Onset of Rheumatoid Arthritis: A Case Report

Idiopathic hypereosinophilic syndrome (HES) is a disorder characterized by the sustained overproduction of eosinophils and multiple organ damage. Rheumatologic manifestations of HES are infrequent, but persistent eosinophilia is observed in approximately 10% to 40% of patients with rheumatoid arthritis (RA). This finding may be a result of the RA itself and is often associated with active disease and the presence of extra-articular features. We describe the case of a 48-year-old man affected by HES who subsequently developed RA. Both HES and RA responded rapidly to the corticosteroid and methotrexate therapy. In this patient, the initiation of RA and HES was related, suggesting a common pathogenetic link between these two diseases.

Neutrophil-to-lymphocyte Ratio in Diagnosis of Systemic Sclerosis for Prediction of Interstitial Lung Disease

OBJECTIVE: The neutrophil-to-lymphocyte ratio (NLR) is elevated in inflammatory diseases, but its clinical significance in systemic sclerosis (SSc) is unclear. This study evaluated NLR in diagnosing SSc and in predicting lung involvement such as interstitial lung disease (ILD). METHODS: The medical records of 88 patients with SSc and 50 healthy controls were reviewed. Exclusion criteria included active infection or the presence of any hematological, cardiovascular, or metabolic disorder. The NLR was compared between patients with SSc and healthy controls, and associations between NLR and lung involvement were analyzed. RESULTS: The NLR was significantly higher in patients with SSc compared to healthy controls (NLR, 3.95±6.59 vs. 2.00±1.07, p<0.01). Patients with SSc and ILD had higher NLR levels than those without ILD (p<0.01, p<0.05). NLR was negatively associated with forced vital capacity (r=−0.341, p<0.01), but not with diffusing capacity for carbon monoxide. Receiver-operating characteristics analysis of NLR to predict ILD in patients with SSc showed that the area under the curve was 0.763. The cut-off NLR value for prediction of lung involvement was determined to be 2.59 (sensitivity, 0.700; specificity, 0.729; p<0.01). CONCLUSION: NLR may be a promising marker that reflects ILD in patients with SSc, and values greater than 2.59 were useful in predicting ILD.

Effect of Tocilizumab on Serum Hepcidin and Anemia Response in Patients with Rheumatoid Arthritis

No abstract available.

Gastrointestinal Risk Factors and Non-steroidal Anti-inflammatory Drugs Use in Rheumatoid Arthritis and Osteoarthritis Patients in Korea

OBJECTIVE: The aim of this study was to examine and compare the gastrointestinal (GI) risk factors and treatment patterns of rheumatoid arthritis (RA) and osteoarthritis (OA) patients in Korea. METHODS: This was a cross-sectional, observational study on RA and OA patients taking non-steroidal anti-inflammatory drugs (NSAIDs) for at least 1 month. A total of 1,896 patients (981 RA patients, 915 OA patients) were recruited from 20 university hospitals. Data were collected through medical records and patient surveys. GI risk factors included age, prolonged (over 3 months) or high-dose use of NSAIDs, alcohol drinking, smoking, use of aspirin, anticoagulants or glucocorticoids, comorbidities, and history of Helicobacter pylori infection or other GI complications. Treatment patterns were classified according to groups using, selective cyclooxygenase (COX)-2 inhibitors+/-gastro-protective agents, non-selective COX-2 inhibitors+proton pump inhibitor, or non-selective COX-2 inhibitors+/-other gastro-protective agents. RESULTS: GI risk factors were highly present in both RA and OA patients. The proportion of prolonged use of NSAIDs, smoking, and glucocorticoid use were higher in RA patients (p<0.001). The proportion of comorbidities and use of aspirin were higher in OA patients (p<0.001). The remaining GI risk factors were present in similar proportions in both groups. Use of selective COX-2 inhibitors or gastro-protective agents was higher in RA patients. CONCLUSION: Prolonged use of NSAIDs and concomitant glucocorticoid use were higher in RA patients, while comorbidities and concomitant aspirin use were predominant in OA patients. These results will provide insights for use in development of future guidelines for proper selection of NSAIDs and effective prevention of GI complications in arthritis patients.

