Penicillamine in rheumatoid arthritis: adverse effects.

The use of penicillamine in rheumatoid arthritis (RA) is limited by the incidence of adverse effects, some of which are potentially hazardous. However, adverse effects are dose-related and the advantages and disadvantages of different fixed and flexible dose regimes are discussed. The incidence of adverse effects is significantly greater in patients previously treated with gold who developed toxicity to that drug--no such increase being found in gold treated patients whose only reason for stopping gold was ineffectiveness. Rashes which develop after several months of treatment are variants of pemphigus and their various presentations are described. Fatal reactions, fortunately rare, are predominantly associated with aplasia of the bone marrow. Monthly haematological checks coupled with meticulous charting of the results may reveal trends as well as numerical changes and serve as an early warning of marrow damage.     

Cancer risk in hospitalized rheumatoid arthritis patients

Objectives. Patients diagnosed with RA have been at an increasedrisk of many cancers and at a decreased risk of some cancers.We planned to revisit the theme by using a nation-wide populationof RA patients. Methods. An RA research database was constructed by identifyinghospitalized RA patients from the Hospital Discharge Registerand cancer patients from the Cancer Registry. Earlier studiesfrom Sweden have shown that some 75% of RA patients have beenhospitalized at some time point. Follow-up of 42 262 RA patientswas carried out from year 1980 to 2004 including separate follow-upsfor shorter intervals. Standardized incidence ratios (SIRs)were calculated for cancer in RA patients by comparing withsubjects without RA. Results. Many cancers were in excess in RA patients, especiallyHodgkin disease, non-Hodgkin lymphoma and squamous cell skincancer; a novel association was found for non-thyroid endocrinetumours. Colon, rectal and endometrial cancers were decreasedin RA patients. When RA patients were first hospitalized after1999, the SIRs for melanoma, squamous cell skin and upper aerodigestivetract cancers and for leukaemia were increased compared withprevious periods. Conclusions. This study, the largest so far published, quantifiedthe increased and decreased site-specific risks of cancer inRA patients. The recent increases in the risks of squamous cellskin and upper aerodigestive tract cancers, melanoma and leukaemiacall for continuous vigilance and recording of changes in treatment. KEY WORDS: Subsequent cancer, Changing risk, Age at onset, National databases Submitted 31 January 2008; revised version accepted 3 March 2008.     

Newer disease-modifying antirheumatic drugs and the risk of serious hepatic adverse events in patients with rheumatoid arthritis

BACKGROUND: Spontaneous cases of hepatic adverse events have been reported in patients with rheumatoid arthritis who were being treated with leflunomide, one of the newer disease-modifying antirheumatic drugs (DMARDs). We assessed the risk of hepatic events associated with the use of leflunomide and other DMARDs. METHODS: Two cohorts comprising 41,885 patients with rheumatoid arthritis who had been dispensed a DMARD between September 1, 1998, and December 31, 2001, were formed using claims databases. Follow-up was from the first dispensing date to the occurrence of a serious or nonserious hepatic event. A nested case-control approach was used to estimate adjusted rate ratios of hepatic events associated with DMARDs dispensed during the prior year, as compared with methotrexate monotherapy. RESULTS: There were 25 cases of serious hepatic events (rate, 4.9 per 10,000 per year) and 411 nonserious hepatic events (rate, 80.0 per 10,000 per year). There was no increase in the rate of serious hepatic events with either leflunomide (rate ratio [RR] = 0.9; 95% confidence interval [CI]: 0.2 to 4.9) or traditional DMARDs (RR = 2.3; 95% CI: 0.8 to 6.5). However, the rate was increased with biologic DMARDs (RR = 5.5; 95% CI: 1.2 to 24.6). The rate of nonserious hepatic events was also increased with biologic DMARDs (RR = 1.5; 95% CI: 1.0 to 2.3), but not with leflunomide (RR = 0.9; 95% CI: 0.7 to 1.3) and traditional DMARDs (RR = 1.1; 95% CI: 0.8 to 1.4). CONCLUSIONS: We found no evidence of an excess risk of serious or nonserious hepatic events with the use of leflunomide as compared with methotrexate. Still, the increased risk observed with the new biologic DMARDs should be investigated further.     

Relationship between frailty and methotrexate discontinuation due to adverse events in rheumatoid arthritis patients

Clinical Rheumatology - Methotrexate (MTX) is an anchor drug in the treatment of rheumatoid arthritis (RA). Frailty is the intermediate condition between being healthy and disabled, and can lead to...     

