Osteoclasts in the Inflammatory Arthritis: Implications for Pathologic Osteolysis

The enhanced differentiation and activation of osteoclasts (OCs) in the inflammatory arthritis such as rheumatoid arthritis (RA) and gout causes not only local bone erosion, but also systemic osteoporosis, leading to functional disabilities and morbidity. The induction and amplification of NFATc1, a master regulator of OC differentiation, is mainly regulated by receptor activator of NF-κB (RANK) ligand-RANK and calcium signaling which are amplified in the inflammatory milieu, as well as by inflammatory cytokines such as TNFα, IL-1β and IL-6. Moreover, the predominance of CD4+ T cell subsets, which varies depending on the condition of inflammatory diseases, can determine the fate of OC differentiation. Anti-citrullinated peptide antibodies which are critical in the pathogenesis of RA can bind to the citrullinated vimentin on the surface of OC precursors, and in turn promote OC differentiation and function via IL-8. In addition to adaptive immunity, the activation of innate immune system including the nucleotide oligomerization domain leucine rich repeat with a pyrin domain 3 inflammasome and TLRs can regulate OC maturation. The emerging perspectives about the diverse and close interactions between the immune cells and OCs in inflammatory milieu can have a significant impact on the future direction of drug development.

Rapid onset of efficacy predicts response to therapy with certolizumab plus methotrexate in patients with active rheumatoid arthritis

BACKGROUND/AIMS: The objective of this study was to determine the efficacy and safety of add-on therapy with certolizumab pegol (CZP) in active rheumatoid arthritis (RA) patients of a single ethnicity. METHODS: In this 24-week, phase 3, randomized, double-blind, placebo-controlled trial, eligible patients (n = 127) were randomized 2:1 to subcutaneous CZP + methotrexate (MTX; 400 mg at week 0, 2, and 4 followed by 200 mg every 2 weeks) or placebo + MTX. RESULTS: At week 24, the American College of Rheumatology criteria for 20% (ACR20) response rate was significantly greater with CZP + MTX than with placebo (66.7% vs. 27.5%, p < 0.001). Differences in ACR20 response rates for CZP vs. placebo were significant from week 1 (p < 0.05) and remained significant through week 24. The CZP group reported significant improvement in physical function and disability compared to the placebo group (p < 0.001) at week 24, as assessed by Korean Health Assessment Questionnaire-Disability Index (KHAQ-DI). Post hoc analysis indicated that the proportion of patients who had ACR70 responses, Disease Activity Score 28 (DAS28) low disease activity, and DAS28 remission at week 24 was greater in CZP + MTX-treated patients who achieved a decrease in DAS28 ≥ 1.2 (43.8%) at week 4 than in nonresponders. Among 18 (22.2%) and 14 patients (35.0%) in CZP and placebo groups who had latent tuberculosis (TB), none developed active TB. Most adverse events were mild or moderate. CONCLUSIONS: CZP treatment combined with MTX in active RA patients with moderate to severe disease activity and an inadequate response to MTX resulted in rapid onset of efficacy, which is associated with better clinical outcome at week 24 and has an acceptable safety profile, especially in an intermediate TB-burden population.

Case of Renal Microaneurysms and Multiple Renal Infarctions in a Patient with Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a chronic inflammatory, heterogeneous autoimmune disease characterized by autoantibody production and the potential involvement of almost every organ system. Although vasculitis usually confined to small vessels is a fairly common feature of SLE, ischemic vasculitis with an aneurysm is an uncommon feature. In particular, renal arterial microaneurysms and multiple renal infarctions are very rarely reported in patients with SLE. Furthermore, to the best of the authors' knowledge, there is no report on renal arterial microaneurysms associated with SLE in Korea. Here, this paper presents a case of renal microaneurysms and multiple renal infarctions in a 41-year-old woman with SLE.

Bilateral Involvement of Juvenile Temporal Arteritis Associated with Kimura Disease

Juvenile temporal arteritis (JTA) is a localized nodular arteritis confined to the temporal artery without evidence of systemic inflammation, and it occurs mainly in patients younger than 50 years. From the first case report, the pathological features of JTA have been suspected to be the morphological equivalent of Kimura disease (KD), which has been supported further by the concurrent cases of JTA with KD. We present the first case of bilateral JTA accompanying KD, which was confirmed by histological and ultrasound evaluations and supports the hypothesis that JTA is a manifestation of KD. The un-excised JTA lesion was resolved completely after corticosteroid therapy with no recurrence.

