Tripterine ameliorates monosodium urate crystal-induced gouty arthritis by altering macrophage polarization via the miR-449a/NLRP3 axis.

OBJECTIVE: Tripterine (Trip) is frequently applied to alleviate inflammation in various diseases such as rheumatoid arthritis. Macrophages have both anti-inflammatory and pro-inflammatory functions. However, whether Trip can inhibit cell inflammation in gouty arthritis (GA) remains undiscovered and whether the mechanism involved in macrophage polarization is also undetermined. This paper aims to study the effects of Trip on inflammation and macrophage polarization in GA. METHODS: Monosodium urate (MSU) crystals were used to establish GA mouse models, and bone marrow-derived macrophages (BMDMs) were induced to construct GA cell models. Pretreatments of Trip and injection of Antagomir-449a/Agomir-449a were performed on mice for 6 days. The effects of Trip and miR-449 on toe swelling, joint damage of GA mouse were examined. The alternations on cell morphology, cell proliferation marker Ki67, inflammatory cytokines, NLRP3 inflammasome, and NF-κB signaling-related proteins were also determined both in vivo and in vitro. Dual-luciferase reporter gene assay and RIP assay were adopted to estimate the targeting relationship between miR-449a and NLRP3. RESULTS: GA mouse model had increased M1 macrophage, intensified inflammation response, along with suppressed miR-449a expression. Following administration of Trip attenuated cell inflammation, promoted macrophage polarize to M2 phenotype, elevated miR-449a expression, repressed the phosphorylation levels of NF-κB signaling-related proteins, and diminished IκBα expression in vivo and in vitro. However, inhibition of miR-449a hindered the favorable effect of Trip on GA and increased NLRP3 inflammasome expression. MiR-449a directly targeted NLRP3. Overexpression of NLRP3 partially eliminated the biological effects of miR-449a agonist. CONCLUSION: Trip regulates macrophage polarization through miR-449a/NLRP3 axis and the STAT3/NF-κB pathway to mitigate GA. The elucidation on the molecular mechanism of Trip in GA may provide theoretical guidance for clinical therapy of GA.

Methotrexate achieves major cDAPSA response, and improvement in dactylitis and functional status in psoriatic arthritis.

OBJECTIVE: Despite the widespread clinical use of MTX in PsA, data from published randomized controlled studies suggest limited efficacy. The objective of the present study was to document the efficacy of MTX. METHODS: This was an open-label, prospective study of patients satisfying the ClASsification criteria for Psoriatic ARthritis study (CASPAR) criteria for PsA who received MTX in doses of ⩾15 mg/week throughout the follow-up period of 9 months. Disease activity was assessed across various domains by tender and swollen joint count, physician and patient global assessment, DAS-28 ESR, Clinical Disease Activity Index for PsA (cDAPSA), Leeds Dactylitis Instrument basic, Leeds Enthesitis Index (LEI), Psoriasis Area and Severity Index (PASI), Minimal Disease Activity and HAQ (CRD Pune version) at baseline and at 3, 6 and 9 months of follow-up. Response to therapy was assessed by EULAR DAS28 ESR, Disease Activity Index for PsA (cDAPSA) response, HAQ response and PASI75. MTX dose escalation and the use of combination DMARDS were dictated by disease activity. RESULTS: A total of 73 patients were included, with mean (s.d.) age 44 (9.7) years. The mean (s.d.) dose of MTX used was 17.5 (3.8) mg/week. Seven patients received additional DMARDS (LEF/SSZ). At the end of 9 months, significant improvement (P < 0.05) was noted in the tender joint count, swollen joint count, global activity, DAS-28ESR, cDAPSA, Leeds Dactylitis Index basic, LEI, PASI and HAQ. Major cDAPSA response was achieved in 58.9% of patients. EULAR DAS28 moderate and good response was achieved in 74% and 6.8% of patients, respectively. Minimal Disease Activity was achieved in 63% of patients. A PASI75 response and HAQ response was achieved in 67.9% and 65.8% of patients, respectively. CONCLUSION: MTX initiated at ⩾15 mg/week with targeted escalation resulted in significant improvement in the skin, joint, dactylitis, enthesitis and functional domains of PsA.

A case of juvenile idiopathic arthritis exhibiting repair of systemic bone erosion in response to continuation of MTX therapy after achievement of clinical remission.

We report a patient with rheumatoid factor-positive polyarthritis-type juvenile idiopathic arthritis (JIA) in whom clinical remission was achieved within 10 months after the start of methotrexate (MTX) therapy, and systemic repair of bone erosion was noted 8 months after clinical remission. These results indicate that even in cases of active JIA with the development of bone erosion, continuation of MTX therapy after the achievement of clinical remission can improve the prognosis, including repair of bone destruction.

Prostaglandin E2 exacerbates collagen-induced arthritis in mice through the inflammatory interleukin-23/interleukin-17 axis.

