Clinical observation of tofacitinib combined with hydroxychloroquine in the treatment of refractory rheumatoid arthritis / 中国药房

OBJECTIVE To observe the clinical efficacy and safety of tofacitinib combined with hydroxychloroquine in the treatment of refractory rheumatoid arthritis （RA）. METHODS From January 1， 2021 to January 1， 2022， 120 patients with refractory RA were selected as the study objects. According to the principle of random allocation， the patients were divided into group A， group B and group C， with 40 patients in each group. Group A was given Tofacitinib citrate tablet + Hydroxychloroquine sulfate tablet； group B was given Tofacitinib citrate tablet + Methotrexate tablet； group C was given Tofacitinib citrate tablet + Leflunomide tablet. Three groups were given relevant medicine for 6 months. Therapeutic efficacy and disease activity score 28 （DAS 28） of 3 groups as well as Sharp score， the levels of biochemical indicators [erythrocyte sedimentation rate （ESR）， C- reactive protein （CRP）]， immune indexes [rheumatoid factor （RF）， anti-cyclic peptide containing citrulline （anti-CCP） antibody]， serum cytokine indicators [interleukin-6 （IL-6） and tumor necrosis factor-α （TNF-α）] before and after treatment were observed； the occurrence of adverse drug reactions during treatment was recorded. RESULTS After treatment， the proportions of ACR50 and ACR70 patients in group A were significantly higher than groups B and C （P＜0.05）； DAS28 score， Sharp score， biochemical indicators， immune indexes and serum cytokine indicators of 3 groups were significantly lower than before treatment （P＜0.05）， and gradually decreased with prolonged treatment time； after 6 months of treatment， DAS28 score， Sharp score， RF， anti-CCP antibody， the levels of IL-6 and TNF-α in group A were significantly lower than group B and C （P＜0.05）. There was no significant difference in the incidence of diarrhea， nausea and vomiting， leukopenia， rash， abnormal liver and kidney function， or dizziness among 3 groups （P＞0.05）. CONCLUSIONS Tofacitinib combined with hydroxychloroquine shows good efficacy and safety for refractory RA.

Efficacy of tumor necrosis factor inhibitor combined with intra-articular injection of triamcinolone acetonide in the treatment of refractory rheumatoid arthritis synovitis: a retrospective study.

OBJECTIVE: To investigate whether there is a difference in the efficacy of intra-articular injection of tumor necrosis factor (TNF) inhibitor and triamcinolone acetonide (HA) in rheumatoid arthritis (RA) patients with recurrent synovitis after the first intra-articular injection of HA. METHODS: RA patients who relapsed 12 weeks after the first HA treatment were enrolled in this study. After joint cavity extraction, recombinant human TNF receptor-antibody fusion protein (TNFR:FC) (25 mg or 12.5 mg) or HA (1 ml or 0.5 ml) was injected then. The changes in the visual analog scale (VAS), joint swelling index, and joint tenderness index before and 12 weeks after reinjection were compared and analyzed. The changes in synovial thickness, synovial blood flow, and fluid dark zone depth before and after reinjection were observed by ultrasound. RESULTS: Forty-two RA patients were enrolled, including 11 males and 31 females, with an average age of 46.79 ± 12.61 years and an average disease duration of 7.76 ± 5.44 years. After 12 weeks of intra-articular injection of HA or TNFR:FC, the VAS scores were significantly lower than those before treatment (P < 0.01). After 12 weeks of injection, the scores of the joint swelling index and tenderness index in both groups were significantly decreased compared with those before treatment. There was no significant difference in synovial thickness under ultrasound in the HA group before and after injection, while the synovial thickness in the TNFR:FC group was significantly improved after 12 weeks (P < 0.01). After 12 weeks of injection, the grade of synovial blood flow signal in both groups decreased significantly compared with that before treatment, especially in the TNFR:FC group. After 12 weeks of injection, the depth of the liquid dark area under ultrasound decreased significantly in the HA group and TNFR:FC group compared with that before treatment (P < 0.01). CONCLUSION: Intra-articular injection of a TNF inhibitor is an effective method for the treatment of recurrent synovitis after conventional hormone therapy. Compared with HA treatment, it can reduce synovial thickness. Key Points • Intra-articular injection of a TNF inhibitor is an effective method for the treatment of recurrent synovitis after conventional hormone therapy. • Compared with HA treatment, intra-articular injection of biological agents combined with glucocorticoids can not only relieve joint pain but also significantly inhibit joint swelling. • Compared with HA treatment, intra-articular injection of biological agents combined with glucocorticoids cannot only improve synovial inflammation but also inhibit synovial proliferation. • For the treatment of refractory RA synovitis, biological agents combined with glucocorticoid injection are an effective and safe option.

