Cost-utility analysis of biologic disease-modifying antirheumatic drugs (bDMARDs), targeted synthetic DMARDs (tsDMARDs) and biosimilar DMARDs (bsDMARDs) combined with methotrexate for Thai rheumatoid arthritis patients with high disease activity.

BACKGROUND: New biologic disease-modifying antirheumatic drugs (bDMARDs), targeted synthetic DMARDs (tsDMARDs) and biosimilar DMARDs (bsDMARDs) all showed greater clinical benefits in the treatment of patients with rheumatoid arthritis (RA) with high disease activity, but imposed higher costs than standard treatment. This study evaluated the cost-effectiveness of 11 alternative treatment strategies for RA patients with high disease activity whose treatment with three conventional synthetic DMARDs (csDMARDs) failed. METHODS: A Markov model was constructed using a societal perspective to estimate relevant costs and health outcomes in terms of quality-adjusted life years (QALYs) for a lifetime horizon (100 years), given a 3% annual discount. Alternative treatment strategies including five bDMARDs, two tsDMARDs, and four bsDMARDs in combination with methotrexate (MTX) were compared with the standard of care (SoC), i.e., cyclosporine and azathioprine. Direct and non-medical care costs were estimated by identifying the resources used, then multiplied by the standard costing menu in the year 2022. Utility and transitional probabilities were collected in three advanced tertiary hospitals. A network meta-analysis was used to estimate the efficacy of each treatment. Lifetime cost, QALYs and an incremental cost-effectiveness ratio were calculated and compared to the cost-effectiveness threshold of 160,000 THB per QALY gained (US $4,634, where 1 USD = 34.53 THB in 2022). Probabilistic and one-way sensitivity analyses were performed to estimate parameter uncertainties. RESULTS: The bDMARDs, tsDMARDs or bsDMARDs combined with MTX provided 0.09 to 0.33 QALYs gained with additional costs of 550,986 to 2,096,744 THB (US $15,957 to $60,722) compared to the SoC. The ICER ranged from 2.3 to 8.1 million THB per QALY (US $65,935 to $234,996) compared to the SoC. None of these combinations was cost-effective in the Thai context. The results were sensitive to the mortality hazard ratio of patients with high disease activity. CONCLUSIONS: Combinations of MTX with either bDMARDs, tsDMARDs or bsDMARDs were not economically attractive compared to the standard practice. However, they reduced disease activity and improved patient quality of life. The price negotiation process for these treatments must be conducted to ensure their financial value and affordability before they are included in the pharmaceutical reimbursement list.

The efficacy of induction treatment in Thai patients with lupus nephritis: Observational cohort analysis.

BACKGROUND: For active proliferative lupus nephritis (LN), intravenous cyclophosphamide (IVCYC) is a standard therapy whereby mycophenolate mofetil (MMF) is less effective than IVCYC, according to the clinical trials in non-Asians. In this observational study, the clinical outcomes will be compared among Thai patients. METHODS: We had analyzed 93 adult patients who underwent a renal biopsy for active proliferative LN confirmation between January 2013 and June 2021. The assessment of the response outcomes compared the induction treatment of IVCYC versus MMF. The primary endpoint had achieved complete remission (CR) at 24 weeks, while the secondary endpoint is overall remission (OR) and urine protein creatinine ratio (UPCR) changed over time. RESULTS: 93 LN patients were separated into two groups; 40 in IVCYC and 53 in MMF. In the 24th week, based on unadjusted analysis, patient had achieved CR 20.0% of IVCYC, whereas 28.3% of MMF had achieved CR. Unadjusted CR Risk difference was -0.08 (95% CI -0.26, -0.09, p-value = 0.351) and the adjusted CR risk difference was -0.19 (95% CI -0.42, 0.04, p-value = 0.098). The unadjusted OR risk difference was -0.06 (95% CI -0.26, 0.14, p-value = 0.553) while adjusted OR risk difference was -0.24 (95% CI -0.50, 0.02, p-value = 0.067). Unadjusted UPCR mean was -0.29 (95% CI -0.77, 0.17, p-value = 0.210) and adjusted UPCR mean was -0.27 (95% CI -0.88, 0.32, p-value = 0.366). CONCLUSIONS: The induction treatment with either IVCYC or MMF had similar efficacy in Thai LN patients. The decision of treatment should be taken by applying an individualized therapeutic strategy and balancing risks, costs, and benefits.