OBJECTIVE: Recently, Th17 cells, a new subset of CD4+ T cells, emerged as major players in inflammation/autoimmunity. Maintenance of the Th17 phenotype requires interleukin-23 (IL-23), whereas the Th1-promoting cytokine IL-12p70 exerts a negative effect on Th17 cell differentiation. The lipid mediator prostaglandin E(2) (PGE(2)) acts primarily as a proinflammatory agent in autoimmune conditions, through mechanisms that remain to be elucidated. The aim of this study was to investigate whether PGE(2) released in inflammatory foci activates resident dendritic cells (DCs) to express IL-23 (at the expense of IL-12) and IL-6, resulting in a shift toward Th17 cell responses. METHODS: The effect of PGE(2) on IL-23 production by DCs and subsequent induction of T cell-derived IL-17 was assessed in vitro and in vivo. The effect of the stable PGE analog misoprostol was evaluated in a murine model of rheumatoid arthritis, in conjunction with IL-23 and IL-17 expression in affected joints and draining lymph nodes. RESULTS: In vivo administration of PGE(2) induced IL-23-dependent IL-17 production. Administration of misoprostol exacerbated collagen-induced arthritis (CIA). CIA exacerbation was associated with increased levels of IL-23p19/p40 messenger RNA and reduced expression of IL-12p35, and with increased levels of the proinflammatory cytokines IL-17, IL-1beta, IL-6, and tumor necrosis factor in the affected joint. Following ex vivo restimulation, draining lymph node cells from misoprostol-treated mice secreted higher levels of IL-17 and lower levels of interferon-gamma. CONCLUSION: Our results indicate that PGE(2) enhances DC-derived IL-6 production and induces a shift in the IL-23/IL-12 balance in favor of IL-23, resulting in increased IL-17 production, presumably through the amplification of self-reactive Th17 cells.

Multivariable analysis of factors influencing outcome of 2 treatment protocols in 128 cases of horses responding positively to intra-articular analgesia of the distal interphalangeal joint.

REASONS FOR PERFORMING STUDY: There is limited knowledge available of factors influencing response to treatments of the DIP-joint in horses with lameness responding to diagnostic analgesia of the DIP-joint. For this reason a multivariable statistical analysis was performed. HYPOTHESIS: Horses with lameness reduced by > or = 75% 10 min after intra-articular analgesia of the DIP-joint, can be treated successfully by intra-articular medication of the joint. Multiple factors influence the response to treatment. METHODS: The study was performed retrospectively based on clinical records of horses treated with either polysulphated glycosaminoglycan (PSGAG) or methylprednisolone acetate (MPA) in the DIP-joint between January 1996 and January 2003. Information was collected from clinical records and from the owners of the horses via a detailed questionnaire, in which they described their perception of the outcome a minimum of one year after treatment. Allocation of the horses to the 2 treatment groups was done mainly because of a change in treatment policy. In Regime A all horses received 3 intra-articular injections of PSGAG approximately 8 days apart, whereas in Regime B all horses received a single intra-articular injection of MPA as a first treatment. If the horse did not improve sufficiently to return to work by 4 weeks, a series of 3 intra-articular PSGAG injections was administered. RESULTS: Of the horses receiving Regime A, 67% had a successful outcome, compared with 46% of the group receiving Regime B. A significantly better result was obtained in dressage horses than in jumping horses (eventing and showjumping). Other variables such as age, duration of lameness, distribution of lameness, degree of lameness, response to DIP-joint analgesia and radiographic observations were also associated with success of treatment. CONCLUSIONS AND POTENTIAL RELEVANCE: There is a rationale for using either PSGAG or MPA intra-articularly in the treatment of lameness, reduced > or = 75% within 10 min of analgesia of the DIP-joint.

Use of a parathyroid hormone peptide (PTH(1-34))-enriched fibrin hydrogel for the treatment of a subchondral cystic lesion in the proximal interphalangeal joint of a warmblood filly.

To describe the treatment of a subchondral bone cyst in the proximal phalanx with parathyroid hormone peptide-enriched fibrin hydrogel in a warmblood filly. The cyst was localized with computer-assisted orthopaedic surgery, then curetted and finally filled with parathyroid hormone fragment peptide 1-34 (PTH(1-34)) covalently attached to a fibrin hydrogel. The cyst healed quickly without any complications. This result supports the hypothesis that PTH(1-34) delivered locally in a fibrin hydrogel may improve the postoperative prognosis of surgical management of subchondral bone cysts in horses. Subchondral bone cysts are fairly common in horses. Especially in older horses, the prognosis is poor, even after surgical curettage. Therefore, different management protocols have been investigated in conjunction with surgical curettage to improve prognosis. Locally delivered PTH(1-34) seems to be a new method in the treatment of subchondral bone cysts.

[The effectiveness and safety of nimesulide (nimesile) in patients with gouty arthritis]. / Effektivnost' i bezopasnost' primeneniia nimesulida (nimesila) u bol'nykh podagricheskim artritom.

