A randomised controlled trial on the efficacy and tolerability with dose escalation of allopurinol 300-600 mg/day versus benzbromarone 100-200 mg/day in patients with gout.

OBJECTIVES: To compare the efficacy and tolerability of allopurinol 300-600 mg/day versus benzbromarone 100-200 mg/day used to attain a target serum urate concentration (sUr) < or =0.30 mmol/l (5 mg/dl). METHODS: A randomised, controlled, open-label, multicentre trial in gout patients with renal function defined as a calculated creatinine clearance > or =50 ml/min. Patients were treated with 300 mg allopurinol or 100 mg benzbromarone once a day (stage 1). If sUr < or =0.30 mmol/l was not attained after 2 months, the dose was doubled to allopurinol 300 mg twice a day or benzbromarone 200 mg once a day (stage 2). The primary end point was treatment success in either of the two stages, defined as clinical tolerability and attainment of biochemical target sUr. RESULTS: Sixty-five patients were enrolled in stage 1; 36 received allopurinol and 29 received benzbromarone. Fifty-five patients (85%) were analysed at stage 1: the success rates were 8/31 (26%) and 13/25 (52%), respectively, and the difference was -0.26 (95% CI from -0.486 to -0.005), p = 0.049. At stage 2, the success rates were 21/27 (78%) and 18/23 (78%), respectively, and the difference was -0.005 (95% CI from -0.223 to 0.220), p = 1.00. Two patients stopped receiving allopurinol and three stopped receiving benzbromarone because of adverse drug reactions. CONCLUSIONS: Increasing the allopurinol dose from 300 to 600 mg/day and the benzbromarone dose from 100 to 200 mg/day according to the target sUr produced significantly higher success rates (both 78% successful in attaining sUr < or =0.30 mmol/l). No significant differences in treatment success between benzbromarone and allopurinol were found after dose escalation. TRIAL REGISTRATION NUMBER: ISRCTN49563848).

Can baseline ultrasound results help to predict failure to achieve DAS28 remission after 1 year of tight control treatment in early RA patients?

BACKGROUND: At present, there are no prognostic parameters unequivocally predicting treatment failure in early rheumatoid arthritis (RA) patients. We investigated whether baseline ultrasonography (US) findings of joints, when added to baseline clinical, laboratory, and radiographical data, could improve prediction of failure to achieve Disease Activity Score assessing 28 joints (DAS28) remission (<2.6) at 1 year in newly diagnosed RA patients. METHODS: A multicentre cohort of newly diagnosed RA patients was followed prospectively for 1 year. US of the hands, wrists, and feet was performed at baseline. Clinical, laboratory, and radiographical parameters were recorded. Primary analysis was the prediction by logistic regression of the absence of DAS28 remission 12 months after diagnosis and start of therapy. RESULTS: Of 194 patients included, 174 were used for the analysis, with complete data available for 159. In a multivariate model with baseline DAS28 (odds ratio (OR) 1.6, 95% confidence interval (CI) 1.2-2.2), the presence of rheumatoid factor (OR 2.3, 95% CI 1.1-5.1), and type of monitoring strategy (OR 0.2, 95% CI 0.05-0.85), the addition of baseline US results for joints (OR 0.96, 95% CI 0.89-1.04) did not significantly improve the prediction of failure to achieve DAS28 remission (likelihood ratio test, 1.04; p = 0.31). CONCLUSION: In an early RA population, adding baseline ultrasonography of the hands, wrists, and feet to commonly available baseline characteristics did not improve prediction of failure to achieve DAS28 remission at 12 months. TRIAL REGISTRATION: Clinicaltrials.gov, NCT01752309 . Registered on 19 December 2012.

Corticosteroid injections reduce size of rheumatoid nodules.

