The Prevalence of SNP rs12517451 in Gene Transcribing Dihydrofolate Reductase and Drug Adverse Effects among MTX-treated Rheumatoid Arthritis Patients in Kelantan, Malaysia

@#Introduction: Disease-modifying anti rheumatic drugs (DMARDs) provide the mainstay for the treatment of rheumatoid arthritis (RA). Adverse effects (AEs) in DMARDs among RA patients are usually related with methotrexate (MTX) use, the common conventional DMARDs. Genetic variant such as single nucleotide polymorphism (SNP) in gene transcribing dihydrofolate reductase (DHFR) (i.e, 829C>T, rs12517451) has been correlated with drug AEs in MTX-treated RA. The prevalence of the DHFR rs12517451 SNP has been reported in other populations, but not in Malaysian. The aim of this study was to determine the prevalence of the DHFR rs12517451 SNP and its association with drug AEs among MTX-treated RA patients from Kelantan, Malaysia. Methods: A total of 78 RA patients receiving MTX (alone or in combination) were included in this study. Based on evidence of clinically perceived drug AEs in MTX-treated RA patients, 33 and 45 samples were assigned as cases and controls, respectively. The genotype of the patients was determined using the polymerase chain reaction-restriction fragment length polymorphism method and validated by sequencing analysis. Results: Minor allele frequency (MAF) for DHFR rs12517451 in cases and controls were 28.8% and 32.2% but there was no significant difference (p=0.727) for the possession of the minor allele T between the two groups. The most reported AEs among cases were haematological effects, gastrointestinal toxicity, and skin problems resulting in 21% withdrawal of MTX. Conclusion: We did not find significant association of the DHFR rs12517451 with drug AEs in MTX-treated RA patients. Our findings warrant replication in a larger patient cohort.

Risk factors for losing hepatitis B virus surface antibody in patients with HBV surface antigen negative/surface antibody positive serostatus receiving biologic disease-modifying anti-rheumatic drugs: a nested case-control study

Abstract Background: Hepatitis B virus (HBV) reactivation consequent to immunosuppressive therapy is an increasingly prevalent problem with serious clinical implications. Treatment with biologic agents conduces to the loss of protective antibody to HBV surface antigen (anti-HBs), which significantly increases the risk of HBV reactivation. Hence, we investigated the risk factors for losing anti-HBs in patients with rheumatic diseases and HBV surface antigen negative/anti-HBs positive (HBsAg-/anti-HBs+) serostatus during treatment with biologic disease-modifying anti-rheumatic drugs (DMARDs). Methods: Using a nested case-control design, we prospectively enrolled patients with rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis/psoriasis, or juvenile idiopathic arthritis, who were treated with biologic DMARDs at Changhua Christian Hospital, Taiwan, from January 2013 to June 2019 and had HBsAg-/anti-HBs+ serostatus; the analytic sample excluded all patients with HBsAg+ or anti-HBs- serostatus. Anti-HBs titers were monitored 6-monthly and cases were defined as anti-HBs < 10 mIU/ml during follow-up. Cases were matched one- to-all with controls with anti-HBs ≥ 10 mIU/ml on the same ascertainment date and equivalent durations of biologic DMARDs treatment (control patients could be resampled and could also become cases during follow-up). Between-group characteristics were compared and risk factors for anti-HBs loss were investigated by conditional logistic regression analyses. Results: Among 294 eligible patients, 23 cases were matched with 311 controls. The incidence of anti-HBs loss was ∼ 2.7%/person-year during biologic DMARDs treatment. Besides lower baseline anti-HBs titer (risk ratio 0.93, 95% CI 0.89-0.97), cases were significantly more likely than controls to have diabetes mellitus (risk ratio 4.76, 95% CI 1.48-15.30) and chronic kidney disease (risk ratio 14.00, 95% CI 2.22-88.23) in univariate analysis. Risk factors remaining significantly associated with anti-HBs loss in multivariate analysis were lower baseline anti-HBs titer (adjusted risk ratio 0.93, 95% CI 0.88-0.97) and chronic kidney disease (adjusted risk ratio 45.68, 95% CI 2.39-871.5). Conclusions: Besides lower baseline anti-HBs titer, chronic kidney disease also strongly predicts future anti-HBs negativity in patients with HBsAg-/anti-HBs+ serostatus who receive biologic DMARDs to treat rheumatic diseases. Patients with low anti-HBs titer (≤ 100 mIU/ml) and/or chronic kidney disease should be monitored during biologic DMARDs therapy, to enable timely prophylaxis to preempt potential HBV reactivation.

