LTBI screening in rheumatoid arthritis patients prior to anti-TNF treatment in an endemic area.

SETTING: Recommendations for screening for latent tuberculous infection (LTBI) in patients eligible for anti-tumour necrosis factor (TNF) agents remain unclear in endemic regions. OBJECTIVE: To evaluate the long-term efficacy of LTBI screening and treatment in patients with rheumatoid arthritis (RA) receiving TNF blockers. DESIGN: A total of 202 RA patients were screened for LTBI before receiving anti-TNF treatment using the tuberculin skin test (TST), chest X-ray (CXR) and history of exposure to tuberculosis (TB). All subjects were regularly followed at 1- to 3-month intervals. RESULTS: Eighty-five patients (42%) were treated with a single anti-TNF agent, while 117 patients (58%) changed anti-TNF agents once or twice. LTBI screening was positive in 66 patients, 44 were TST-positive, 23 had a history of TB exposure and 14 had an abnormal CXR. Exposure alone accounted for LTBI diagnosis in 14 patients with a negative TST. LTBI patients were treated with isoniazid (300 mg/day) for 6 months, and none developed TB. During follow-up, TST was repeated in 51 patients. Conversion was observed in 5; 3 were diagnosed with LTBI and 2 with active TB respectively 14 and 36 months after receiving anti-TNF treatment, suggesting new TB exposure. CONCLUSION: LTBI screening and treatment before anti-TNF treatment is effective in endemic areas and reinforces the importance of establishing contact history for diagnosing LTBI in RA patients.

Wrist ultrasound analysis of patients with early rheumatoid arthritis

In the present study, we evaluated 42 wrists using the semi-quantitative scales power Doppler ultrasound (PDUS) and gray scale ultrasound (GSUS) with scores ranging from 0 to 3 and correlated the results with clinical, laboratory and radiographic data. Twenty-one patients (17 women and 4 men) with rheumatoid arthritis according to criteria of the American College of Rheumatology were enrolled in the study from September 2008 to July 2009 at Universidade Estadual de Campinas (UNICAMP). The average disease duration was 14 months. The patients were 66.6 percent Caucasians and 33.3 percent non-Caucasians, with a mean age of 42 and 41 years, respectively. A dorsal longitudinal scan was performed by ultrasound on the radiocarpal and midcarpal joints using GE LOGIQ XP-linear ultrasound and a high frequency (8-10 MHz) transducer. All patients were X-rayed, and the Larsen score was determined for the joints, with grades ranging from 0 to V. This study showed significant correlations between clinical, sonographic and laboratory data: GSUS and swollen right wrist (r = 0.546), GSUS of right wrist and swelling of left wrist (r = 0.511), PDUS of right wrist and pain in left wrist (r = 0.436), PDUS of right wrist and C-reactive protein (r = 0.466). Ultrasound can be considered a useful tool in the diagnosis of synovitis in early rheumatoid arthritis mainly when the anti-cyclic citrullinated peptide and rheumatoid factor are negative, and can lead to an early change in the therapeutic decision.

Wrist ultrasound analysis of patients with early rheumatoid arthritis.

In the present study, we evaluated 42 wrists using the semi-quantitative scales power Doppler ultrasound (PDUS) and gray scale ultrasound (GSUS) with scores ranging from 0 to 3 and correlated the results with clinical, laboratory and radiographic data. Twenty-one patients (17 women and 4 men) with rheumatoid arthritis according to criteria of the American College of Rheumatology were enrolled in the study from September 2008 to July 2009 at Universidade Estadual de Campinas (UNICAMP). The average disease duration was 14 months. The patients were 66.6% Caucasians and 33.3% non-Caucasians, with a mean age of 42 and 41 years, respectively. A dorsal longitudinal scan was performed by ultrasound on the radiocarpal and midcarpal joints using GE LOGIQ XP-linear ultrasound and a high frequency (8-10 MHz) transducer. All patients were X-rayed, and the Larsen score was determined for the joints, with grades ranging from 0 to V. This study showed significant correlations between clinical, sonographic and laboratory data: GSUS and swollen right wrist (r = 0.546), GSUS of right wrist and swelling of left wrist (r = 0.511), PDUS of right wrist and pain in left wrist (r = 0.436), PDUS of right wrist and C-reactive protein (r = 0.466). Ultrasound can be considered a useful tool in the diagnosis of synovitis in early rheumatoid arthritis mainly when the anti-cyclic citrullinated peptide and rheumatoid factor are negative, and can lead to an early change in the therapeutic decision.

