Comparative effectiveness of JAK inhibitors and biologic disease-modifying antirheumatic drugs in patients with rheumatoid arthritis.

BACKGROUND/AIMS: We aimed to compare the effectiveness and safety of Janus kinase inhibitors (JAKi) vs. biologic disease- modifying antirheumatic drugs (bDMARD) in Korean patients with rheumatoid arthritis (RA) who had an inadequate response to conventional synthetic DMARDs. METHODS: A quasi-experimental, multi-center, prospective, non-randomized study was conducted to compare response rates between JAKi and bDMARDs in patients with RA naïve to targeted therapy. An interim analysis was performed to estimate the proportion of patients achieving low disease activity (LDA) based on disease activity score (DAS)-28- erythroid sedimentation rate (ESR) (DAS28-ESR) at 24 weeks after treatment initiation and to evaluate the development of adverse events (AEs). RESULTS: Among 506 patients enrolled from 17 institutions between April 2020 and August 2022, 346 (196 JAKi group and 150 bDMARD group) were included in the analysis. After 24 weeks of treatment, 49.0% of JAKi users and 48.7% of bDMARD users achieved LDA (p = 0.954). DAS28-ESR remission rates were also comparable between JAKi and bDMARD users (30.1% and 31.3%, respectively; p = 0.806). The frequency of AEs reported in the JAKi group was numerically higher than that in the bDMARDs group, but the frequencies of serious and severe AEs were comparable between the groups. CONCLUSION: Our interim findings reveal JAKi have comparable effectiveness and safety to bDMARDs at 24 weeks after treatment initiation.

Quality Indicators for Evaluating the Health Care of Patients with Rheumatoid Arthritis: a Korean Expert Consensus.

BACKGROUND: There is increasing interest in the quality of health care and considerable efforts are being made to improve it. Rheumatoid arthritis (RA) is a disease that can result in favorable outcomes when appropriate diagnosis and treatment are provided. However, several studies have shown that RA is often managed inappropriately. Therefore, the Korean College of Rheumatology aimed to develop quality indicators (QIs) to evaluate and improve the health care of patients with RA. METHODS: Preliminary QIs were derived based on the existing guidelines and QIs for RA. The final QIs were determined through two separate consensus meetings of experts. The consensus was achieved through a panel of experts who voted using the modified Delphi method. RESULTS: Fourteen final QIs were selected among 70 preliminary QIs. These included early referral to and regular follow-up with a rheumatologist, radiographs of the hands and feet, early initiation and maintenance of disease-modifying anti-rheumatic drug (DMARD) therapy, periodic assessment of disease activity, screening for drug safety and comorbidities, including viral hepatitis and tuberculosis before biologic DMARD therapy, periodic laboratory testing, supplementation with folic acid, assessment of the risk for cervical spine instability before general anesthesia, patient education, and specialized nurse. CONCLUSION: These QIs can be used to assess and improve the quality of health care for patients with RA.

A case of microscopic polyangiitis associated with aortic valve insufficiency.

Microscopic polyangiitis (MPA) is an anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis characterized by inflammation of small-sized vessels. Although there have been some reports of ANCA-associated vasculitis presenting as aortitis syndrome, MPA rarely involves large-sized vessels such as the aorta. We report an unusual case of MPA combined with severe acute aortic valve insufficiency in a 56-year-old man. He initially presented with prolonged fever, skin rash, and rapidly progressive glomerulonephritis. P-ANCA and anti-myeloperoxidase (MPO) antibodies were positive, but the c-ANCA and anti-proteinase-3 antibodies were negative. Skin biopsy of the lower leg showed necrotizing arteritis. Kidney biopsy was also performed, which revealed diffuse necrotizing and crescentic glomerulonephritis (GN) consistent with pauci-immune ANCA-associated GN. Serial echocardiographic evaluations revealed aortic valve changes and worsening acute aortic valve insufficiency over a two-month period. Despite intensive treatment, our patient developed sudden cardiac arrest and died. Our patient demonstrated typical clinical features and histopathologic findings for systemic vasculitis and had a positive anti-MPO antibody, all of which were consistent with the diagnosis of MPA. Thus, MPA may have been the cause of acute aortic valve insufficiency in this case.