Increased risk of tuberculosis in patients with rheumatoid arthritis

OBJECTIVE: To quantify the risk of tuberculosis (TB) in an unselected sample of patients with rheumatoid arthritis (RA) compared to the risk in the general population. METHODS: The incidence of TB in the general population of Spain was obtained from the National Network of Epidemiological Surveillance reports. The incidence of TB was ascertained from a cohort of 788 patients with RA selected randomly from the registries of 34 participating centers throughout Spain. A patient was considered a TB case only if information about disease symptoms, microorganism identification, and TB treatment were confirmed in the clinical records. The relative risk of TB in RA was calculated by dividing the standardized mean incidence of TB from 1990 to 2000 in the RA cohort by the mean incidence of TB in Spain during the same years. RESULTS: The mean incidence of TB in the general population of Spain from 1990 to 2000 was 23 cases per 100,000. Seven cases of TB were identified in the RA cohort, yielding a mean annual incidence (1990-2000) of 134/100,000 patients. The incidence risk ratio of pulmonary TB in patients with RA compared to the general population is 3.68 (95% CI 2.36-5.92). CONCLUSION: We found a 4-fold increased risk of TB infection in patients diagnosed with RA. These results might help to interpret the magnitude of the problem attributable to the introduction of new therapies in RA.     

Cardiovascular risk factors in Chilean patients with rheumatoid arthritis

OBJECTIVE: Epidemiologic studies have shown an increased mortality rate in patients with rheumatoid arthritis (RA). The most common cause of death in these patients is cardiovascular disease. We estimated the frequency of and examined risk factors for coronary artery disease in Chilean patients with RA. METHODS: Fifty-four patients with RA were studied: 87% were women, with a mean age (+/- standard deviation) of 51 +/- 13 yrs, 92% were rheumatoid factor positive, and 51% had radiological erosions; 32 age and sex matched healthy controls were studied. Traditional cardiovascular risk factors and RA-specific variables were determined. Lipid profile, lipoprotein(a) [Lp(a)], homocysteine, ultrasensitive C-reactive protein (CRP), anticardiolipin (aCL), anti-beta2-glycoprotein I (anti-beta2-GPI) and antioxidized low density lipoprotein (ox-LDL) antibodies were measured. RESULTS: Median concentration of homocysteine was significantly higher in patients with RA than in controls: 10 (range 5.4-37.4) versus 8.3 (3.6-17.8) micromol/l (p = 0.001). Patients with RA who gave a history of cardiovascular disease had the highest concentrations of homocysteine: 15.1 (13.1-19.7) versus 9.9 (5.4-37.4) micromol/l (p = 0.001). We found no differences between patients and controls in lipid profiles or Lp(a), or for other traditional risk factors. Anti-ox-LDL, IgG aCL, and IgG anti-beta2-GPI antibody levels were similar in both groups. IgM subtypes were higher in patients with RA than in controls, but in low titers. CONCLUSION: Our data suggest that a high homocysteine concentration could be an important risk marker for cardiovascular disease in patients with RA.     

Antibodies to dna in patients with rheumatoid arthritis and juvenile rheumatoid arthritis

Antibodies to double-stranded DNA (DSDNA) were found in 18 patients with RA, in 5 patients with JRA, and in 5 patients with undiagnosed connective tissue disease. Five patients had clinical features consistent with both RA and SLE, 11 with only RA, and 5 with only JRA. Based on these observations, the presence of serum anti-DSDNA antibodies should not be used as a sole criterion in the diagnosis of SLE.     

Usefulness of risk scores to estimate the risk of cardiovascular disease in patients with rheumatoid arthritis

Patients with rheumatoid arthritis (RA) have an excess burden of cardiovascular (CV) disease (CVD). CV risk scores for the general population may not accurately predict CV risk for patients with RA. A population-based inception cohort of patients who fulfilled 1987 American College of Rheumatology criteria for RA from 1988 to 2007 was followed until death, migration, or December 31, 2008. CV risk factors and CVD (myocardial infarction, CV death, angina, stroke, intermittent claudication, and heart failure) were ascertained by medical record review. Ten-year predicted CVD risk was calculated using the general Framingham and the Reynolds risk scores. Standardized incidence ratios were calculated to compare observed and predicted CVD risks. The study included 525 patients with RA aged ≥30 years without previous CVD. The mean follow-up period was 8.4 years, during which 84 patients developed CVD. The observed CVD risk was 2-fold higher than the Framingham risk score predicted in women and 65% higher in men, and the Reynolds risk score revealed similar deficits. Patients aged ≥75 years had observed CVD risk >3 times the Framingham-predicted risk. Patients with positive rheumatoid factor or persistently elevated erythrocyte sedimentation rates also experienced more CVD events than predicted. In conclusion, the Framingham and Reynolds risk scores substantially underestimated CVD risk in patients with RA of both genders, especially in older ages and in patients with positive rheumatoid factor. These data underscore the need for more accurate tools to predict CVD risk in patients with RA.     