Combination of Methotrexate and Leflunomide for Adult-onset Still's Disease: A Case Report and Literature Review

The treatment of adult-onset Still's disease (AOSD) aims to control systemic inflammation and prevent organ damage. Systemic inflammation can be controlled with corticosteroid (CS) monotherapy in most cases. However, symptoms often flare as CS is tapered, often requiring long-term CS treatment, with its associated risks of infection, cardiovascular disease, and osteoporosis. Disease-modifying antirheumatic drugs (DMARDs) are often used as CS-sparing agents; however, the choice of DMARD has been largely empirical. Methotrexate (MTX) is recommended as the first-line steroid-sparing drug due to its well-known efficacy and safety in rheumatoid arthritis (RA). When MTX treatment is unsuccessful in AOSD, the choice of a second-line drug has not been established. In RA, leflunomide (LEF) has been used as an alternative to or in combination with MTX. To date, there has been no adequate assessment of the combination of LEF and MTX in AOSD. Here, we report a case of refractory chronic AOSD successfully treated with the MTX-LEF combination.

The plasma Tumor Necrosis Factor-α (TNF-α) does not have any correlation with disease activity in rheumatoid arthritis patients treated with disease modifying anti-rheumatic drugs (DMARDs)

We performed this study to measure the Tumor Necrosis Factor-alpha (TNF-α) plasma level and to survey its correlation with disease activity in the newly diagnosed Rheumatoid Arthritis (RA) patients and those who were under treatment with the combination of Disease-Modifying Anti-Rheumatic Drug (DMARD) plus Prednisolone (PSL).We enrolled 30 newly diagnosed RA patients who received no treatment regarding their disease, 30 patients under treatment with the combination of Methotrexate (MTX) + Hydroxychloroquine (HCQ) + PSL and 30 healthy subjects in this case-control study from September 2017 to December 2017. The level of plasma TNF-α was measured by enzyme-linked immunosorbent assay (ELISA) in each group. For assessment of disease severity, we used Disease Activity Score-28 (DAS-28) formula, and regarding DAS-28, we divided patients into four groups, including remission, low, moderate and high disease activity. There were no significant differences in the plasma level of TNF-α between the newly diagnosed RA patients and subjects who received MTX + HCQ + PSL, as well as healthy controls (p>0.05). There was a significant correlation between plasma levels of TNF-α and DAS-28 in the newly diagnosed patients with RA (r = 0.594, P = 0.001). Targeting TNF-α at the early stage of RA could have more beneficial effects on the amelioration of disease activity

The Risk of Cardiovascular Disease and Diabetes in Rheumatoid Arthritis Patients: A Propensity Score Analysis