Low-dose cyclosporine for active lupus nephritis: a dose titration approach.

OBJECTIVE: Achievement of complete renal remission (CR) is an important goal in lupus nephritis (LN) treatment. The use of cyclosporine (CsA) for active LN has been challenged because of variations in CsA doses and reports of adverse reactions (AR). METHOD: A cohort of 62 patients with active LN (induction-resistant LN and flared LN) who were treated with CsA was evaluated. CsA was started at 50 mg/day and titrated up 25 mg/day every 2-4 weeks until CR was achieved or until treatment termination because of AR. RESULTS: The range of CsA dosage was 50-200 mg/day, and mean CsA dose was 102.8 ± 50.43 mg/day (1.73 ± 0.91 mg/kg/day). CsA plus mycophenolate mofetil and prednisolone was administered to 35.5% of patients, while the other 64.5% were treated with CsA and prednisolone. 90.32% had achieved CR and 4.84% had partial remission after 12 months of treatment. UPCR (urinary protein:creatinine ratio) decreased significantly in both groups (2.58 ± 3.37 to 0.36 ± 0.71 and 2.32 ± 1.45 to 0.29 ± 0.24 respectively) (P < 0.001). Non-renal activity including arthritis, alopecia, hematologic and cutaneous conditions improved in all patients. Patients whose prednisolone dose were increase received higher doses of prednisolone at baseline than patients who had stable prednisolone dose, but after 12 months the difference in dosage was insignificant (p = 0.58). CONCLUSION: Patients with active LN can be effectively treated with low dose CsA, and the dose titration approach can lead to 90.32% CR with low AR rates. No difference in clinical response was observed among patients who received CsA plus prednisolone or CsA plus MMF and prednisolone.

Effectiveness and Drug Survival of Anti-Tumor Necrosis Factor α Therapies in Patients With Spondyloarthritis: Analysis From the Thai Rheumatic Disease Prior Authorization Registry.

OBJECTIVE: This study aimed to evaluate the long-term effectiveness and safety of the first anti-tumor necrosis factor α therapy (TNFi) and to identify the associated factors of drug discontinuation in patients with spondyloarthritis. METHODS: This was a medical records review study. Patients with spondyloarthritis who were prescribed the first TNFi between December 2009 and October 2014 in the Rheumatic Disease Prior Authorization registry were enrolled. Baseline clinical data were retrieved. The Cox proportional hazards model was used to identify factors associated with discontinuation of drugs. RESULTS: Among 138 patients, 97 had ankylosing spondylitis (AS), and 41 had psoriatic arthritis (PsA). The effectiveness of TNFi in AS and PsA was 55% to 59% at 4 months and 75% to 96% at 3 years, as measured by a 50% decrease in the Bath Ankylosing Spondylitis Disease Activity Index from baseline. For PsA with peripheral arthritis, improvement of the joint count by 50% was observed in 61.8% of patients at 4 months and 100% at 3 years. Survival from TNFi was 63% for AS and 56% for PsA at 3 years. For AS, the factors associated with good response leading to discontinuation of TNFi were baseline patient global assessment 3 to 6/10 (hazard ratio [HR], 6.3) and the use of leflunomide (HR, 6.0) and infliximab (HR, 4.8). A good response (38.5%) was the most common cause of discontinuation of the first TNFi, followed by toxicity (28.2%), nonadherence (20.5%), and lack of effectiveness (12.8%). CONCLUSIONS: Ankylosing spondylitis and PsA responded well to TNFi during the 3-year follow-up. The retention rate was approximately 60% for AS and PsA. A good response to the first TNFi was the most common reason for discontinuation.

CNTO6785, a Fully Human Antiinterleukin 17 Monoclonal Antibody, in Patients with Rheumatoid Arthritis with Inadequate Response to Methotrexate: A Randomized, Placebo-controlled, Phase II, Dose-ranging Study.