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.

Sorafenib Treatment in Advanced Hepatocellular Carcinoma with Tumor Thrombus Nearly Occupying the Entire Right Atrium

Advanced hepatocellular carcinoma (HCC) with tumor thrombus extending through the hepatic veins, inferior vena cava, and right atrium (RA) is very rare. However, whether active treatments such as radiation, transcatheter arterial chemoembolization, and sorafenib in advanced HCC with RA involvement prolong survival is uncertain. We present a rare case of advanced HCC with tumor thrombus nearly occupying the entire RA that was treated with sorafenib. The patient received 400 mg sorafenib twice daily. However, her liver enzyme levels continued to increase and abdominal computed tomography showed an increase in the tumor size in the liver and RA. In the present case, active treatment with sorafenib was ineffective; thus, palliative care may be more beneficial in advanced HCC with extensive RA involvement.

Focal Eosinophilic Myositis Associated with Behçet's Disease

Behçet's disease (BD) is a systemic vasculitis commonly accompanied by recurrent mucosal ulceration and other systemic manifestations, but rarely by myositis. Focal eosinophilic myositis is the most limited idiopathic eosinophilic myopathy characterized by peripheral blood eosinophilia and/or eosinophilic muscle infiltration. Clinical manifestations include myalgia, muscle weakness, and cutaneous lesions, such as subcutaneous induration and erythema. Given that BD can mimic deep vein thrombosis or pseudotumor, muscle biopsy should be performed to enhance the accuracy of diagnosis. Microscopic examination reveals extensive infiltration of eosinophils and mononuclear cells into muscle, myofiber necrosis, and regeneration. To the best of our knowledge, there have not been any published reports on MEDLINE regarding focal eosinophilic myositis associated with BD. Here, we presented a case of focal eosinophilic myositis associated with intestinal BD in a 23-year-old man who suffered from a large ulcer in the terminal ileum.

Metastatic breast cancer with osteolytic skull lesions suspected to be multiple myeloma

We report a case of breast cancer with osteolytic skull lesions which mimicked osteolytic lesions in multiple myeloma. A 60-year-old female was admitted to our hospital due to confused mentality. Laboratory tests showed the findings of an increased calcium level, kidney failure, and anemia. Multiple osteolytic lesions were detected in the ribs, spine, humerus, and pelvis on X-rays. The skull showed the punched out sign. Accordingly we initially suspected multiple myeloma; however, monoclonal protein was not detected in serum and urine and the number of plasma cells was not increased in bone marrow examination. In bone marrow examination, metastatic cancer was detected and biopsy revealed breast cancer. Finally, breast cancer with multiple metastases including those to bone, liver, and lung was diagnosed. Therefore, when a patient presents with multiple osteolytic lesions, we need to consider metastasis from solid cancer in the differential diagnosis as well as multiple myeloma.

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.

Biopsy-Proven Dermatomyositis with Normal Creatine Kinase / 대한내과학회지

Dermatomyositis (DM) is an idiopathic inflammatory myopathy (IIM) characterized by skeletal muscle inflammation and typical skin manifestations. Creatine kinase (CK) has traditionally been considered to be the most useful serum enzyme for the diagnosis and assessment of adult patients with IIM. To our knowledge, there has been no reported case of biopsy-proven DM without CK elevation in Korea, to date. Panniculitis is an uncommon cutaneous manifestation in adult patients with DM. A search of the PubMed database reveals fewer than 30 reported cases of panniculitis in adult patients with DM. Here, we report a case of a 42-year-old female who was diagnosed with biopsy-proven DM with normal serum CK levels and panniculitis.