Gender, body mass index and rheumatoid arthritis disease activity: results from the QUEST-RA Study.

OBJECTIVES: To investigate whether body mass index (BMI), as a proxy for body fat, influences rheumatoid arthritis (RA) disease activity in a gender-specific manner. METHODS: Consecutive patients with RA were enrolled from 25 countries into the QUEST-RA program between 2005 and 2008. Clinical and demographic data were collected by treating rheumatologists and by patient self-report. Distributions of Disease Activity Scores (DAS28), BMI, age, and disease duration were assessed for each country and for the entire dataset; mean values between genders were compared using Student's t-tests. An association between BMI and DAS28 was investigated using linear regression, adjusting for age, disease duration and country. RESULTS: A total of 5,161 RA patients (4,082 women and 1,079 men) were included in the analyses. Overall, women were younger, had longer disease duration, and higher DAS28 scores than men, but BMI was similar between genders. The mean DAS28 scores increased with increasing BMI from normal to overweight and obese, among women, whereas the opposite trend was observed among men. Regression results showed BMI (continuous or categorical) to be associated with DAS28. Compared to the normal BMI range, being obese was associated with a larger difference in mean DAS28 (0.23, 95% CI: 0.11, 0.34) than being overweight (0.12, 95% CI: 0.03, 0.21); being underweight was not associated with disease activity. These associations were more pronounced among women, and were not explained by any single component of the DAS28. CONCLUSIONS: BMI appears to be associated with RA disease activity in women, but not in men.

Methotrexate inhibition of bone mineral density increase in growing rabbits: prevention by folinic acid.

OBJECTIVE: Methotrexate (MTX) action on bone metabolism is as yet not completely understood. The results of clinical studies are controversial, since it is difficult to distinguish the side effects of MTX from those of the primary disease. This study assessed the effect of MTX, with and without folinic acid supplementation, on bone mineral density in growing normal rabbits. METHODS: Three groups of young NZW growing female rabbits were treated with: saline (n = 6) or MTX (0.25 mg/kg/week, n = 5) or MTX (same dose as above) plus folinic acid (0.25 mg/kg/week, n = 6) for a period of 3 months. The dose, duration and frequency of MTX administration were similar to the treatment of RA patients. The animals were submitted to dual-energy absorptiometry densitometry (HologicQDR 2000) before and after treatment; total body and L4-L5 BMD were evaluated. Histomorphometric analysis (L4 vertebrae) was also performed. RESULTS: Growing control rabbits showed increased total body BMD from a baseline of 0.180 +/- 0.006 to 0.198 +/- 0.007 gm/cm2 (mean +/- S.E.M, p < 0.006). In contrast, no increase in BMD (0.182 +/- 0.006 versus a baseline of 0.184 +/- 0.004, ns) was observed in the group treated with MTX, while the addition of folinic acid resulted in an increase in BMD values similar to controls, from a baseline of 0.181 +/- 0.004 to 0.198 +/- 0.003, p < 0.02), thus preventing adverse MTX bone effects. Average percent variations in BMD were +7.7%, -1% and +8.4% respectively. Spine (L4-L5) BMD showed analogous results, in line with the histomorphometric data. CONCLUSION: These results strongly support a deleterious action of MTX on bone metabolism, which is prevented by folinic acid supplementation. The potential clinical implications of our data are particularly significant for paediatric therapy.

Methotrexate as a preferential cyclooxygenase 2 inhibitor in whole blood of patients with rheumatoid arthritis.