OBJECTIVE: To evaluate the efficacy, safety, pharmacokinetics, and immunogenicity of CNTO6785, a fully human monoclonal antibody that binds to human interleukin 17A, in patients with active rheumatoid arthritis (RA) with inadequate response to methotrexate (MTX) therapy. METHODS: This randomized, double-blind, placebo-controlled, dose-ranging study enrolled patients aged 18 to 80 years (inclusive) with active RA (≥ 6/66 swollen and ≥ 6/68 tender joints) who were refractory to MTX treatment (7.5-25 mg weekly, inclusive). The study duration was 38 weeks, containing a 10-week safety followup. Patients were randomized 1:1:1:1:1 to receive CNTO6785 15, 50, 100, or 200 mg every 4 weeks + MTX or placebo + MTX. The primary endpoint was American College of Rheumatology 20 (ACR20) response at Week 16. RESULTS: There were no significant differences from placebo in the proportion of patients treated with CNTO6785 in the primary endpoint of ACR20 response at Week 16. There were no significant findings in any additional efficacy variables through Week 32. No dose-response relationships or specific patterns were observed in adverse event profiles among CNTO6785 treatment groups. Infections occurred with similar frequency across all groups, and injection site reactions were mild or moderate and did not demonstrate a dose-response relationship. Median serum CNTO6785 concentration increases through Week 38 were about dose-proportional; the incidence of neutralizing antidrug antibodies was 19.4% and was not associated with study drug dose level. CONCLUSION: CNTO6785 was well tolerated, but did not demonstrate clinical efficacy in patients with active RA with inadequate response to MTX.

Drug survival and reasons for discontinuation of the first biological disease modifying antirheumatic drugs in Thai patients with rheumatoid arthritis: Analysis from the Thai Rheumatic Disease Prior Authorization registry.

AIM: To evaluate and compare the retention rate of biological disease-modifying antirheumatic drugs (bDMARDs) in real-life practice and identify risk factors related to remission and drug discontinuation in patients with rheumatoid arthritis (RA). METHOD: A total of 256 patients fulfilling criteria for RA and starting bDMARD between December 2009 and October 2014 were selected from the Rheumatic Disease Prior Authorization registry. Baseline demographic and clinical data were recorded. The cumulative probability of bDMARD discontinuation over 5 years of follow-up and factors associated with RA remission and bDMARD withdrawal were analyzed. RESULTS: Almost half (46%) of patients were initially treated with rituximab (RTX), with 33% treated with etanercept (ETN) and 21% with infliximab (IFX). Fewer than 10% were subsequently switched to a second bDMARD. The 1- and 5-year remission rates in patients continuing their first bDMARD were 7.2% and 21.5%, respectively. At 5 years, the drug survival rates for RTX, ETN and IFX were 50%, 25% and 22%, respectively. Multivariate analysis showed that RTX was significantly associated with highest drug survival. Relative to RTX, the hazard ratios for discontinuation of IFX and ETN were 2.60 (95% confidence interval [CI] 1.53-4.42) and 2.15 (95% CI 1.36-3.42), respectively. Thirty-nine percent of patients stopped treatments, due to inadequate response (42%), serious adverse events (22%), nonadherence (14%) or remission/low disease activity (13%). CONCLUSION: Over 5 years, only one-third of patients continued using their first bDMARD. The leading cause of drug discontinuation was inadequate response.

2016 updated Thai Rheumatism Association Recommendations for the use of biologic and targeted synthetic disease-modifying anti-rheumatic drugs in patients with rheumatoid arthritis.

AIM: In June 2015, the Thai Rheumatism Association (TRA) approved an update of its recommendation for the use of biologic disease-modifying anti-rheumatic drugs (bDMARDs) and targeted synthetic (tsDMARD) in the treatment of rheumatoid arthritis (RA) to cover those currently available in Thailand (etanercept, infliximab, golimumab, rituximab, tocilizumab, abatacept and tofacitinib). METHOD: A search of the literature was performed between January 2000 and June 2015. Existing RA recommendations, in relation to the use of bDMARDs and tsDMARD, were identified and evaluated by the AGREE II instrument prior to their use as a 'guide' for developing this TRA recommendation. An additional literature search was performed in order to answer specific clinical questions that could not be found in existing guidelines. RESULT: Thirteen recommendations were developed. They covered the use of RA classification criteria, the aim of RA treatment, when to initiate bDMARDs/tsDMARD or taper or switch them to other medications, as well as monitoring these drugs during their use. In addition, specific issues including their use and vaccination, malignancies, pregnancy and lactation, and perioperative period also were addressed. Public hearings were performed at the annual meeting of the TRA and of the Royal College of Physicians of Thailand. The recommendations were distributed to other professional associations related to RA management, as well as government sectors associated with the reimbursement policy, prior to development of the final version. CONCLUSION: These recommendations will help Thai rheumatologists prescribe bDMARDs and tsDMARD more appropriately when treating RA patients.