Impact of Childbearing Decisions on Family Size of Korean Women with Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) predominantly affects women in their reproductive years and has a significant impact on childbearing. We investigated the influence of personal decision on family size among Korean women with SLE and factors that affect the decisions. A case-control study comparing childbearing history and decisions of 112 SLE patients and 135 controls was performed. Women with SLE participating in the Network for Lupus Clinical Research in South Korea and matching controls between ages of 18-45, who are/were married or living with a partner were included. Data regarding socio-demographics, reproductive history, and childbearing decisions were collected through a survey using a standardized questionnaire and medical record review. More women with SLE reported at least one pregnancy (85.7% vs. 71.9%, P = 0.009) or at least one live birth (85.7% vs. 71.9%, P = 0.003) compared with controls. Mean number of pregnancies was significantly higher (2.4 ± 1.6 vs. 1.4 ± 1.3, P < 0.001), and mean number of live births was significantly lower in women with SLE (1.2 ± 0.8 vs. 1.6 ± 0.8, P < 0.001). Significantly more women with SLE made the decision not to have children compared with controls (54.5% vs. 40.7%, P = 0.031), and health-related concerns were the major cause of the decision. Other socio-demographic factors did not influence the decision to limit childbearing in SLE women. The disease-related concerns had significant impact on family size and childbearing decisions among Korean women with SLE.

A Case of Azygos Vein Thombosis Associated with Transient Antiphospholipid Syndrome in Urinary Tract Infection with Escherichia coli

A 73-year-old female with diabetes admitted for treatment of an intertrochanter fracture of the femur and a urinary tract infection (UTI) with Escherichia coli developed thrombosis in her right azygos vein, which was thought to be associated with antiphospholipid and immunoglobulin M anticardiolipin antibodies. After antibiotic therapy, antiphospholipid antibody was undetectable, and a repeat chest computed tomography showed complete resolution of the azygos vein thrombosis. A wide variety of infections can be associated with thrombotic events in patients with transient antiphospholipid syndrome (APS), and this case serves as a reminder that the possibility of transient APS should be considered in patients with venous thrombosis in the setting of a UTI.

A Case of IgG4-Related Disease with Pachymeningitis and Periaortitis / 대한내과학회지

Immunoglobulin G4 (IgG4)-related disease (RD) is an immune-mediated, systemic fibroinflammatory condition characterized by a lymphoplasmacytic infiltration of IgG4-positive plasma cells, storiform fibrosis, and obliterative phlebitis. IgG4-RD has become recognized with increasing frequency since the turn of the century and may affect almost any organ. IgG4-RD also involves the meninges but, to the best of our knowledge, no case of IgG4-related intracranial pachymeningitis with periaortitis has been reported in Korea to date. Here, we report on a 65 year-old male with IgG4-RD involving the meninges and aorta.

Preventive Efficacy and Safety of Rebamipide in Nonsteroidal Anti-Inflammatory Drug-Induced Mucosal Toxicity

BACKGROUND/AIMS: The use of proton pump inhibitors or misoprostol is known to prevent the gastrointestinal complications of nonsteroidal anti-inflammatory drugs (NSAIDs). Rebamipide is known to increase the mucosal generation of prostaglandins and to eliminate free oxygen radicals, thus enhancing the protective function of the gastric mucosa. However, it is unknown whether rebamipide plays a role in preventing NSAID-induced gastropathy. The aim of this study was to determine the effectiveness of rebamipide compared to misoprostol in preventing NSAID-induced gastrointestinal complications in patients requiring continuous NSAID treatment. METHODS: We studied 479 patients who required continuous NSAID treatment. The patients were randomly assigned to groups that received 100 mg of rebamipide three times per day or 200 microg of misoprostol three times per day for 12 weeks. The primary endpoint of the analysis was the occurrence rate of gastric ulcers, as determined by endoscopy after 12 weeks of therapy. RESULTS: Of the 479 patients in the study, 242 received rebamipide, and 237 received misoprostol. Ultimately, 44 patients (18.6%) withdrew from the misoprostol group and 25 patients (10.3%) withdrew from the rebamipide group. There was a significant difference in withdrawal rate between the two groups (p=0.0103). The per protocol analysis set was not valid because of the dropout rate of the misoprostol group; thus, the intention to treat (ITT) analysis set is the main set for the efficacy analysis in this study. After 12 weeks, the occurrence rate of gastric ulcers was similar in the rebamipide and misoprostol groups (20.3% vs 21.9%, p=0.6497) according to ITT analysis. In addition, the therapeutic failure rate was similar in the rebamipide and misoprostol groups (13.6% vs 13.1%, p=0.8580). The total severity score of the gastrointestinal symptoms was significantly lower in the rebamipide group than in the misoprostol group (p=0.0002). The amount of antacid used was significantly lower in the rebamipide group than in the misoprostol group (p=0.0258). CONCLUSIONS: Rebamipide can prevent gastric ulcers when used with NSAIDs and can decrease the gastrointestinal symptoms associated with NSAID administration. When the possibility of poor compliance and the potential adverse effects of misoprostol are considered, rebamipide appears to be a clinically effective and safe alternative.