Patients with gout are at a high risk for drug-induced complications associated with the use of nonsteroidal anti-inflammatory drugs due to the baseline renal and hepatic abnormalities, metabolic disturbances, and concomitant diseases, such as arterial hypertension or type 2 diabetes mellitus. In this connection, it is expedient to use safer selective cycloxygenase-2 (COG-2) inhibitors. However, there are only single reports dealing with studies of the effectiveness and safety of selective COG-2 inhibitors in gout. The study was undertaken to evaluate the effectiveness and safety of the selective COG-2 inhibitor nimesulide (nimesile) in acute gouty arthritis (GA). Twenty male patients (whose mean age was 51.1 +/- 8.4 years) with PA were examined. Seven patients were found to have monoarthritis of 1 metatarsophalangeal joint, oligoarthritis was present in 9 patients and 4 patients had polyarthritis. The history of arthritis was as long as 6 days in 16 patients and 21-30 days in 4. Nimesulide was given in a dose of 200 mg/day for at least 14 days. The time course of changes in the objective and subjective symptoms of arthritis was studied. The tolerability of the drug was evaluated by its effect on renal (the levels of creatinine and urea, creatinine clearance) and hepatic (alanine transferase (ALT), aspartate transferase (AST), gamma-glutamyltranspeptidase (gamma-GTP)) functions, and blood pressure (BP) [24-hour BP monitoring (24-h BPM) before and after treatment. There were clear positive changes in the major parameters of arthritis: the swelling index was 4.5 +/- 2.7 and 0.5 +/- 0.5 scores before and after treatment, respectively; hyperemia, 3.5 +/- 2.5 and 0.1 +/- 0. 1 scores; articular index, 3.6 +/- 2.0 and 0.7 +/- 0.6 scores; pain (visual analogue scale) when resting, 53.8 +/- 17.6 and 4.7 +/- 4.6 scores, and that when moving, 68.3 +/- 16.0 and 9.0 +/- 8.8 mm, respectively. Negative changes in the levels of creatinine and uric acid and a reduction in creatinine clearance were not observed. There were no increases in the levels of ACT, ALT, gamma-GTP. 24-h BPM did not reveal any significant changes in the mean 24-hour, mean diurnal and nocturnal variables of BP. The 24-hour BP profile became better in some patients. Thus, nimesulide is an effective and safe drug for the treatment of PA.

[Development and evaluation of a modified version of the Larsen method for evaluating roentgenologic changes in chronic polyarthritis]. / Entwicklung und Evaluation einer modifizierten Version der Larsen-Methode zur Bewertung röntgenologischer Veränderungen bei chronischer Polyarthritis.

AIM OF THE STUDY: To develop and evaluate a modification of the Larsen scoring method aimed at a clear definition of the different grades and a better correlation of the numerical scale with the amount of joint destruction. DESCRIPTION OF THE METHOD: While the original method described by Larsen is based on a comparison with standard reference films the modification defines the different grades semiquantitatively by the amount of destruction of the joint surface: grade II is a destruction (erosion) of the joint surface of up to 25%, in grade III it is 26-50%, in grade IV 51-75% and in grade V over 75%. Grade I is characterized by soft tissue swelling and in addition subchondral osteoporosis and remains unchanged compared with the original method. 32 joints of the hands, wrists and forefeet are counted summing up to a total score of 0-160. Examples for different joints are given. EVALUATION OF THE METHOD: Standard ap-x-rays of hands, wrists and forefeet of 24 patients with early erosive rheumatoid arthritis at baseline (T0) and after 36 months (T1) were graded by two investigators (G.H. and R.R.). The difference of the scoring between both observers (inter-observer-difference) was related to the difference between the two timepoints (T0 and T1) in the same patient (intra-patient-difference) by means of a hierarchical analysis of variance (ANOVA). The intra-patient variance (from T0 to T1) was 259.3, which is 8 times greater than the inter-observer-variance of 32.1. The square root of intra-patient-standard deviation (16.1) and inter-observer-standard deviation (5.7) is 2.8. These data show that the progression between T0 and T1 is real. The method was easily applicable to patients in a 2-year-DMARD-trial with x-rays at baseline after 6, 12 and 24 months, showing a slowing of radiologic progression after month 6 under treatment with parenteral gold and methotrexate. CONCLUSION: The modification of Larsen's scoring method is a reliable measure to assess radiologic progression in patients with RA. Possibilities for further improvement are discussed.

[Erbium 169 synoviortheses and infiltrations of triamcinolone hexacetonide in metatarsophalangeal arthritis of chronic inflammatory rheumatism]. / Synoviorthèses à l'erbium 169 et infiltrations d'hexacétonide de triamcinolone dans les arthrites métatarsophalangiennes des rhumatismes inflammatoires chroniques.

The authors report their experience in the treatment of metatarsophalangeal arthritis of chronic inflammatory rheumatism by Erbium 169 synoviortheses (112 joints treated) and by infiltrations of triamcinolone hexacetonide (53 joints treated). The steroid appears to have a marked early superiority as it gives 85% good results compared to 61.6% for Erbium 169 after a period of one to three months. However, its results then deteriorate more rapidly and after 6 months, the proportion of good results is greater with the radioactive treatment (64% compared to 46.7%). The authors consider it reasonable to use triamcinolone hexacetonide as the first line treatment as it is easier to manage and less expensive, reserving the radioactive synoviortheses for later with the prospect of more lasting results.