Evidence-based recommendations for the diagnosis and management of rheumatoid arthritis for non-rheumatologists: Integrating systematic literature research and expert opinion of the Thai Rheumatism Association.

AIM: Rheumatoid arthritis (RA) is a chronic inflammatory joint disease leading to joint damage, functional disability, poor quality of life and shortened life expectancy. Early diagnosis and aggressive treatment are a principal strategy to improve outcomes. To provide best practices in the diagnosis and management of patients with RA, the Thai Rheumatism Association (TRA) developed scientifically sound and clinically relevant evidence-based recommendations for general practitioners, internists, orthopedists, and physiatrists. METHODS: Thirty-seven rheumatologists from across Thailand formulated 18 clinically relevant questions: three for diagnosis, 10 for treatments, four for monitoring, and one for referral. A bibliographic team systematically reviewed the relevant literature on these topics up to December 2013. A set of recommendations was proposed based on the results of systematic reviews combined with expert opinions. Group consensus was achieved for all statements and recommendations using the nominal group technique. RESULTS: A set of recommendations was proposed. For diagnosis, either American College of Rheumatology (ACR) 1987 or ACR/European League Against Rheumatism 2010 classification criteria can be applied. For treatment, nonsteroidal anti-inflammatory drugs, glucocorticoid, and disease-modifying antirheumatic drugs, including antimalarials, methotrexate and sulfasalazine are recommended. Physiotherapy should be suggested to all patients. Tight control strategy and monitoring for efficacy and side effects of treatments, as well as indications for referral to a rheumatologist are provided. CONCLUSIONS: These evidence-based recommendations provide practical guidance for diagnosis, fundamental management and referral of patients with RA for non-rheumatologists. However, it should be incorporated with clinical judgments and decisions about care for each individual patient.

The predictive factors of low serum 25-hydroxyvitamin D and vitamin D deficiency in patients with systemic lupus erythematosus.

Vitamin D is a steroid hormone with pleiotropic effects. The association between serum 25-hydroxyvitamin D level [25(OH) D] and lupus nephritis are not clearly known. We aim to determine serum 25(OH) D levels in patients with inactive SLE, active SLE without lupus nephritis (LN) and active SLE with LN and to identify clinical predictor of vitamin D deficiency. One hundred and eight SLE patients were included. Patients were classified as Group (Gr) 1, 2 and 3 if they had SLE disease activity index (SLEDAI) <3, ≥ 3 but no LN and ≥ 3 with LN. Important baseline characteristics were collected. 25(OH) D was measured by high performance liquid chromatography (HPLC). SLEDAI in Gr1, Gr2 and Gr3 was 0.7 (0.9), 5.6 (2.3) and 9.2 (5.2), respectively. 43.5 % had vitamin D insufficiency and 29.6 % had vitamin D deficiency. Mean 25(OH) D in each groups was 28.3 (8.0), 26.7 (9.5) and 19.9 (7.6) ng/ml (p < 0.001 comparing Gr1 and 3) (p = 0.003 comparing Gr2 and 3). Vitamin D deficiency was found in 11.1, 22.2 and 55.6 % of Gr1, 2 and 3. Linear regression analysis found that 25(OH) D was significantly correlated with serum albumin (r = 0.28, p = 0.004), inversely correlated with SLEDAI (r = -0.22, p = 0.03) and urinary protein creatinine index (UPCI) (r = -0.28, p = 0.005), but not with sun exposure score, body mass index and estimated GFR. Only UPCI was significantly inversely correlated with 25(OH) D (p = 0.02) from multiple linear regression. LN was a significant predictor of vitamin D deficiency from multivariate logistic regression (OR 5.97; p = 0.006). Vitamin D deficiency and insufficiency was found in 93 and 86 % of LN with proteinuria ≥ and <500 mg/day. We conclude that SLE patients with LN have significantly lower vitamin D level than inactive SLE and active SLE without LN. Hence, nephritis is a significant predictor of vitamin D deficiency in SLE patients.