The risk of hospitalized infection in patients with rheumatoid arthritis

OBJECTIVE: To determine whether patients with rheumatoid arthritis (RA) are at increased risk of hospitalized infection and whether the risk varies by RA treatment. METHODS: A retrospective cohort study was conducted using data from a medical and pharmacy claims managed-care database from 1999 to 2006. A total of 24,530 patients were included in the RA cohort; a random sample of non-RA patients served as a comparison cohort (n = 500,000). Rates of hospitalized infection were compared between the cohorts. A nested case-control analysis was performed within the RA cohort to assess the effect of current RA medication use on hospitalized infection risk. RESULTS: A total of 1,993 patients with RA and 11,977 non-RA patients experienced a hospitalized infection. The rate of first hospitalized infection was higher in the RA cohort [adjusted hazard ratio = 2.03; 95% confidence interval (CI) 1.93-2.13]. In the case-control analysis, the current use of biological disease modifying antirheumatic drugs (DMARD) was associated with slightly increased risk of hospitalized infection [rate ratio (RR) = 1.21; 95% CI 1.02-1.43]. Methotrexate and hydroxychloroquine were associated with decreased risk. Oral corticosteroid use increased risk (RR = 1.92; 95% CI 1.67-2.21), and there was a dose-related effect [< or = 5 mg/day: RR = 1.32 (95% CI 1.06-1.63), 6-10 mg/day: RR = 1.94 (95% CI 1.53-2.46), > 10 mg/day: RR = 2.98 (95% CI 2.41-3.69)]. CONCLUSION: These data confirm that individuals with RA are at increased risk of hospitalized infection compared to those without RA. Oral corticosteroid use was associated with a dose-related increase. Biological DMARD use was associated with slightly elevated risk; however, this may reflect confounding and channeling bias.     

Clinical efficacy and adverse effects of weekly single dose leflunomide in refractory rheumatoid arthritis

AimTo study the clinical efficacy and adverse events of weekly single dose of leflunomide in patients with refractory rheumatoid arthritis in comparison with conventional daily regimen.MethodsPatients with refractory rheumatoid arthritis were taken up for the study; 91 patients were enlisted of whom 3 became non-compliant and were excluded. A concurrent parallel study was designed with the patients divided into two groups and efficacy and adverse events recorded at third and sixth months.ResultsA total of 88 patients were included in the study and were divided into two groups. At the end of 6 months, in the daily group 37 (82.2%) out of 45 patients had disease activity score (DAS) less than 3.2 indicating a low disease activity and 8 patients (17.8%) had moderate disease activity. None had high disease activity. In the weekly group, 36 (83.7%) out of 43 patients had low disease activity and 7 (16.3%) had moderate disease. None had high disease activity. Four (8.9%) patients developed adverse reactions in the daily group. One patient (2.2%) had alopecia and the other (2.2%) had diarrhoea and were withdrawn from the study. Two (4.4%) patients had elevated liver enzymes and the drug was stopped at 6 months. None in the weekly group reported any adverse events.ConclusionsWeekly regimen was found to be better in terms of compliance and had a lower adverse effect profile. The result was statistically significant. Clinical efficacy of weekly therapy was found to be similar to that of conventional therapy in terms of DAS.     

Prior gold therapy does not influence the adverse effects of D-penicillamine in rheumatoid arthritis

One hundred fourteen patients with definite or classic rheumatoid arthritis were followed prospectively between January 1976 and April 1981 to monitor their toxicity pattern to D-penicillamine. The influence of previous sodium aurothiomalate therapy on the toxicity pattern of D-penicillamine is described. There was no significant difference in overall outcome of the patients treated with D-penicillamine with respect to adverse effects, whether they had previous gold toxicity, previous gold therapy but no toxicity, or no previous gold therapy. The time from gold toxicity to the start of D-penicillamine therapy was greater in those who did not develop D-penicillamine toxicity compared with those who did. This difference just reached statistical significance. Total gold salt received had no effect on eventual outcome of D-penicillamine treatment, and the toxicity pattern of D-penicillamine in those patients who had previous gold therapy was similar to those patients who had never received gold therapy.     