BACKGROUND: Rheumatoid arthritis (RA) is a systemic inflammatory disease that manifests as joint damage or athletic disability via sustained inflammation of the synovial membrane. The risk of cardiovascular disease (CVD) is higher in RA patients. This study aimed at evaluating the association between CVD comorbidities and RA by comparing a pharmacotherapy group with a non-pharmacotherapy group. METHODS: Patient sample data from the Health Insurance Review and Assessment Service (HIRA-NPS-2016) were used. Inverse probability of treatment weighting (IPTW) using the propensity score was used to minimize the differences in patient characteristics. Logistic regression analysis was used to evaluate the risk of CVD comorbidities. RESULTS: The analyses included 1,207,213 patients, of which 33,122 (2.8%) had RA. The odds ratios (OR) of CVD comorbidities were increased in RA patients; ischemic heart disease (IHD: OR 1.75; 95% CI 1.73, 1.77), cerebral infarction (CERI: OR 1.28; 95% CI 1.26, 1.30), hypertension (HTN: OR 1.44; 95% CI 1.43, 1.45), diabetes mellitus (DM: OR 2.04; 95% CI 2.03, 2.06), and dyslipidemia (DL: OR 3.49; 95% CI 3.47, 3.51). The ORs of IHD, CERI, HTN, and DM in the traditional DMARD and biologic treatment groups were decreased, compared with those in the non-pharmacotherapy group. CONCLUSIONS: Thus, CVD risk was higher in RA patients, considering age, sex, and socioeconomic status. Appropriate pharmacotherapy could decrease the risk of CVD comorbidities in RA patients.

Study of Prognostic Significance of Anti Cyclic Citrullinated Peptide Antibodies in Patients with Rheumatoid Arthritis

Background: Rheumatoid arthritis is a chronic autoimmune inflammatory disease with articular and extra-articular manifestation that affects 0.5 to 1 % of total population. Aim and Objectives: To correlate Rheumatoid factor (RF) and Anti-CCP antibody in RA, to evaluate prognostic value of RF and Anti-CCP antibody in RA. Materials and methods: Retrospective study of total 50 patients admitted to our hospital from January 2018 to December 2018 was done. All patients were diagnosed as rheumatoid arthritis as per diagnostic criteria of American College of Rheumatology. All patients had symptom duration of at least one Year. Anti-CCP and lgM-RF were evaluated in all patients. Disease activity score 28 was calculated in all patients. Radiological Damage was assessed by Larsen Score. Results: Anti-CCP and RF were significantly correlated with each other and both were seen as significant independent predictors of radiological outcomes (p value 0.01 and <0.05 respectively). Combination of these two had highest risk for erosive joint damage. Conclusion: RA is more common in female. Anti-CCP antibody and RF both in combination were associated with higher probabilities of erosive disease.

Clinical profile of rheumatic patients with infectious complications

Background: The objective of the present research was to study clinical profile of rheumatic patients having infections including correlation of infection with different parameters and DMARDS and to study incidence pattern of various infections.Methods: All patients of various Rheumatic diseases with infections who fulfil inclusion criteria who were enrolled in this study. Duration of study was six months. A total of 300 patients where studied out of which 50 were cases and the rest were control.Results: Incidence of infection was high in extremes of age. Overall incidence of infection was slightly higher in females. Infection rate was 16.66%. Incidence of infection was highest among vasculitis group. Kidney was the most common organ involved. Incidence of infection was more in patients having anemia and leukopenia. Tuberculosis was the most common infection found in Rheumatic patients.Conclusions: Infection was more common at extremes of age and more common in females. SLE was most common disease encountered while kidney was most common organ to get involve in disease process. Patients with anemia and leukopenia had statistically significant incidence of infections. Tuberculosis is most common infection encountered in Indian rheumatic patients.

Characteristics of rheumatoid arthritis patients at first presentation to a specialized rheumatology department.