Complex repetitive discharge on electromyography as a risk factor for malignancy in idiopathic inflammatory myopathy

BACKGROUND/AIMS: We investigated the electromyography (EMG) findings and demographic, clinical, and laboratory features that may predict the development of malignancy in patients with idiopathic inflammatory myopathy (IIM). METHODS: In total, 61 patients, 36 with dermatomyositis and 25 with polymyositis, were included. Patients were divided into those with and without malignancies, and comparisons were made between the groups in terms of their demographic, clinical, laboratory, and EMG findings. RESULTS: The frequencies of malignancies associated with dermatomyositis and polymyositis were 22% and 8%, respectively. Patients with malignancies showed a significantly higher incidence of dysphagia (odds ratio [OR], 21.50; 95% confidence interval [CI], 3.84 to 120.49), absence of interstitial lung disease (ILD; OR, 0.12; 95% CI, 0.01 to 0.98), and complex repetitive discharge (CRD) on the EMG (OR, 26.25; 95% CI, 2.67 to 258.52), versus those without. After adjustment for age, dysphagia and CRD remained significant, while ILD showed a trend for a difference but was not statistically significant. Multivariate analysis revealed that the CRD conferred an OR of 25.99 (95% CI, 1.27 to 531.86) for malignancy. When the frequency of malignancy was analyzed according to the number of risk factors, patients with three risk factors showed a significantly higher incidence of malignancy, versus those with fewer than two (p = 0.014). CONCLUSIONS: We demonstrated for the first time that CRD on the EMG was an additional independent risk factor for malignancy in IIM. Further studies on a larger scale are needed to confirm the importance of CRD as a risk factor for malignancy in IIM.

Hypercalcemia Refractory to Pamidronate Associated with Metastatic Calcifications in Multiple Organs / 대한내과학회지

Paget's disease of bone (PDB) is a disorder featuring high-level bone turnover associated with the presence of disorganized and immature bone tissue with excessive levels of fibrosis. The risk of deformity is very high. The etiology of PDB is not well understood, but includes both genetic and environmental factors among which is bone trauma. Hypercalcemia can occur as a complication of PDB in patients who are immobilized and dehydrated. However, to date, no case of severe hypercalcemia with metastatic calcifications in multiple organs has been reported in any PDB patient. The drugs of choice for treatment of PDB are bisphosphonates. These drugs effectively suppress bone turnover. Patients with extensive PDB may require higher doses of bisphosphonates, and acquired resistance to a particular bisphosphonate may be overcome by use an alternative drug. Here, we report a case of suspicion of PDB. The patient presented with hypercalcemia and metastatic calcifications and his condition improved dramatically after treatment with zoledronic acid.

Hypercalcemia Refractory to Pamidronate Associated with Metastatic Calcifications in Multiple Organs / 대한내과학회지

Paget's disease of bone (PDB) is a disorder featuring high-level bone turnover associated with the presence of disorganized and immature bone tissue with excessive levels of fibrosis. The risk of deformity is very high. The etiology of PDB is not well understood, but includes both genetic and environmental factors among which is bone trauma. Hypercalcemia can occur as a complication of PDB in patients who are immobilized and dehydrated. However, to date, no case of severe hypercalcemia with metastatic calcifications in multiple organs has been reported in any PDB patient. The drugs of choice for treatment of PDB are bisphosphonates. These drugs effectively suppress bone turnover. Patients with extensive PDB may require higher doses of bisphosphonates, and acquired resistance to a particular bisphosphonate may be overcome by use an alternative drug. Here, we report a case of suspicion of PDB. The patient presented with hypercalcemia and metastatic calcifications and his condition improved dramatically after treatment with zoledronic acid.