Predictive model to identify multiple failure to biological therapy in patients with rheumatoid arthritis.

Background: Despite advances in the treatment of rheumatoid arthritis (RA) and the wide range of therapies available, there is a percentage of patients whose treatment presents a challenge for clinicians due to lack of response to multiple biologic and target-specific disease-modifying antirheumatic drugs (b/tsDMARDs). Objective: To develop and validate an algorithm to predict multiple failure to biological therapy in patients with RA. Design: Observational retrospective study involving subjects from a cohort of patients with RA receiving b/tsDMARDs. Methods: Based on the number of prior failures to b/tsDMARDs, patients were classified as either multi-refractory (MR) or non-refractory (NR). Patient characteristics were considered in the statistical analysis to design the predictive model, selecting those variables with a predictive capability. A decision algorithm known as 'classification and regression tree' (CART) was developed to create a prediction model of multi-drug resistance. Performance of the prediction algorithm was evaluated in an external independent cohort using area under the curve (AUC). Results: A total of 136 patients were included: 51 MR and 85 NR. The CART model was able to predict multiple failures to b/tsDMARDs using disease activity score-28 (DAS-28) values at 6 months after the start time of the initial b/tsDMARD, as well as DAS-28 improvement in the first 6 months and baseline DAS-28. The CART model showed a capability to correctly classify 94.1% NR and 87.5% MR patients with a sensitivity = 0.88, a specificity = 0.94, and an AUC = 0.89 (95% CI: 0.74-1.00). In the external validation cohort, 35 MR and 47 NR patients were included. The AUC value for the CART model in this cohort was 0.82 (95% CI: 0.73-0.9). Conclusion: Our model correctly classified NR and MR patients based on simple measurements available in routine clinical practice, which provides the possibility to characterize and individualize patient treatments during early stages.

Novel treatment for refractory rheumatoid arthritis with total glucosides of paeony and nobiletin codelivered in a self-nanoemulsifying drug delivery system.

Patients with refractory rheumatoid arthritis (RA) remain a substantial clinical problem, while the overexpression of P-glycoprotein (P-gp) on their lymphocytes may contribute to resistance to anti-rheumatic drugs. This study aims to develop a novel treatment for refractory RA consisting of the combination of total glucosides of paeony (TGPs) and the P-gp inhibitor nobiletin (N), which are codelivered in a self-nanoemulsifying drug delivery system (SNEDDS). Based on the solubility, compatibility, and pseudoternary phase diagram tests, a nano-SNEDDS formulation composed of capryol 90-cremophor EL35-tcranscutol HP (CET) to codeliver TGP and N was developed, and this formulation increased the bioavailability of TGP by 435.04% (indicated with paeoniflorin). A modified adjuvant-induced arthritis (AIA) rat model was verified for the overexpression of P-gp in lymphocytes and resistance to methotrexate (MTX) treatment at the reported anti-inflammatory dosage. CET formulation not only increased the solubility and permeability of TGP but also inhibited the function and expression of P-gp, leading to enhanced bioavailability and intracellular concentration in the lymphocytes of AIA rats and consequently boosting the anti-arthritic effects of TGP. Moreover, TGP and N coloaded CET reduced the expression of P-gp in AIA rats partly by inhibiting the phosphorylated AKT and HIF-1α pathways. In summary, TGP-N coloaded SNEDDS is a novel and effective treatment for refractory RA.

[The rich diversity of Whipple's disease]. / Facettenreichtum des Morbus Whipple.