OBJECTIVE: To investigate the regulation of whole-blood cyclooxygenase-1 and -2 (COX-2 and COX-1) activities by methotrexate (MTX) in rheumatoid arthritis (RA) patients. METHODS: Whole blood was withdrawn from nine healthy volunteers, 12 RA patients treated with MTX (RA/MTX) and six RA patients treated with chloroquine (RA/CQ). COX-1 activity was quantified as platelet thromboxane B(2) production in unstimulated blood and COX-2 activity was measured as prostaglandin E(2) (PGE(2)) production in whole blood stimulated with LPS. Thromboxane B(2) and PGE(2) were measured by radioimmunoassay. We studied the drug effect in vitro by direct incubation of MTX with blood obtained from normal donors. Ex vivo assays were performed with blood collected from RA/MTX and RA/CQ patients. The influence of serum factors on enzyme activities was analysed in blood collected from normal donors and incubated with RA/MTX, autologous or heterologous serum. RESULTS: In vitro assays showed no direct action of MTX on the activity of either enzyme. Assays performed with blood from RA/MTX patients showed preferential inhibition of COX-2 activity (PGE(2) = 10.11 +/- 2.42 ng/ml) when compared with blood of normal donors (PGE(2) = 37.7 +/- 4.36 ng/ml; P = 0.001). Inhibition of COX-2 activity was also observed when blood of normal donors was co-incubated with RA/MTX serum. CONCLUSION: Our results clearly show that the anti-inflammatory action of low-dose MTX is partly mediated by a serum factor induced by MTX or a MTX metabolite that preferentially inhibits the activity of COX-2.

Interrelationship of the kinin system, nitric oxide and eicosanoids in the antigen-induced arthritis in rabbits.

The aim of the present study was to investigate the interrelationship of the kinin system, nitric oxide and eicosanoids in the acute phase of antigen-induced arthritis (AIA) in rabbits. The arthritis was induced in immunized rabbits and the following parameters were evaluated 24 hours later: leukocyte influx (total and differential white cell count), vascular permeability (Evans's blue method), and synovial PMN cell infiltrate. PGE2 and LTB4 (radioimmunoassay) levels were quantified in the synovial fluid. The animals were pre-treated with 20mg/kg/day during 14 days with L-NAME or D-NAME and/or Enalapril (0.12 mg/kg/day-14 days), and/or the B2 antagonist of Bradykinin HOE 140 (0.9 mg/kg). Our results showed that L-NAME was effective in the prevention of AIA with reduction of all Inflammatory parameters analyzed. Enalapril partially reverted the L-NAME anti-inflammatory effects. The simultaneous treatment with HOE 140 abolished this reversion and returned the inflammatory parameters to the levels observed in L-NAME treated animals. Our results suggest that pressoric alterations induced by L-NAME could not account for all its anti-inflammatory action in this model of experimental arthritis. Additionally the contribution of the kinin system in AIA was characterized as well as its interaction with eicosanoids and nitric oxide.

[Intra-articular nitric oxide levels in patients with rheumatoid arthritis]. / Níveis intra-articulares de óxido nítrico em pacientes com doença reumatóide.

The aim of this study was the appraisal of the nitrite and nitrate levels in the synovial fluid of patients with rheumatoid arthritis (RA). The synovial fluid of patients with osteoarthritis (OA) was also evaluated by comparison. Demographic characteristics such as age and sex, and clinical and laboratorial parameters like duration of disease, functional class and erythrocyte sedimentation rate (ESR) were evaluated too. In the synovial fluid of all patients the total and differential leukocyte count, and the nitrite and nitrate levels determined by Griess reaction were analyzed. The results were statistically analyzed by Student's t test and correlation test. We found a significant increase in the intraarticular nitrite and nitrate levels in patients with RA when compared with OA patients (30.68 +/- 2.94 microM x 16.15 +/- 2.73 microM). We did not find any correlation between intraarticular nitrite and nitrate levels and the ESR or the total and differential leukocyte count in the RA synovial fluid. In this study we clearly found an increase in the intraarticular nitrite and nitrate levels in patients with rheumatoid arthritis.

[Role of free radicals in articular inflammatory process]. / Participação dos radicais livres na inflamação articular.

The authors review recent studies supporting the role of free radicals in the inflammatory articular process. More specifically, superoxide anion and its derived active species and nitric oxide are analyzed regarding their generation by the articular cells and tissues, their destructive activity n these specialized tissues. Likewise, effects of the inhibition of free radicals production or activity in the inflammatory process is also commented.

[Aminotransferase levels in rheumatoid arthritis patients treated with methotrexate]. / Aminotransferases em pacientes com artrite reumatóide tratados com metotrexate.