The major determinants of arterial stiffness in Korean patients with rheumatoid arthritis are age and systolic blood pressure, not disease-related factors.

Patients with rheumatoid arthritis are at increased risk of cardiovascular morbidity and mortality. This study was undertaken to investigate the prevalence of peripheral arterial disease, and to identify factors, especially those related to rheumatoid arthritis, influencing arterial stiffness in Korean patients with rheumatoid arthritis. A total of 262 patients with rheumatoid arthritis managed in a tertiary clinic were included. Ankle-brachial index and brachial-ankle pulse wave velocity were measured. Rheumatoid arthritis-related factors were determined, as well as the traditional cardiovascular risk factors. The prevalence of peripheral arterial disease was only 1.5%. Mean pulse wave velocity was 1,559 ± 354 cm/s. Age, body mass index, blood pressure, lipid profile, and glucose, not rheumatoid arthritis-related factors such as disease duration, seropositivity and disease activity, were significantly correlated with pulse wave velocity. Moreover, stepwise multiple regression analysis revealed that only age over 65 (OR = 9.1, 95% CI 4.3-19.1, P < 0.001), systolic blood pressure over 140 mmHg (OR = 15.7, 95% CI 7.4-33.1, P < 0.001), and corticosteroid use (OR = 2.1, 95% CI 1.03-4.3, P = 0.04) were independent risk factors for high pulse wave velocity. The prevalence of peripheral arterial disease in Korean patients with rheumatoid arthritis is very low. Among the many factors related to arterial stiffness, only old age, high systolic blood pressure, and, to a certain extent, corticosteroid use appear to be major determinants, especially in clinical setting with relatively well controlled patients with rheumatoid arthritis.

Korean Observational Study Network for Arthritis (KORONA): establishment of a prospective multicenter cohort for rheumatoid arthritis in South Korea.

OBJECTIVES: The object of this study was to introduce the KORean Observational study Network for Arthritis (KORONA) registry with an emphasis on the design of the Korean rheumatoid arthritis (RA) national database, as well as to provide an overview of the RA patients who are currently registered in KORONA. METHODS: The KORONA was established in July 2009 by the Clinical Research Center for Rheumatoid Arthritis (CRCRA) in South Korea. KORONA is based on a prospective protocol and standard, defined data collection instruments. Demographic and clinical features, laboratory and radiologic data, health-related outcomes, treatment side effects, resource utilization, and health behaviors of the RA cohort patients are recorded in a database. RESULTS: A total of 23 institutions, which are about 38% of the rheumatologic departments at tertiary academic hospitals across South Korea, are part of KORONA. The quality control of data collection and management has been performed through annual monitoring and auditing, staff training, and providing standard operation protocol by the executive committee of CRCRA. As of 31 December 2010, 4721 patients with established RA were included in KORONA, because an annual survey had started to be performed in July 2010. CONCLUSIONS: KORONA is the first nationwide Korean RA-specific cohort and it will provide valuable "real-world" information for Korean RA patients.

Incidence of tuberculosis among korean patients with ankylosing spondylitis who are taking tumor necrosis factor blockers.

OBJECTIVE: To assess the incidence and relative risk of new tuberculosis (TB) infections in Korean patients with ankylosing spondylitis (AS) and patients with AS who are undergoing treatment with tumor necrosis factor (TNF) blockers. METHODS: New cases of TB were identified by reviewing the medical records of 919 patients with AS not treated with TNF blockers and those of 354 patients with AS treated with adalimumab (n = 66), infliximab (n = 78), or etanercept (n = 210) between 2002 and 2009. Reference data were obtained from the Korean National Tuberculosis Association. RESULTS: The mean incidence rate of TB was 69.8 per 100,000 person-years (PY) in the general population, 308 per 100,000 PY in the TNF blocker-naive AS cohort, and 561 per 100,000 PY in the TNF blocker-exposed AS cohort. The incidence rate of TB in the infliximab-treated AS cohort (540 per 100,000 PY) was higher than that in the adalimumab-treated AS cohort (490 per 100,000 PY). No cases of TB occurred in the etanercept-treated AS cohort. Comparing the relative risks of TB infections between the TNF blocker-exposed AS cohort and the TNF blocker-naive AS cohort, no statistically significant difference was identified (risk ratio 0.53; 95% CI 0.144-1.913). CONCLUSION: The risk of TB was higher in the TNF blocker-naive AS cohort than it was in the general population. However, the risk of TB was not increased in the TNF blocker-exposed AS cohort compared with the TNF blocker-naive AS cohort. Among patients with AS, etanercept is associated with a lower risk of TB compared with monoclonal antibodies.