BACKGROUND: Symptomatic rheumatoid nodules are frequently surgically treated. Injection with steroids might be an alternative treatment. PATIENTS AND METHODS: To determine whether injection with triamcinolon acetonide reduces the size of rheumatoid nodules, we randomized twenty patients with symptomatic nodules to either triamcinolon acetonide 40 mg/ml plus lidocaine 2% or lidocaine 1% (placebo). We measured the nodules before injection and 2, 4, 8, and 12 weeks after injection. Possible side effects were recorded. RESULTS: We found that the volume of the nodules injected with triamcinolon acetonide reduced significantly (p = 0.011), from 130 to 8 mm(3) (median calculated size) at 12 weeks, compared with baseline. Furthermore, at 12 weeks, the difference between the groups was significant (p = 0.03). The median size of the placebo nodules diminished as well, from 358 to 237 mm(3), but this was not significant. Pain at injection was the only side effect, equally distributed in both treatment groups. CONCLUSION: Injection with triamcinolon acetonide seems to be an alternative for surgery of rheumatoid nodules. No adverse events occurred but the limited sample does not allow definitive conclusions.

Hyperimmunoglobulinemia D and periodic fever syndrome. The clinical spectrum in a series of 50 patients. International Hyper-IgD Study Group.

We studied 50 patients (28 male and 22 female) with the hyper-IgD and periodic fever syndrome. Most patients originated from Europe, namely The Netherlands (28 cases; 56%), France (10 cases, 20%), and Italy (3 cases, 6%), but 1 patient was from Japan. A hereditary component is suggested by 18 patients coming from 8 families. The syndrome is typified by a very early age at onset (median, 0.5 years) and life-long persistence of periodic fever. Characteristically, attacks occur every 4-8 weeks and continue for 3-7 days, but the individual variation is large. Attacks feature high spiking fever, preceded by chills in 76% of patients. Lymphadenopathy is commonly present (94% of patients). During attacks, 72% of patients complained of abdominal pains, 56% of vomiting, 82% of diarrhea, and 52% of headache. Joint involvement is common in the hyper-IgD syndrome with poly-arthralgia in 80% and a non-destructive arthritis, mainly of the large joints (knee and ankle), in 68% of patients. Eighty-two percent of patients reported skin lesions with some attacks; these demonstrated vasculitis histologically. Serositis has been seen in only 3 patients (6%), while amyloidosis has not been recorded in any of the patients with this syndrome. Immunizations precipitated attacks in 54% of patients. All patients had a persistently elevated serum IgD level (> 100 U/mL), and in 82% of cases the serum IgA was likewise elevated. During attacks there is an acute-phase response adjudged by leukocytosis, neutrophilia, and increased ESR. The etiology remains to be elucidated, and treatment is supportive. The hyper-IgD syndrome is distinct from other periodic fever syndromes like systemic-onset juvenile rheumatoid arthritis, adult-onset Still disease, and familial Mediterranean fever.

Clinically important drug interactions with disease-modifying antirheumatic drugs.

Rheumatic diseases are mostly chronic in nature and often require long term drug treatment. An increasing number of disease-modifying antirheumatic drugs (DMARDs) are used earlier in the course of disease and increasingly in combination with each other. Often there is comorbidity with ensuing pharmacotherapy, especially in the elderly, and therefore the risk of unwanted drug interactions increases. Awareness of these interactions is important in order to either avoid or manage them. Antimalarials, gold, penicillamine (D-penicillamine), sulfasalazine and azathioprine have few clinically important drug interactions. The renal excretion of the antifolate methotrexate is affected by drugs that influence kidney function. This is of particular importance in patients with compromised renal function, e.g. the elderly. Other drugs with influence on folate metabolism, such as trimethoprim, should not be given concomitantly. Cyclosporin is an agent recently introduced in rheumatological practice, and shows a myriad of clinically significant drug interactions mainly based on interference with its metabolic degradation by cytochrome P450 3A, leading to increased or decreased blood concentrations and toxicity or lack of effect. Although most of these interactions with cyclosporin are described in organ transplant patients, they may apply to rheumatological practice as well.

Drug use and adverse drug reactions in 105 elderly patients admitted to a general medical ward.