Increase of the aminotransferase levels in 53 patients treated with methotrexate (MTX) were analysed in a retrospective study. The mean dose of MTX was 7.46 mg/week (range 2.5-15 mg) during at least 30 weeks (mean time of MTX use 124 weeks). The aminotransferase levels were transitorily increased in 13 patients, always less than three times the upper limit of normal. Only in three patients the AST and ALT levels were persistently increased and lead to the drug discontinuation in two cases. These results showed that increase of aminotransferases was a frequent observation (24.5%) during the first two-three years of follow-up, without interference in the overall clinical management.

Nitric oxide synthase inhibitor influences prostaglandin and interleukin-1 production in experimental arthritic joints.

OBJECTIVE: To assess involvement of nitric oxide (NO) in the increase in eicosanoid and interleukin- 1 (IL-1) levels in the synovial fluid during antigen-induced arthritis (AIA) in rabbits treated with a competitive inhibitor of NO synthesis. SUBJECTS: Thirteen New Zealand White rabbits were sensitized with 5 mg of methylated bovine serum albumin (mBSA). Arthritis was induced in the knee joint by injecting 0.5 ml of a sterile solution of mBSA (2 mg/ml) into the intra-articular cavity. TREATMENT: Prior to the induction of arthritis, the animals received N-Omega-Nitro-L-Arginine Methyl Ester (LNAME) or N-Omega-Nitro-D-Arginine Methyl Ester (DNAME) for 2 weeks, both at a dose of 20 mg/kg/day mixed with drinking water. METHODS: Leukocyte efflux (total and differential white cell count), vascular permeability (Evans's blue method), synovial PMN cell infiltrate, and total nitrite (NO2.)/nitrate (NO3.) (HPLC), PGE2, TxB2, LTB4 (radioimmunoassay), and IL-1 beta (ELISA) levels were quantified in the synovial fluid. RESULTS: LNAME but not DNAME significantly suppressed leukocyte efflux and protein leakage into the articular cavity as well as synovial PMN cell infiltrate. Total NO2./NO3., PGE2 and IL-1 beta levels were significantly reduced in the synovial fluid of LNAME treated animals. TxB2 and LTB4 were not affected by LNAME treatment. CONCLUSION: These data clearly show NO involvement in the IL-1-induced PGE2 production in the synovial fluid of antigen-induced arthritis in rabbits.

Low dose methotrexate decreases intraarticular prostaglandin and interleukin 1 levels in antigen induced arthritis in rabbits.

OBJECTIVE: To investigate the effects of methotrexate (MTX) on inflammation variables of antigen induced arthritis (AIA) in rabbits, such as protein leakage to the articular cavity, synovial fluid (SF) leukocyte count, synovial membrane polymorphonuclear (PMN) cell infiltrate, and intraarticular production of eicosanoids and interleukin 1 (IL-1). Dexamethasone and indomethacin were used for comparison. METHODS: NZW rabbits were treated with the following drugs: MTX (0.25 mg/kg), dexamethasone (0.15 mg/kg), indomethacin (4 mg/kg), and sterile saline (control group). All drugs were given by intramuscular route before arthritis was induced and the animals were sacrificed 4 or 24 h later. Leukocyte migration, protein leakage (Evans blue method), synovium PMN cell infiltrate, and intraarticular concentration of prostaglandin E2 (PGE2), thromboxane B2 (TXB2), leukotriene B4 (LTB4) (radioimmunoassay), and IL-1 beta (ELISA) were quantified in SF. RESULTS: Significant reduction of leukocyte migration and protein leakage was observed in the joint fluid of all treated animals. Decrease in the intensity of synovium PMN cell infiltrate also occurred with all treatments. Intraarticular PGE2, TXB2, and IL-1 beta were significantly reduced after 4 h of arthritis induction in animals treated with MTX and dexamethasone. Treatment with indomethacin reduced only PGE2 and TXB2 in SF. Treatments did not change SF IL-1 beta concentration 24 h after arthritis induction. Treatment with dexamethasone increased inflammatory variables and SF LTB4 concentration 24 h after the synovial cavity was challenged with antigen. CONCLUSION: Our results show that MTX, like dexamethasone, reduces the intensity of leukocyte afflux, protein leakage, synovial membrane PMN cell infiltrate, as well as the intraarticular production of PGE2, TXB2, and IL-1 beta in the early phase of antigen induced arthritis in rabbits.