Whipple's disease (WD) is a rare, chronic multiorgan disease which can caused by Tropheryma whipplei, a ubiquitous gram positive bacterium. Detection of T. whipplei is mostly performed histologically using periodic acid-Schiff (PAS) staining in affected tissues to visualize characteristic PAS-positive macrophages and by the polymerase chain reaction (PCR). Clinically, WD is often characterized by gastrointestinal symptoms (diarrhea, colic-like abdominal pain and weight loss). Arthritis is a common presentation of WS, often leading to a misdiagnosis of seronegative rheumatoid arthritis and as a consequence to immunosuppressive therapy. The clinical presentation of WD is highly polymorphic affecting different organ systems (e. g. cardiac or neurological manifestation) and making an appropriate clinical diagnosis and even the diagnostic process itself difficult. This article reports on three cases presenting with completely different leading symptoms (initially misdiagnosed as seronegative rheumatoid arthritis, spondyloarthritis and adult onset of Still's disease, respectively) that illustrate the rich diversity of WD. The cases were chosen to draw attention to the fact that although WD is mainly associated with the field of gastroenterology and gastrointestinal (GI) involvement is common, it may appear without GI symptoms. In cases of a clinical suspicion of WD, diagnostic efforts should be made to detect the bacterium in the affected organ. The German S2k guidelines on GI infections and WD published in January 2015 summarized the current state of the art for WD. The currently recommended primary treatment is antibiotics that can infiltrate the cerebrospinal fluid, e. g. ceftriaxone, followed by cotrimoxazole, which should be maintained over several months.

Repository corticotropin injection in patients with rheumatoid arthritis resistant to biologic therapies.

INTRODUCTION: Although synthetic and biologic disease-modifying antirheumatic drugs are available, many patients with rheumatoid arthritis have a difficult-to-control disease and need other treatment options. Repository corticotropin injection (RCI) may alleviate symptoms and exacerbations in patients with refractory disease. METHODS: Nine patients with refractory rheumatoid arthritis were included in this study. Patients were maintained on their baseline therapies with a minimum of 7.5 mg prednisone daily. RCI was given daily at 40 U for 7 days. Patients who had an adequate disease response were given 40 U twice weekly through Week 12. For patients who had inadequate disease response, the dose was increased to 80 U daily for 7 days, followed by 80 U twice weekly through Week 12. RESULTS: The primary endpoint was >1.2 point reduction in the Disease Activity Score 28 using C-reactive protein (DAS28-CRP) at Week 12. Secondary endpoints were improvements in Health Assessment Questionnaire-Disease Index and Functional Assessment of Chronic Illness Therapy scores. Six of the nine patients met the primary endpoint. The average change in DAS28-CRP from baseline to Week 12 was numerically greater with 40 U than with 80 U RCI. Functional Assessment of Chronic Illness Therapy and Health Assessment Questionnaire-Disease Index improved as early as Week 1, and the improvements remained throughout treatment. CONCLUSION: There was no association between cortisol levels and low-dose RCI response. No serious adverse events occurred. RCI produced a clinically meaningful reduction in markers of disease activity, improved health-related quality of life, and a favorable safety profile. The response rate to RCI was substantial and shows promise in this difficult-to-treat population.

Repository corticotropin injection as adjunctive therapy in patients with rheumatoid arthritis who have failed previous therapies with at least three different modes of action.

OBJECTIVE: Many types of treatment are available for patients with rheumatoid arthritis (RA), however, some patients fail to achieve remission. This report aims to determine the safety and efficacy of using repository corticotropin injection (RCI) as an adjunctive therapy in patients with RA refractory to at least three therapeutics with different mechanisms of action. METHOD: In this open-label, interventional, single-group study, patients received 80 U RCI twice weekly via subcutaneous injection over 12 weeks. Changes in the Ritchie-Camp Articular Index and health assessment questionnaire scores were monitored for changes from baseline measures. RESULTS: Eight patients were enrolled and consisted of seven females and one male with an average age of 64.6 years and disease duration of 20.9 years. Use of RCI resulted in significant improvement in swollen and tender joint counts. The disease activity score 28 and the physician and patient visual analog scale scores were significantly reduced at treatment week 12. The reduction in health assessment questionnaire scores did not reach statistical significance after RCI treatment. Once RCI therapy was discontinued, all improvements in disease activity score 28, physician and patient visual analog scale, and tender and swollen joint counts achieved during treatment were lost by the week 16 follow-up visit. CONCLUSION: While larger clinical trials are necessary to further confirm the efficacy of RCI in patients with refractory RA, the response of patients with refractory RA in this study suggests that RCI can be an effective add-on therapy for patients who have exhausted several classes of treatments. Furthermore, this study suggests that RCI has an alternative mode of action, compared to other available antirheumatic drugs.