Acute retropharyngeal calcific tendinitis in an unusual location: a case report in a patient with rheumatoid arthritis and atlantoaxial subluxation.

Retropharyngeal calcific tendinitis is defined as inflammation of the longus colli muscle and is caused by the deposition of calcium hydroxyapatite crystals, which usually involves the superior oblique fibers of the longus colli muscle from C1-3. Diagnosis is usually made by detecting amorphous calcification and prevertebral soft tissue swelling on radiograph, CT or MRI. In this report, we introduce a case of this disease which was misdiagnosed as a retropharyngeal tuberculous abscess, or a muscle strain of the ongus colli muscle. No calcifications were visible along the vertical fibers of the longus colli muscle. The lesion was located anterior to the C4-5 disc, in a rheumatoid arthritis patient with atlantoaxial subluxation. Calcific tendinitis of the longus colli muscle at this location in a rheumatoid arthritis patient has not been reported in the English literature.

Safety and clinical responses in ankylosing spondylitis after three months of etanercept therapy.

We aimed to evaluate the safety and clinical responses in Korean ankylosing spondylitis (AS) patients after three months of etanercept therapy. AS patients satisfying the Modified New York Criteria were enrolled. They were assessed for safety and clinical responses at enrollment and after three months of etanercept therapy. A total of 124 patients completed the study. After three months, the rate of ASsessment in AS International Working Group 20% improvement (ASAS 20) response was 79.8%. The rates of ASAS 40 and ASAS 5/6 responses were 58.5 and 62.8%, respectively. Significant improvement of Korean version of Bath AS Disease Activity Index (KBASDAI) (p<0.0001), Bath AS Functional Activity Index (BASFI) (p<0.0001), and Bath AS Metrology Index (BASMI) (p=0.0009) were achieved after three months. Quality of life was also significantly improved after three months, as demonstrated by scores for SF-36 (p<0.0001) and EQ-5D (p<0.0001). Erythrocyte sedimentation rate and C-reactive protein were significantly decreased (p<0.0001, p<0.0001, respectively). None of the patients developed tuberculosis and there were no serious adverse event. AS patients with inadequate response to conventional therapy showed significant clinical improvement without serious adverse events after three months of etanercept therapy.

Single nucleotide polymorphism of COL6A1 in patients with ankylosing spondylitis.

OBJECTIVE: To investigate the genetic association between ankylosing spondylitis (AS) and single nucleotide polymorphisms (SNP) of collagen 6A1 gene (COL6A1), the candidate gene for ossification of the posterior longitudinal ligament. METHODS: One-hundred thirty Korean patients with AS (M: 116, F: 14, age: 29.0 +/- 4.6) and 130 age- and sex-matched healthy subjects were recruited. The SNP of G365G, IVS15+39 C/T, IVS21+18 A/C by Snap shot assay and the SNP of IVS32-29T/C, IVS33+15G/A, IVS33+20A/G, and IVS33+55A/G by direct sequencing were genotyped and analyzed. Bonferroni correction was applied to multiple comparisons. RESULTS: The observed allelic frequencies for these SNP met Hardy-Weinberg equilibrium in all AS and controls. We also found an additional 2 SNP (R783Q and IVS33+88C/T) during direct sequencing. Therefore, a total of 9 SNP were analyzed in this study. There were no significant associations of allelic and genotype variations between AS and controls. The presence of uveitis was marginally associated with a haplotype (CC in G365G + IVS15+39 C/T). The variation of allele or haplotype of COL6A1 is not significantly associated with "more ossified disease." CONCLUSION: Because the genetic variations of COL6A1 could not be correlated with the occurrence of AS in Koreans, we conclude that despite common clinical features, AS and ossification of posterior longitudinal ligament are not genetically related, and the hyperostotic condition seen in the 2 diseases might be regulated differently. Further SNP of COL6A1 were not related to radiographic progression of AS. However, we found that the occurrence of uveitis might be related to the genetic variations of COL6A1 in patients with AS.