Decreased pain and synovial inflammation after etanercept therapy in patients with reactive and undifferentiated arthritis: an open-label trial.

OBJECTIVE: Elevated levels of tumor necrosis factor alpha (TNFalpha) have been identified in the synovium of patients with reactive and undifferentiated arthritis, implicating TNFalpha in the pathogenesis of these disorders. This finding has provided a rationale for the use of TNFalpha antagonists in the treatment of reactive arthritis; however, the possibility that the triggering microorganism might persist in affected joints and become activated with use of these agents has been of concern. METHODS: The efficacy and safety of etanercept (25 mg subcutaneous twice weekly) in 16 patients with undifferentiated or reactive arthritis was assessed in a 6-month open-label trial. Synovial biopsies were performed before and after treatment with etanercept. Polymerase chain reaction (PCR) analysis was performed on the synovial biopsy samples to evaluate for the presence of nucleic acid material of bacterial organisms. Outcome measures including tender and swollen joint counts, pain assessment on a 10-point visual analog scale, and functional ability as measured by the Health Assessment Questionnaire were determined before and after etanercept therapy. RESULTS: Ten of 16 patients completed the trial. Six patients withdrew, but none had a worsening of arthritis or infection. Of the 10 completers, 9 could be classified as treatment responders, despite the evidence of bacterial organisms on PCR analysis prior to initiating etanercept in 3 patients; 2 patients became PCR negative on etanercept. Five of 6 patients with adequate synovial biopsy specimens showed improvement, but not normalization of histology. CONCLUSION: Etanercept was well-tolerated without clinical exacerbation of any suspected underlying infections and appeared to provide therapeutic benefit in our cohort of patients with reactive and undifferentiated arthritis.

Ultrasonography for assessment of subcutaneous nodules.

OBJECTIVE: To characterize a variety of subcutaneous lesions by their ultrasonographic (US) appearance, and establish these images as a starting point to measure changes with treatments. METHODS: Twenty-six patients with 48 subcutaneous nodular swellings of various types were imaged using a portable US machine equipped with a 10 MHz linear transducer. All patients had a known diagnosis of a rheumatic disease. We used US to examine subcutaneous lesions and the underlying cortical surface of the bone or joint. Two measurements of some tophi and rheumatoid nodules were done on different dates to examine reproducibility of the measurements. RESULTS: Nodular lesions included 20 tophi and 20 rheumatoid nodules, 2 sarcoid nodules, 2 lipomas, and 4 synovial cysts. Tophi most often appeared as heterogeneous masses; hypoechoic areas in 2 tophi were decreased after aspiration of chalky liquid tophaceous material. Occasionally tophi had calcifications appearing hyperechoic with acoustic shadowing. Cortical bone erosions could be seen adjacent to some tophi. The nodules in patients with rheumatoid arthritis were often attached closely to the bone surface and less erosive to bone, allowing the cortical bone to be seen easily. The nodules were more homogeneous. Some showed a central sharply demarcated hypoechoic area, possibly corresponding to necrosis inside the rheumatoid nodules. Nodules were easily measured. The repeated measurements of both tophi and rheumatoid nodules showed excellent reproducibility. Lipomas had different echogenic patterns depending on composition of the associated connective tissue and position of the mass. They could be hypoechogenic, hyperechogenic, or mixed, but were easily distinguished by oval shapes with well demarcated capsules. Synovial cysts seen in this study had a characteristic hypoechoic pattern. CONCLUSION: Subcutaneous nodules examined by sonography show characteristics and patterns that, although not diagnostic, can be used to help distinguish their etiology. Tophi and rheumatoid nodules can be easily measured and these measurements used to help follow disease progression or response to therapy.