Influence of low doses of methotrexate on superoxide anion production by polymorphonuclear leukocytes from patients with rheumatoid arthritis.

OBJECTIVE: The mechanism of methotrexate (MTX) action in rheumatoid arthritis (RA) is unclear. We assessed the influence of MTX on neutrophil superoxide production evaluated by ferricytochrome c reduction. METHODS: Neutrophils were collected from MTX treated patients with RA (MTX-RA), patients with RA without medication (RA) and healthy donors, cocultured with MTX or MTX-RA serum. RESULTS: Polymorphonuclear leukocytes (PMN) from MTX-RA showed decreased superoxide production when compared with cells collected from patients with RA and controls. Control PMN superoxide production was inhibited (36%) by MTX-RA serum incubation. This reduction was accompanied by clinical improvement. MTX had no activity in the in vitro assays. CONCLUSION: MTX treatment may interfere with neutrophil superoxide production.

Action of the 4-nitro-2-phenoximethanesulphonanilide (nimesulide) on neutrophil chemotaxis and superoxide production.

4-nitro-2-phenoximethanesulphonanilide (nimesulide) is a nonsteroidal anti-inflammatory agent that has been employed in the treatment of inflammatory diseases because of its specific actions on the inflammatory response mechanisms caused by injury. The objectives of this paper were to determine the action of this agent on two notable neutrophil functions, chemotaxis and production of the superoxide anion. These two functions were studied after the neutrophils were pre-incubated with three different concentrations of 4-nitro-2-phenoximethanesulphonanilide (0.1; 0.3 and 0.5 mN). The results obtained herein demonstrated that 4-nitro-2-phenoximethanesulphonanilide-exposed peripheral blood neutrophils from healthy subjects produced significantly less superoxide when challenged by phorbolmirystate acetate (PMA at 50 ng/ml) or formy-methionil-leucyl-phenilalanine (FMLP 10-7 M) and opsonizided zymozan (1 mg/ml). Additionally, the agent was equally effective in reducing the PMN chemotoaxis when challenged by C5a factor (2% zimozan activated solution), FMLP 10-9 M and leukotrien (3.10-7 M). The results obtained suggest that in addition to its interference in the metabolism of the aracdonic acid, the 4-nitro-2-phenoximethanesulphonanilide may interfere in a more direct fashion with the neutrophil function. This specific action may contribute to its anti-inflammatory activity.

Long-term remission of neutropenia in Felty's syndrome after a short GM-CSF treatment.

We report a case of Felty's syndrome in which neutropenia was corrected by a short-term treatment with recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF, 5 micrograms/kg/day s.c. for 14 days). Absolute neutrophil counts rose from 0.1 to 2.2 x 10(9)/l and remained > 1.0 x 10(9)/l 8 weeks after discontinuation of the GM-CSF therapy. A flare-up of arthritis and a decrease in platelet counts were observed.

[Role of oxygen free radicals in the physiopathology of rheumatoid arthritis]. / Participação dos radicais livres de oxigênio na fisiopatologia da artrite reumatóide.

The authors present a review of the mechanisms of free radicals production and report the results of "in vivo" and "in vitro" studies correlating these agent with the physiopathologic changes of the rheumatoid arthritis. The data reviewed in this paper support the idea of the participation of free radicals in the articular lesion. However new studies are necessary to determine the contribution of free radicals on disease development, chronicity and the efficacy of antioxidant agents.

[Percutaneous synovial biopsy in the diagnostic evaluation of the patient with rheumatic disease]. / Biopsia sinovial percutânea na avaliação diagnóstica do paciente reumatológico.

Forty seven percutaneous synovial biopsies from 22 patients with rheumatoid arthritis, four of whom with the juvenile form, 13 with indetermined polyarthritis and 12 with monoarthritis, were evaluated. The histopathological examination confirmed the clinical diagnosis in 76% of cases with rheumatoide arthritis and juvenile rheumatoid arthritis, and it suggested the diagnosis of rheumatoid arthritis in 80% of cases with indetermined polyarthritis. In two cases of monoarthritis it reveled acid-fast bacilli, and a granulomatous process in one. These resuls suggest that the synovial biopsies can be useful for the establishment of diagnosis in patients suffering from indetermined poly or monoarthritis.