OBJECTIVE: To examine the influence of admission to hospital on the number of drugs used by the elderly and to study the occurrence of adverse drug reactions (ADRs), their contribution to the need for hospitalization and the relation to hospital stay. PATIENTS AND METHODS: Drug use and its sequelae were studied by one observer in 105 patients aged 65 years and older, successively admitted to a general medical ward. Naranjo's algorithm was used to estimate the probability of an ADR. Multiple regression analysis was used to measure interrelationships between variables. RESULTS: There was a slight but significant increase in drug use per patient (4.9 prescriptions on admission, 5.3 at discharge); 120 ADRs occurred, 57 on admission, 63 during stay. Two ADRs were potentially fatal. Drugs most often involved were diuretics, ADRs occurring mainly on admission. During stay in hospital antimicrobials were mainly responsible. There was a strong correlation of both ADRs on admission and ADRs during stay with duration of hospital stay. ADRs did not correlate with the number of drugs in use on admission or with the number of diagnoses. A direct correlation between the occurrence of ADRs and age could not be confirmed, when corrected for possible confounding factors. Fourteen of 105 admissions were definitely or probably drug-induced; diuretics were incriminated 6 times. CONCLUSIONS: Drug use per patient corresponded with that in the literature. Thirty-seven per cent of patients experienced a definite or probable ADR. The percentage of drug-induced admissions (14.7%) agrees with the literature, although the drugs involved (mainly diuretics in our study) were markedly different. The occurrence of ADRs, both on admission and during stay is correlated with the duration of hospital stay, but not with drugs in use or with the number of diagnoses.

[The effect of admission to a geriatric department of a general hospital on drug consumption of the elderly]. / De invloed van opname op de geriatrische afdeling van een algemeen ziekenhuis op het geneesmiddelengebruik van bejaarden.

Admission to a geriatric department of a general hospital of 100 elderly patients admitted in succession, resulted in a slight decrease in number of the prescribed medication. The data were gathered retrospectively. Cardiovascular drugs accounted for the main decrease, sedatives and laxatives showed the highest increase. The use of diuretics is significantly associated with dehydration; 43% of the users of diuretics were dehydrated. The most striking conclusion was that 25% of the prescriptions could be stopped for lack of indication.

Intermittent rises in plasma homocysteine in patients with rheumatoid arthritis treated with higher dose methotrexate.

OBJECTIVES: To investigate the effect of higher weekly maintenance dose methotrexate (MTX) (> or =25 mg/week) on plasma homocysteine concentrations in adults with RA. METHODS: Patients with RA were treated with high doses of MTX with adjuvant folic acid. Plasma homocysteine was determined at baseline and 1, 2, 4, 8, 12, and 48 hours after subcutaneous MTX administration. Maximum homocysteine concentrations after MTX administration were compared with baseline concentrations. RESULTS: Fifteen patients with RA (11 women) were included, with a median age of 61 years (range 31-72) and median disease duration 7 years (range 2-32). Median MTX dose was 30 mg (range 25-40). All patients received folic acid supplementation (5-30 mg/week). Median plasma homocysteine concentration at baseline was 10.1 mumol/l (range 6.6-12.7; normal 6-15). Homocysteine concentrations increased after MTX administration by a median of 2.5 mumol/l (range 0.7-5.1). Median maximum plasma homocysteine was significantly higher than at baseline. Peak homocysteine was reached after 12 hours. No relation between serum folate concentrations and plasma homocysteine concentrations was found. CONCLUSIONS: In patients with RA higher MTX doses with adjuvant folic acid do not increase baseline concentrations of homocysteine. An intermittent significant rise in plasma homocysteine occurs in the 48 hours after MTX administration.

Combination of second-line antirheumatic drugs.

Single drug therapy is often not satisfactory in the treatment of chronic arthritis. The combination of second-line antirheumatic drugs is therefore increasingly employed. Various strategies of combining drugs can be used, starting with combinations or adding agents in case of insufficient effect of single therapy. Effective combinations have to be found empirically because lack of knowledge about pharmacodynamics and pharmacokinetics often hinders rational choices. Few controlled studies on combinations of second-line antirheumatic drugs exist, results suggesting very moderately increased efficacy and increased toxicity. Recently, results of combinations, mainly with methotrexate, have become available. Combining this agent with azathioprine did not offer advantages. Cyclosporin added to insufficiently effective methotrexate possibly has some value and antimalarials combined with methotrexate may be beneficial regarding effectivity and/or toxicity. Methotrexate added to insufficiently effective sulphasalazine seems to be better than methotrexate alone, although this combination when used from the start of the therapy was disappointing. Triple therapy of the latter combination together with hydroxychloroquine turned out to be superior to single methotrexate and to the combination of sulphasalazine and hydroxychloroquine. Surprisingly, the toxicity of these combinations was mainly comparable to single therapy. In conclusion, combinations of second-line antirheumatic drugs have a role, although not yet clearly defined, in the therapy of chronic arthritis.