Comparison of the Effects of Iguratimod Combined with Methotrexate and Diacerein Respectively on Relat-ed Indexes of Refractory Rheumatoid Arthritis / 中国药房

OBJECTIVE:To compare the effects of iguratimod combined with methotrexate and diacerein respectively on relat-ed indexes of refractory rheumatoid arthritis (RRA). METHODS:98 RRA patients were randomly divided into control group (48 cases)and observation group(50 cases). Control group received Iguratimod tablet 25 mg,twice a day+Methotrexate tablet with ini-tial dose of 10 mg,once a week,increased to 12.5 mg after 2 weeks,increased to 15 mg in the second courses,once a week. Ob-servation group received Iguratimod tablet(the same dosage and usage with control group)+Diacerein granule 50 mg,twice a day. 4-week was a course,they were treated for 6 courses. Morning stiffness time,the numbers of 28 joints tenderness and swelling,28 joint disease activity score (DAS28),erythrocyte sedimentation rate (ESR),rheumatoid factor (RF),IL-1,vascular endothelial growth factor (VEGF),tumor necrosis factor (TNF)-α,C-reaction protein (CRP),malondialdehyde (MDA),superoxide dis-mutase(SOD),total antioxidant capacity(TAOC),early peak flow(peak E),left ventricular late flow peak flow(peak A),E/A and left ventricular ejection fraction(LVEF)before and after treatment,and the incidence of adverse reactions in 2 groups were ob-served. RESULTS:Before treatment,morning stiffness time,the numbers of 28 joints tenderness and swelling,DAS28 score, ESR,RF,IL-1,TNF-α,CRP,VEGF,MDA,TAOC and peak A in 2 groups were significantly lower than before treatment,and observation group was significantly lower than control group;SOD,peak E,E/A and LVEF in 2 groups were significantly higher than before treatment,and observation group was significantly higher than control group,with statistical significances (P0.05). CONCLUSIONS:Iguratimod combined with diacerein is superior to iguratimod combined with methotrexate in improving cardiac function,oxidation-antioxidant imbalance play and reducing inflammatory reactions in the treatment of RRA,with similar safety.

Predictors of European League Against Rheumatism (EULAR) good response, DAS-28 remission and sustained responses to TNF-inhibitors in rheumatoid arthritis: a prospective study in refractory disease.

The aim of this study was to survey factors related to EULAR good response, the DAS-28 definition of remission, ACR 50 response, sustained response to tumor necrosis factor inhibitors (TNF-I) therapy in biologic naïve patients with refractory rheumatoid arthritis. This was a single center observational clinical prospective 2 years' study, EULAR response criteria, DAS 28, HAQ and radiographic changes were recorded. Eighty patients included (64 females and 16 males, mean age was 48.4 + -17.9 years, mean disease duration 7.3 + -5.9 years). At 6 months 70% achieved EULAR good response, 51.8% achieved DAS-28 remission. Good response/sustained responses inversely correlated with baseline DAS-28 and radiographic erosions P <0.05. EULAR good response/remission by 6 months, sustained response at 2 years positively correlated with the decline in RF titers (r = 0.33, P < 0.05 & r = 0.30, P < 0.03 respectively), negatively correlated with the baseline HAQ. Regression analysis identified higher serum hemoglobin concentration, lower baseline HAQ scores, and the absence of radiographic erosions as significant predictors of good as well as sustained responses after adjustment for potential covariates. Methotrexate was associated with favorable responses and remission at 6 months (ORs = 1.13, 1.30 respectively). The study concluded that a lower baseline DAS-28 and HAQ scores, the lack of radiographic erosions favored EULAR good response and were significant predictors of sustained response to TNF-I.