Efficacy and safety of low-dose tacrolimus for active rheumatoid arthritis with an inadequate response to methotrexate

BACKGROUND/AIMS: To determine the efficacy and safety of low-dose tacrolimus in Korean rheumatoid arthritis (RA) subjects with an inadequate response to methotrexate (MTX). METHODS: This was a multicenter, open-label study conducted at five Korean sites. Fifty-six patients with active RA, despite treatment for ≥ 1 month with a stable, maximally tolerated dosage of oral MTX (median dosage, 15 mg/wk), were enrolled and received 1.5 mg/day of tacrolimus as a single oral dose once per day for 16 weeks while continuing to receive MTX. All other disease-modifying anti-rheumatic drugs were discontinued, whereas stable dosages of nonsteroidal anti-inflammatory drugs and oral corticosteroids (≤ 10 mg/day of prednisone or an equivalent corticosteroid) were allowed. The primary clinical response criterion was the American College of Rheumatology's definition of 20% improvement (ACR20) at the end of treatment. RESULTS: The ACR20 response rate was 42.9% (24 of 56 patients) in patients who had received tacrolimus at least once. The overall ACR50 and ACR70 responses at the end of treatment for all patients were 30.4% and 10.7%, respectively. Throughout the treatment period, 37 patients experienced 71 adverse events (AEs) in total, and four patients left the study because of AEs. In addition, 15 patients in total experienced treatment-related AEs. Throughout the treatment period, two patients were reported to experience two serious AEs, and one patient left the study because of a serious AE. CONCLUSIONS: In patients whose active RA persists despite treatment with MTX, low-dose tacrolimus in combination with MTX appears to be safe and well tolerated, and provides clinical benefit.

Factors Contributing to Discordance between the 2011 ACR/EULAR Criteria and Physician Clinical Judgment for the Identification of Remission in Patients with Rheumatoid Arthritis

Remission is a primary end point of in clinical practice and trials of treatments for rheumatoid arthritis (RA). The 2011 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) remission criteria were developed to provide a consensus definition of remission. This study aimed to assess the concordance between the new remission criteria and the physician’s clinical judgment of remission and also to identify factors that affect the discordance between these two approaches. A total of 3,209 patients with RA were included from the KORean Observational Study Network for Arthritis (KORONA) database. The frequency of remission was evaluated based on each approach. The agreement between the results was estimated by Cohen's kappa (κ). Patients with remission according to the 2011 ACR/EULAR criteria (i.e. the Boolean criteria) and/or physician judgment (n = 855) were divided into three groups: concordant remission, the Boolean criteria only, and physician judgment only. Multinomial logistic regression analysis was used to identify factors responsible for the assignment of patients with remission to one of the discordant groups rather than the concordant group. The remission rates using the Boolean criteria and physician judgment were 10.5% and 19.9%, respectively. The agreement between two approaches for remission was low (κ = 0.226) and the concordant remission rate was only 5.5% (n = 177). Pain affected classification in both discordant groups, whereas fatigue was associated with remission only by physician clinical judgment. The Boolean criteria were more stringent than clinical judgment. Patient subjective symptoms such as pain and fatigue were associated with discordance between the two approaches.

Pathogenic Role of Autophagy in Rheumatic Diseases

Autophagy is a principle catabolic process mediated by lysosomes in eukaryotic cells. This is an intracellular homeostatic mechanism crucial for degradation in acidic lysosomal compartments of waste components from the cytoplasm. Autophagy research was initially focused on its degradation mechanism, but focus is now shifting to its effects on immunity. It contributes to detection and removal of pathogens as well as regulation of inflammasomes and neutrophil extracellular traps. Moreover, it is pivotal in antigen presentation and immune cell maturation, survival and homeostasis. The importance of autophagic pathways in normal and dysregulated immunity has become increasingly recognized in the past several years. Dysregulation of the autophagic pathway is implicated in the pathogenesis of several rheumatic diseases. In this review, we summarize the immunological function of autophagy in innate and adaptive immunity, and the functions of autophagy in the pathogenesis of rheumatic diseases.