Treatment of early rheumatoid arthritis patients with slow-acting anti-rheumatic drugs (SAARDs).

Treatment with slow-acting anti-rheumatic drugs (SAARDs) is nowadays initiated earlier in the disease course, preferably before any radiographic damage has occurred. SAARDs have the ability to decrease inflammatory synovitis as measured by clinical and laboratory variables, and there is some evidence that they improve physical function and decrease the progression rate of joint damage in patients with early rheumatoid arthritis. There is a clear difference in survival time between the various SAARDs. The efficacy/toxicity profiles of the SAARDs show equal variation. Rank order of prescription or disease duration may have an effect on drug survival, but different treatment strategies are also important sources of variation. Efficacy might be improved by combining different SAARDs (starting with a multiple drug regimen, or adding a drug to the first one), but further research is necessary to prove this hypothesis.

Validation of rheumatoid arthritis improvement criteria that include simplified joint counts.

OBJECTIVE: To study the validity of response criteria for rheumatoid arthritis (RA) that included 28-joint counts instead of more comprehensive joint counts. METHODS: In a double-blind, placebo-controlled trial of 105 patients treated with methotrexate, sulfasalazine, or both, response was evaluated at week 52. Both European League Against Rheumatism and American College of Rheumatology definitions of response, with comprehensive as well as simplified joint counts, were calculated. We studied the differences between the criteria with and without simplified joint counts, the discriminating capacity between treatment groups, and the association with change in functional capacity and joint damage. RESULTS: Response criteria that included 28-joint counts classified patients' responses more conservatively. No differences between treatment groups were found with either set of response criteria. The association with change in functional capacity was significant in all cases. All response criteria were significantly associated with radiographic progression of RA. CONCLUSION: Improvement criteria that include 28-joint counts are as valid as the original improvement criteria that included more comprehensive joint counts.

Combining sulphasalazine and methotrexate in rheumatoid arthritis: early clinical impressions.

The use of combinations of second line antirheumatic agents (SLAs) is increasing. There are several reasons for combination therapy, e.g. the unsatisfactory effects of single therapy. Strategies for combining SLAs are to begin with combinations, or to add one or more agents to another. The strategy of adding one agent to another is illustrated by a study of 40 patients having insufficient effect from sulphasalazine (SASP). Patients were randomized between methotrexate (MTX) and the combination of SASP and MTX. The patients were evaluated by a single observer in an open design. The follow-up was 24 weeks. The mean decrease in disease activity score was significantly greater and occurred earlier in the combination group. This favourable response was also present in the other efficacy variables. The incidence of toxicity was equal in both groups. These results support the strategy of adding MTX to SASP when combining these second line antirheumatic drugs.

Pharmacotherapeutic combination strategies with disease-modifying antirheumatic drugs in established rheumatoid arthritis.

Pharmacotherapy is still the cornerstone in the management of rheumatoid arthritis (RA). Due to several reasons the pharmacotherapeutic strategy has changed dramatically in the past decades. It has become clear that in most cases single treatment with disease modifying antirheumatic drugs (DMARDs) is insufficient to control the disease on the long term. This is the main reason why combinations of second-line agents are increasingly being used in the treatment of established RA. Many different ways of prescribing combination treatment and a large number of different combinations have been published. However definite conclusions which drugs to combine or what strategy to apply are difficult to make as solid studies which enable these conclusions are sparse. Several studies have shown that the best opportunity to achieve a good response is to use a set-up approach, in addition different studies have shown that corticosteroids do have a profound effect on disease activity variables.

Combination of sulphasalazine and methotrexate versus the single components in early rheumatoid arthritis: a randomized, controlled, double-blind, 52 week clinical trial.