A Case of Prostate Cancer Associated with Dermatomyositis and Interstitial Lung Disease / 대한내과학회지

Dermatomyositis (DM) is a kind of systemic autoimmune disease characterized by chronic inflammation leading to progressive weakness of proximal muscles and typical cutaneous lesions. DM has been known to be strongly associated with malignancies, such as ovarian, lung, and gastric cancers. Prostate cancer is rarely associated with DM and, to our knowledge, no case of prostate cancer has been reported in patients with DM combined with interstitial lung disease in Korea. Here, we report a case of DM with bronchiolitis obliterans organizing pneumonia that was simultaneously diagnosed as advanced prostate cancer by a thorough evaluation for hidden malignancy.

Therapeutic Effect of a Recombinant betaig-h3 Fragment-RGD Peptide for Chronic Inflammatory Arthritis

OBJECTIVE: betaig-h3 is a 68kDa extracellular matrix protein which is overexpressed in synovial tissues of rheumatoid arthritis (RA). Previous results proved that betaig-h3 fragments are relevant to adhesion and migration of synovial fibroblast and angiogenesis through interaction with alphavbeta 3 integrin. We designed a recombinant betaig-h3 protein consisting of a fas-1 domain and RGD motif and evaluated the therapeutic efficacy in RA. METHODS: Inhibitory effect of adhesion and migration of NIH3T3 cell line was evaluated in 96 well microtiter and transwell plates coated with betaig-h3. Clinical arthritis index was evaluated after treating CIA mice with MFK12. Immunohistochemical staining in synovial tissues were performed. Expression of transcripts and proteins of inflammatory mediators were analyzed by semi-quantitative RT-PCR and immunoblotting. RESULTS: Recombinant protein consisted of 4th fas-1 domain truncated for H1 and H2 sequences and RGD peptide (MFK12), had M.W. of 10.4kDa. betaig-h3 mediated adhesion and migration of NIH3T3 cell line were significantly inhibited in a dose-dependent manner. Arthritis severity and incidence were efficiently reduced when CIA mice were treated with MFK12 at 30 mg/kg/day compared with the control. Immunohistochemical staining of joint tissues in MFK12 treated mice exhibited reduced angiogenesis. In treated mice, expression of transcripts regarding inflammatory mediators was markedly suppressed and immunoblotting of ICAM-1 and RANKL from whole extract of hind paws also showed a significant reduction. CONCLUSION: This study shows that MFK12 is effective in treating RA, although further study is warranted to improve the therapeutic efficacy.

Identification of Independent Predictive Factors for Atherosclerosis in Rheumatoid Arthritis: Based on KARRA Cohort Study

OBJECTIVE: This study sought to investigate independent predictive factors for subclinical atherosclerosis in Korean patients with rheumatoid arthritis (RA). METHODS: We used high-resolution B-mode ultrasonography to measure the carotid artery intima-media thickness (IMT) and carotid plaque in 367 patients with RA. Detailed information on the demographic characteristics, cardiovascular (CV) risk factors, and RA disease characteristics were collected on all subjects. The relationship of the carotid artery IMT and carotid plaque to relevant clinical and laboratory variables were examined. RESULTS: Old age and male sex had the most significant association with increased IMT and presence of plaque than other factors. Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and mKHAQ (Korean version of modified health assessment questionnaire) were significantly associated with both increased IMT and presence of plaque after univariate analysis adjusting for age and sex. A multivariable logistic regression analysis revealed that ESR and TJC68 were independent factors associated with the presence of plaque (p<0.001 and p=0.019, respectively). There was a significant linear correlation between the number of plaques and ESR (p<0.001 and R2=0.07). CONCLUSION: Our results indicated that markers of systemic inflammation contributed significantly to subclinical atherosclerosis in patients with RA. We emphasize the need for aggressive control of RA disease activity in patients who persistently demonstrate highly elevated ESR levels.