Multiple Sclerosis in a Patient with Primary Sjogren Syndrome / 대한내과학회지

Sjogren syndrome (SS) is a chronic inflammatory autoimmune disorder involving the exocrine glands, which often presents with salivary and tear gland dysfunction leading to dry mouth and eyes (sicca symptoms). This disease occurs alone as primary SS, or in the background of connective tissue diseases as secondary SS. Neurological involvement is seen in 20-25% of SS cases. Cerebral involvement is generally heterogeneous both in terms of localization (focal or diffuse) and progression (acute, progressive or reversible) and may resemble the clinical and radiological findings of multiple sclerosis (MS). Here we present the case of a patient with primary SS who experienced acute progressive diffuse MS.

Churg-Strauss Syndrome Presenting with Diffuse Alveolar Hemorrhage / 대한내과학회지

Churg-Strauss syndrome (CSS), known as eosinophilic granulomatosis with polyangiitis, is a rare type of systemic vasculitis characterized by the presence of asthma, peripheral eosinophilia, and necrotizing vasculitis with eosinophilic infiltration of multiple organs. Approximately 3-4% of all CSS cases are associated with alveolar hemorrhage. Untreated CSS may lead to a poor prognosis, but glucocorticoid and cytotoxic agent treatments may result in clinical remission. The careful diagnosis and understanding of CSS is important for making treatment decisions and providing effective care. Here, we report a case of CSS with diffuse alveolar hemorrhage.

Retroperitoneal Fibrosis in a Patient with Rheumatoid Arthritis

A 54-year-old male diagnosed with rheumatoid arthritis (RA) was effectively treated with methotrexate and adalimumab. He was admitted with fatigue and right lower back pain which had persisted for 1 month. An enhanced abdominal computed tomography scan showed an ill-defined mass with soft tissue attenuation surrounding the right common iliac artery involving the right middle portion of the ureter. Laparoscopic ureterolysis and biopsy were performed. Microscopic evaluation confirmed the presence of fibroblastic proliferation, with a pleomorphic inflammatory cell infiltrate consisting predominantly of lymphocytes, macrophages, and vascular endothelial cells, without granuloma or neoplastic cells. Therefore, our diagnosis was retroperitoneal fibrosis (RPF)-associated RA. Clinicians should consider the possibility of RPF in patients with RA who experience lower back pain, abdominal pain, or dysuria, and order suitable imaging studies.

Homonymous hemianopia in a patient with Behcet's disease

No abstract available.

A Case of Dermatomyositis Complicated with Pneumomediastinum Successfully treated with Cyclosporine A: a Case Report and Review of Literature

Dermatomyositis (DM) is a systemic inflammatory disease affecting skeletal muscles and other organs. Spontaneous pneumomediastinum (PnM) has been previously reported as a rare complication of DM and it is known to occur more frequently in patients with interstitial lung disease (ILD). Here we report on a case of a 52-year-old woman with DM who developed spontaneous PnM, which was treated successfully with high-dose steroid pulse therapy and cyclosporine A (CsA). This case suggests that CsA can be an effective therapeutic agent in DM refractory to glucocorticoid therapy, with ILD or pulmonary fibrosis accompanied by DM. CsA should be considered as an initial immunosuppressive agent for patients with PnM in DM.

Coexisting Rheumatoid Arthritis and Takayasu's Arteritis: a Case Report and Review of the Literature

The coexistence of rheumatoid arthritis (RA) and Takayasu's arteritis (TA) is a rare combination and described only in case reports in the literature. Although concurrent presence of RA and TA has been described only in a few literatures to date and the number of reports is increasing, the association between RA and TA remains to be clarified. We present a case of a female patient with both RA and TA, presenting with polyarthritis. We also reviewed the clinical features of the cases with coexistence of RA and TA.

Hemorrhagic Cystitis with Giant Cells in Rheumatoid Arthritis Treating with Tacrolimus

Hemorrhagic cystitis is a diffuse inflammation of the mucosa of the bladder, characterized by hematuria and burning upon urination. This might be caused by a variety of reasons, including undergoing chemotherapy (such as cyclophosphamide), radiation therapy, bladder cancer, certain viruses, urinary infections, and thrombocytopenia. There are no previous reports of hemorrhagic cystitis associated with the use of tacrolimus. This is the first case of hemorrhagic cystitis due to tacrolimus for the treatment of rheumatoid arthritis. We describe a case of hemorrhagic cystitis with giant cells in a patient with rheumatoid arthritis treating with tacrolimus. Hematuria resolved spontaneously with discontinuation of the drug.