To compare the efficacy of sulphasalazine, methotrexate, and the combination of both in patients with early rheumatoid arthritis (RA), not treated with disease-modifying anti-rheumatic drugs previously, we conducted a double-blind, double-dummy, controlled, clinical trial. One hundred and five patients with active, early RA, rheumatoid factor and/or HLA DR1/4 positive were randomized between sulphasalazine (SSZ) 2000 (maximum 3000) mg daily, or methotrexate (MTX) 7.5 (maximum 15) mg weekly, or the combination (COMBI) of both, and were followed up by a single observer for 52 weeks. The mean change over time per patient, including all visits, in Disease Activity Score (DAS) was: SSZ: -1.6 (95% CI -2.0 to -1.2); MTX: -1.7 (-2.0 to -1.4); COMBI: -1.9 (-2.2 to -1.6); the difference week 0-week 52 (SSZ, MTX, COMBI respectively); DAS: -1.8, -2.0, -2.3, Ritchie articular index: -9.2, -9.5, -10.6, swollen joints: -9.2, -12.4, -14.3, erythrocyte sedimentation rate: -17, -21, -28. Nausea occurred significantly more in the COMBI group. The numbers of drop-outs due to toxicity were SSZ 9, MTX 2, COMBI 5. In conclusion, there were no significant differences in efficacy between combination and single therapy, only a modest trend favouring COMBI. The results of MTX and SSZ were very comparable. Nausea occurred more often in the COMBI group: the number of withdrawals due to adverse events did not differ significantly.

Combination of methotrexate and sulphasalazine in patients with rheumatoid arthritis: pharmacokinetic analysis and relationship to clinical response.

1. The influence of sulphasalazine (SASP) on the pharmacokinetics of low dose methotrexate (MTX) and the relation between pharmacokinetic variables and clinical response was studied in 15 patients with active rheumatoid arthritis despite > 6 months of SASP treatment. 2. SASP was stopped for 2 weeks. Thereafter a single oral dose of 7.5 mg MTX was administered after a standard breakfast. Blood was sampled initially every 30 min, thereafter hourly during 8 h. Urine was sampled every hour. Then 2000 mg SASP daily + 7.5 mg MTX weekly was given. After 4 weeks the same procedure was repeated supplemented with concomitant administration of 1000 mg SASP. Clinical measurements included Ritchie articular index, number of swollen joints, ESR and the disease activity score. Pharmacokinetic analysis was performed using a two-compartment model with first order absorption and lag time. Results are given as mean (s.d.). Paired t-test or signed rank test were applied in the statistical analysis. 3. Pharmacokinetics of MTX without vs with SASP, means +/- s.d. were follows: AUC: 673 +/- 179 vs 628 +/- 210 (95% confidence interval [CI] of the difference was -71 to 159) ng ml-1, MRT: 5.2 +/- 1.3 vs 5.2 +/- 1.1 (95% CI -0.4 to 0.4) h, t1/2,z: 4.3 +/- 1.1 vs 4.2 +/- 1.1 (95% CI -0.3 to 0.5) h, V/F: 59.3 +/- 29.3 vs 65.5 +/- 25.3 (95% -23.8 to 11.4) 1, CL/F: 12.3 +/- 5.0 vs 13.5 +/- 4.8 (95% CI -4.5 to 2.3) 1 h-1. CLR/F: 6.2 +/- 1.3 vs 6.3 +/- 2.1 (95% CI -1.3 to 1.1) l h-1. All P values were > or = 0.3. 4. A weak correlation existed between the change of ESR and the MRT, the t1/2,z and the V/F (Spearman correlation coefficients of 0.43, 0.50 and 0.50 respectively, 0.05 < P < 0.1). 5. There is no significant influence of chronic SASP administration on the pharmacokinetics of MTX or vice versa. Of the clinical variables, only the ESR correlated consistently with some pharmacokinetic variables on MTX.

Effect of methotrexate alone or in combination with sulphasalazine on the production and circulating concentrations of cytokines and their antagonists. Longitudinal evaluation in patients with rheumatoid arthritis.