Background: Rheumatoid arthritis (RA) is a chronic, progressive, debilitating, systemic, autoimmune disease that mainly affects the diarthrodial joints. It is the most common form of inflammatory arthritis that occurs in approximately 1% of adults. The main objective is to study the characteristics of patients with Rheumatoid Arthritis (RA) at first presentation to a specialized rheumatology department. Methods: The study included 122 consecutive patients with RA, fulfilling 1987 American College of Rheumatology (ACR) criteria for RA at ‘Joint Disease Clinic’ of rheumatology department, at ISIC, New Delhi. Results: The mean age was 45.3 ± 12.4 years, F:M ratio, 8.4:1; maximum patients (31.1%) belonging to age group 30-40 years. Mean age at onset of symptoms was 38.1 ± 12.9 years and disease duration mode 5 years. 88% patients were literate and 59% referred by other patients. 14.8% patients had family history of RA, 7.38% (all males) were smokers. 16.4% female patients developed symptoms of arthritis within one year after delivery. 44.3% patients had severe, 50.8% moderate, 3.3% mild and 1.6% inactive disease (DAS 28[ESR] scoring system). 28.7% patients were taking treatment from alternative systems, 25.4% from orthopaedicians, 15.6% from internists and 8.2% from rheumatologists. Methotrexate and glucocorticoids were the most prescribed drugs (50.8% each) but in inappropriate doses. 23.8% patients had co-morbidities, hypothyroidism (9%) being the commonest. Conclusions: RA affects middle aged women. Hypothyroidism is the mostly associated autoimmune disease. The majority receive suboptimal / inappropriate treatment before visiting a rheumatologist. Most patients consult a rheumatologist at late stage in the disease often with deformities. Hence, increased awareness is needed about this disease among patients and doctors so that patients get timely referral to a rheumatologist for the proper management of this disease.

Artrite reumatóide / Rheumatoid arthritis

A artrite reumatóide (AR) é uma doença crônica, sistêmica, auto-imune, de etiologia desconhecida, que envolve, predominantemente, as pequenas articulações das mãos e dos pés. Punhos, articulações metacarpofalangeanas, interfalangeanas proximais e metatarsofalangeanas são as articulações mais envolvidas. A patogênese é complexa e multifatorial, com participação de fatores genéticos, ambientais e hormonais. A realização do diagnóstico o mais rápido possível e o estabelecimento imediato de terapia adequada nas fases mais iniciais da doença são de fundamental importância para o prognóstico do paciente. O diagnóstico da AR é realizado através da avaliação das manifestações clínicas, achados laboratoriais e de imagem. O paciente apresenta, na maioria das vezes, um quadro de poliartrite tendendo a evoluir para deformidades articulares, com importante perda funcional devido à característica crônica e progressiva da doença. O fator reumatóide (FR) se encontra positivo em 70% a 80% dos pacientes com AR. Corresponde a um auto-anticorpo, geralmente classe IgM, dirigido contra a porção Fc da imunoglobulina IgG. Quando presente em títulos elevados, a doença é, geralmente, mais agressiva e tem maiores chances de apresentar manifestações extra-articulares. O início da terapêutica o mais rápido possível é baseado em dados de estudos clínicos, que demonstraram o benefício no curso evolutivo, prevenindo o dano articular, a perda da função e a redução da dor. O principal objetivo do tratamento é o de atingir a remissão. A base do tratamento da AR é a utilização das drogas modificadoras do curso da doença (DMCD), associadas a antiinflamatórios não hormonais (AINH) e antiinflamatórios hormonais (AIH). Os agentes biológicos são novas drogas que têm indicação nos pacientes que não responderam adequadamente ao uso dos DMCD.

Recent Advances in the Treatment of Spondyloarthropathy

Spondyloarthropathy is a chronic inflammatory disease involving axial joints and peripheral joints, and finally induces ankylosis of the spine. Treatment of spondyloarthropathy including ankylosing spondylitis has many limitations. Nonsteroidal anti-inflammatory drugs have played an important role in the control of pain and stiffness, however, could not inhibit the development of axial joint deformity. Although disease-modifying antirheumatic drugs, such as sulfasalazine, methotrexate, and cyclosporine, are currently used in the clinic, clinical data supporting their efficacy from randomized controlled studies are still not enough. Also the efficacy of pamidronate, thalidomide, or other potential therapeutic agents needs to be con-firmed by randomized controlled trials. Lately the introduction of inhibitors of tumor necrosis factor alpha in the rheumatic diseases has made a great advance in the management of spondyloarthropathy. Here I review the conventional and newly introduced options in the management of spondyloarthropathy.