Prevalence of ossification of the posterior longitudinal ligament of the cervical spine.

OBJECTIVES: To determine the prevalence of ossification of the posterior longitudinal ligament (OPLL) in cervical spines in Koreans. METHODS: We reviewed the reports of the radiologic examination of cervical spines from January 2002 to September 2005 in Hanyang University Hospital, Seoul, Korea. OPLL was indicated by the presence of heterotopic ossification in the posterior longitudinal ligament on lateral cervical radiograph. RESULTS: Among 11,774 adults aged 16 years or more, 71 cases of OPLL were found (0.60%). The male to female ratio was 42:29 (1.45:1). The highest prevalence was in patients aged 50-59 years. In terms of the types of OPLL, the continuous type was noted in 32.0% of the patients, the segmental type in 31.0%, the mixed type in 31.0%, and the localized type in 5.6%. C4, C5, and C3 were most commonly involved, in that order of frequency. Diffuse idiopathic skeletal hyperostosis, which is another common hyperostotic disorder, was also found in eight male patients. CONCLUSIONS: The prevalence of cervical OPLL in Koreans was 0.60%, which was lower than that of Japanese and some previous western reports.

Prevalence of ossification of posterior longitudinal ligament in patients with ankylosing spondylitis.

OBJECTIVE: To determine the prevalence of ossification of the posterior longitudinal ligament (OPLL) in patients with ankylosing spondylitis (AS). METHODS: A cross-sectional radiological examination was performed in patients diagnosed with AS. A bone and joint radiologist screened and confirmed the cervical radiographs of these patients. A review of the medical records was also conducted to investigate the relationship between the clinical manifestations and the actual expression of OPLL in patients with AS. RESULTS: Among 544 patients with AS, 470 (86.4%) were men and 96.1% were HLA-B27-positive. The mean age was 34.3 +/- 9.3 years and mean disease duration was 12.4 +/- 7.2 years. After reviewing the cervical radiographs, OPLL was found in 19 patients (3.5%; 95% CI 1.9, 5.0). The mean age of these 19 patients was 39.9 +/- 10.7 years, and the male to female ratio was 18:1. Interestingly, a statistically significant number of patients who expressed OPLL were older (p = 0.007). However, we were unable to determine whether OPLL was significantly associated with AS disease duration, peripheral arthritis, anterior uveitis/iritis, HLA-B27, anterior atlantoaxial subluxation, diffuse idiopathic skeletal hyperostosis, or other paraspinal ligament disorders. CONCLUSION: Our study showed that the frequency of OPLL in Korean patients with AS was 3.5%, which was considerably lower than previously reported values (15.5% in 103 Mexican AS). We were able to determine that OPLL in AS was associated with older age.

Incidence of tuberculosis in Korean patients with rheumatoid arthritis (RA): effects of RA itself and of tumor necrosis factor blockers.

OBJECTIVE: To elucidate the incidence rate and relative risk of tuberculosis (TB) in patients with rheumatoid arthritis (RA) and in patients with RA treated with tumor-necrosis-factor (TNF) blockers in Korea. METHODS: Using data from the Korean National Tuberculosis Association (KNTA) as a control and data from a single-center cohort of patients with RA, we conducted an evaluation of 1285 patients with RA not exposed to TNF blockers and reviewed medical records of 90 and 103 patients with RA treated with infliximab and etanercept, respectively, between 2001 and 2005. RESULTS: The mean incidence rate of TB, reported by the KNTA, was 67.2 per 100,000 person years (PY) from 2001 to 2004. In the TNF-blocker-naïve RA cohort, 9 cases of TB developed during 3497 PY of followup (257 per 100,000). In the infliximab-treated RA group, 2 cases of TB developed during 78.17 PY of followup (2558 per 100,000 PY), and there was no case of TB during 73.67 PY of followup in the etanercept-treated RA group. The risk of TB was higher in RA patients not treated with TNF blockers (sex- and age-adjusted risk ratio 8.9; 95% confidence interval 4.6-17.2), and in those treated with infliximab (sex- and age-adjusted risk ratio, 30.1; 95% confidence interval, 7.4-122.3) compared with the general Korean population. CONCLUSION: The risk of TB infection is 8.9-fold higher in Korean patients with RA and 30.1-fold higher in RA patients treated with infliximab, compared with the general Korean population.