In a recent study from our group, the combination of methotrexate and sulphasalazine (MTX + SASP) seemed superior to MTX alone in the treatment of rheumatoid arthritis (RA). To assess the impact of these therapies on the cytokine cascade, the in vitro production and circulating concentrations of several cytokines and endogenous cytokine antagonists were measured in 30 healthy controls and longitudinally in a subset of 26 patients enrolled in this study. Compared to controls, RA patients had significantly higher circulating concentrations of interleukin-6 (IL-6), soluble receptors for tumour necrosis factor (sTNFR), soluble receptors for interleukin-2 (sIL-2R) and interleukin-1 receptor antagonists (IL-1RA), and their peripheral blood mononuclear cells (PBMNC) showed a higher spontaneous production of interleukin-1 beta (IL-1 beta), tumour necrosis factor alpha (TNF alpha) and IL-1RA (both secreted and cell-associated) and a higher stimulated production of cell-associated TNF alpha, IL-1RA and (to a lesser extent) IL-1 beta. Treatment with MTX alone (n = 12) or combined with SASP (n = 14), resulted in significant reductions of circulating IL-6 and sIL-2R but did not alter IL-1 beta, TNF alpha or IL-1RA concentrations. Decreases in circulating levels of sTNFR and in the in vitro production of cell-associated IL-1 beta and IL-1RA after stimulation were only observed in patients treated with MTX + SASP. The concentrations of IL-1RA and sTNFR in the circulation exceeded moderately those of IL-1 beta and TNF alpha but this is probably insufficient to block IL-1 and TNF alpha activity. In conclusion, therapy with MTX alone or with SASP modulates IL-6 and sIL-2R concentrations in RA. Decreased production of IL-1 beta and IL-1RA and circulating sTNFR levels were only observed during therapy with MTX + SASP. Whether this relates to the better clinical effect observed with the combination therapy remains to be investigated. Circulating levels of IL-6, sIL-2R and sTNFR seem useful markers of disease activity in RA.

Oral steroids as bridge therapy in rheumatoid arthritis patients starting with parenteral gold. A randomized double-blind placebo-controlled trial.

The efficacy of oral prednisone as bridge therapy in rheumatoid arthritis (RA) was studied. Forty patients starting aurothioglucose were randomized to receive either prednisone or placebo for 18 weeks. The dose was 10 mg/day in the first 12 weeks, 7.5 mg/day in weeks 13 and 14, 5 mg/day in weeks 15 and 16, and 2.5 mg/day in weeks 17 and 18. Patients were followed for 44 weeks. We found that disease activity was significantly lower in the prednisone group as early as week 1 and continued up to week 12. Response to prednisone was noticed in 60% of the patients. After tapering prednisone, a rebound deterioration was noticed at weeks 20 and 24 in 58% of the responders. No significant differences in X-ray progression were found between the two groups. We concluded that oral prednisone (10 mg/day) significantly reduces short-term disease activity in 60% of patients with active RA. The rebound deterioration after tapering the dose means that bridge therapy with prednisone using this dose-reduction scheme is not recommended.

Combination of methotrexate and sulphasalazine vs methotrexate alone: a randomized open clinical trial in rheumatoid arthritis patients resistant to sulphasalazine therapy.

To compare efficacy, toxicity, and the pharmacokinetics of the combination of sulphasalazine (SASP) and methotrexate (MTX) vs MTX alone in the treatment of SASP-resistant RA we conducted a controlled open clinical trial. Forty RA patients with active arthritis despite adequate SASP therapy, were allocated randomly to regimes of either SASP+MTX or MTX alone. The patients were evaluated openly by a single observer for 24 weeks. In the first 15 patients using the combination, pharmacokinetics of MTX without and with SASP were studied. Thirty-eight patients completed the trial. The mean decrease in the disease activity score in the group of patients receiving the combination was significantly greater than in the MTX group (-2.6 vs -1.3 respectively). The same pattern was seen concerning the other efficacy variables. There was no difference in the occurrence of toxicity. SASP had no influence on the pharmacokinetics of MTX. In conclusion in this open study the efficacy of the combination of MTX and SASP seems to be superior to MTX alone, the toxicity of both therapies was similar. This effect was not explained by the pharmacokinetics of MTX which were not altered by concomitant SASP administration.