Cyclooxygenase-2 genotype and rheumatoid arthritis.

OBJECTIVE: To determine the association between cyclooxygenase-2 (COX-2) genotypes and risk and severity of rheumatoid arthritis (RA) in a Korean population. METHODS: A total of 258 Korean patients with RA and 400 control subjects were recruited from Hanyang University Hospital. Subjects were genotyped for the -765G/C polymorphism of the COX-2 gene by RFLP-PCR analysis. Odds ratios (OR) and 95% confidence intervals (CI) were calculated to estimate risk. Severity of RA was assessed by anatomical stage according to Steinbrocker, et al. RESULTS: No association was observed between COX-2 genotype and risk or severity of RA. However, among those without the shared epitope (SE), carriers of the low activity C allele had a lower risk of RA and less severe form of RA than subjects with the G/G genotype. The OR (95% CI) was 0.36 (0.14-0.95) for risk of RA and 0.04 (0.01-0.41) for severity. CONCLUSION: These results suggest that COX-2 genotyping might be useful in predicting the risk and severity of RA in individuals without the SE.

Angiotensin-converting enzyme gene insertion/deletion polymorphism in Korean patients with systemic sclerosis.

To determine whether angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism is associated with the development and clinical features of systemic sclerosis (SSc) in Korean, we studied seventy two Korean patients with SSc fulfilling the ACR preliminary classification criteria. The controls were 114 healthy, disease free Koreans. ACE I/D genotypes were determined by PCR method using oligonucleotides. Sixty eight patients (94.4%) were women and age at diagnosis was 43.5+/-12.6 yr old (mean+/-SD). Thirty nine patients (54.2%) had a diffuse type of SSc. There were no statistical differences in the frequencies of all ACE I/D genotypes and D allele between patients and controls, and neither between diffuse and limited types of SSc. ACE I/D gene polymorphism was not associated with the development of SSc in Korea. The investigation for the pathogenesis of SSc requires more studies about the role of other candidate genes such as endothelin, TGF-beta, nitric oxide, or angiotensin II receptor in addition to the ACE genes.

Eosinophilic fasciitis associated with autoimmune thyroiditis.

Eosinophilic fasciitis (EF) is scleroderma-like disease without Raynaud's phenomenon or visceral involvement. It is characterized by painful swelling of the extremities, accompanied by rapid weight gain, fever and myalgia. The acute state of disease is associated with significant peripheral blood eosinophilia, an elevated erythrocyte sedimentation rate and hypergammaglobulinemia. EF is also frequently associated with hematological abnormalities, including malignant lymphoproliferative diseases, but rarely associated with autoimmune thyroiditis. In the present study we report a case of eosinophilic fasciitis associated with autoimmune thyroiditis.

Cross-cultural adaptation and validation of the Korean version of the EQ-5D in patients with rheumatic diseases.

OBJECTIVES: This study aimed to determine the cross-cultural adaptation and validation of the Korean version of the EQ-5D in rheumatic conditions. METHODS: Translation, back-translation and cognitive debriefing were performed according to the EuroQol group's guidelines. For validity, 508 patients were recruited and administered the EQ-5D, Short-Form 36 and condition-specific measures. Construct validity and sensitivity were evaluated by testing a-priori hypotheses. For reliability, another 57 patients repeated the EQ-5D at 1-week interval, and intra-class correlations (ICC) and kappa statistics were estimated. For responsiveness, another 60 patients repeated it at 12-week interval within the context of clinical trial, and standardized response mean(SRM) were calculated. RESULTS: The cross-cultural adaptation produced no major modifications in the scale. The associations of the EQ-5D with the generic- and condition-specific measures were observed as expected in hypotheses: the higher EQ-5Dindex and EQ-5D(VAS) scores, the better health status by generic- or condition-specific measures, and the better functional class. The ICCs were 0.751 and 0.767, respectively, and kappa ranged from 0.455 to 0.772. The SRM were 0.649 and 0.410, respectively. CONCLUSION: The Korean EQ-5D exhibits good validity and sensitivity in various rheumatic conditions. Although its reliability and responsiveness were not excellent, it seems acceptable if condition-specific measures are applied together.

Pathogenesis of ankylosing spondylitis and reactive arthritis.

PURPOSE OF REVIEW: The hallmark of ankylosing spondylitis is acute and chronic spinal inflammation initiating in the sacroiliac joints, often coupled with enthesitis, presenting as chronic inflammation at the sites of ligamentous and tendinous insertions into bone. Peripheral joint synovitis can be a prominent feature as well. Reactive arthritis is a sterile synovitis arising after an extra-articular infection of enteric or urogenital tracts. HLA-B27 has been known for about the past 30 years to be associated with ankylosing spondylitis and reactive arthritis, but the pathogenesis of ankylosing spondylitis and reactive arthritis is still not well defined. Although the clinical manifestations of ankylosing spondylitis and reactive arthritis may differ, this update discusses the two diseases together and focuses on recent evidence in both. RECENT FINDINGS: With respect to HLA-B27 several recent studies address arthritogenic peptides, molecular mimicry, and aberrant forms of B27. Several candidate genes in addition to B27 have been implicated in recent genetic studies. With respect to bacterial infection, recent findings in bacterial antigenicity, host response through interactions of antigen-presenting cells, T cells, and cytokines are providing new understanding of host-pathogen interactions and the pathogenesis of arthritis. Endogenous host factors such as proteoglycans may play a role as autoantigens and contribute to chronic inflammation on that basis. SUMMARY: Recent advances provide additional new insights into distinct pathogenetic mechanisms in AS and ReA that arise from a complex interplay between genetic factors including HLA-B27 and environmental factors.

Association analyses of DNA methyltransferase-1 (DNMT1) polymorphisms with systemic lupus erythematosus.

The etiology of systemic lupus erythematosus (SLE) is very complex, and genetic factors appear to play a significant role in susceptibility to SLE, in determining the disease expression, and in the autoantibody profiles of individuals with SLE. DNA methyltransferase-1 (DNMT1) is a major enzyme that determines genomic methylation patterns and both maintains methyltransferase and exhibits de novo DNA methylation activity in vivo. In order to clarify the association of DNMT1 polymorphisms with SLE, we scrutinized the genetic polymorphisms in exons and their boundaries of DNMT1, including the -1,500 bp promoter region, by direct sequencing in 24 Korean individuals. Twenty-nine sequence variants were identified: two in 5'UTR, six in exons, and 21 in introns. Eight of these polymorphisms were selected for a larger-scale genotyping (n=680) by considering their allele frequencies, haplotype-tagging status, and linkage disequilibrium coefficiencies (LDs) among polymorphisms. The associations between DNMT1 polymorphisms and the clinical profiles of SLE were analyzed. No significant associations with the risk of SLE were detected. However, further analyses of association with autoantibody production among SLE patients revealed that one nonsynonymous SNP, +14463G>C (V120L) in exon 4, was weakly associated with an increased risk of anti-La antibody production (P=0.04), although the significance could not be retained after correction of multiple tests. The DNMT1 variations and haplotypes clarified in this study would provide valuable information for future genetic studies of other autoimmune diseases.

A case of refractory Henoch-Schönlein purpura treated with thalidomide.

Henoch-Schönlein purpura is an acute, self-limited vasculitis syndrome which shows characteristic skin, joint, renal and gastrointestinal manifestations. It is common in childhood and may also occur in adults with fatal complications such as nephritis and gastrointestinal bleeding. We experienced a case of a 20-year-old woman who presented with palpable purpura and severe arthritis. The histopathologic examination of the skin revealed leukocytoclastic vasculitis with perivascular deposition of IgA and she was diagnosed with Henoch-Schönlein purpura. Despite treatment with prednisolone for one month, she had more aggravated purpura and fatal gastrointestinal bleeding. The symptoms were improved shortly by cyclophosphamide pulse therapy with plasmapheresis but symptoms were aggravated and symmetric mononeuropathy of the ulnar nerve developed. She was treated with 400 mg/day of thalidomide and symptoms were improved. We herein report a case of Henoch-Schönlein purpura successfully treated with thalidomide which was refractory to prednisolone, immunosuppressive drugs and plasmapheresis.