Systematic review of NSAID-induced adverse reactions in patients with rheumatoid arthritis in Japan

Abstract

A systematic review of randomized controlled clinical trials of nonsteroidal antiinflammatory drugs (NSAIDs) in rheumatoid arthritis (RA) patients was conducted to evaluate the risk of NSAID-induced adverse reactions. Double-blind, randomized, controlled trials with 6-week treatments for RA patients were included in the study. The endpoints for the analysis included any adverse reactions, digestive adverse reactions, and upper gastrointestinal (GI) adverse reactions. A fixed-effect model was used for estimation of the risk. Time-to-event analysis of the incidence of adverse reactions was also conducted. A total of 28 trials was included for the analysis, and a total of 30 NSAIDs were used in the trials. The proportion of patients who experienced any adverse reaction was as follows: piroxicam 18.9% (3 trials), diclofenac 18.8% (4 trials), indomethacin 22.1% (14 trials), and aspirin 25.0% (4 trials). The proportion of patients who experienced digestive adverse reactions was as follows: piroxicam 10.2%, diclofenac 10.6%, indomethacin 13.1%, and aspirin 14.1%. Most withdrawals due to adverse reaction occurred during the first 3 weeks after administration of the NSAID. Although the risk of NSAID-induced adverse reaction was different from drug to drug, the risk of adverse reaction was clinically significant.     

Low-dose prednisolone in rheumatoid arthritis: adverse effects of various disease modifying antirheumatic drugs

OBJECTIVE: To assess the incidence and severity of disease modifying antirheumatic drug (DMARD)-induced adverse effects (AE) in patients with rheumatoid arthritis (RA) taking/not taking glucocorticoids (GC). More specifically, we tested whether GC can prolong the survival time of DMARD in patients receiving combination therapy. METHODS: In a retrospective study of 154 patients with RA, data were examined for DMARD therapy and duration of low-dose GC ((3/4) 7.5 mg prednisone equivalent/day). Patients were followed for 2-62 months, and AE were graded following WHO criteria. RESULTS: GC therapy significantly increased the duration of therapy with sulfasalazine (SSZ) from 10.4 +/- 2.3 to 22.5 +/- 1.9 months and for methotrexate (MTX) from 21.8 +/- 2.9 to 43.3 +/- 2.7 months. Stratifying the withdrawal of DMARD for occurrence of AE and loss of efficacy revealed that GC comedication significantly increased the time until AE for users of MTX (3.0 +/- 0.6 vs 18.8 +/- 1.3 mo; p < 0.05), hydroxychloroquine (HCQ; 34.5 +/- 4.6 vs 54.4 +/- 5.1 mo; p < 0.05), and gold (6.6 +/- 0.9 vs 10.5 +/- 0.9 mo; p < 0.05). In patients taking SSZ the time until cessation due to loss of efficacy increased significantly under GC comedication (16.8 +/- 1.2 vs 31.3 +/- 2.9 mo; p < 0.05). However, in patients taking azathioprine (AZA) the duration of therapy decreased from 44.4 +/- 2.6 to 22.3 +/- 1.6 months under GC due to both time until AE and loss of efficacy. Patients under comedication of MTX + GC, HCQ + GC, and AZA + GC experienced significantly more AE compared to the respective DMARD monotherapy. A highly significant reduction was observed in the frequency of erosive RA in patients with GC comedication (n = 30; 49.1%) compared to patients without low-dose GC (n = 81, 80.4%; OR 4.05, 95% CI 1.91-8.66, p < 0.0001). CONCLUSION: Low-dose GC retard radiological progression of RA and exhibit a differential effect on survival of DMARD and degree of AE due to DMARD. Further studies are warranted to address safety and interactions of chronic low-dose GC in RA patients treated with DMARD.     

Systematic review of NSAID-induced adverse reactions in patients with rheumatoid arthritis in Japan

 A systematic review of randomized controlled clinical trials of nonsteroidal antiinflammatory drugs (NSAIDs) in rheumatoid arthritis (RA) patients was conducted to evaluate the risk of NSAID-induced adverse reactions. Double-blind, randomized, controlled trials with 6-week treatments for RA patients were included in the study. The endpoints for the analysis included any adverse reactions, digestive adverse reactions, and upper gastrointestinal (GI) adverse reactions. A fixed-effect model was used for estimation of the risk. Time-to-event analysis of the incidence of adverse reactions was also conducted. A total of 28 trials was included for the analysis, and a total of 30 NSAIDs were used in the trials. The proportion of patients who experienced any adverse reaction was as follows: piroxicam 18.9% (3 trials), diclofenac 18.8% (4 trials), indomethacin 22.1% (14 trials), and aspirin 25.0% (4 trials). The proportion of patients who experienced digestive adverse reactions was as follows: piroxicam 10.2%, diclofenac 10.6%, indomethacin 13.1%, and aspirin 14.1%. Most withdrawals due to adverse reaction occurred during the first 3 weeks after administration of the NSAID. Although the risk of NSAID-induced adverse reaction was different from drug to drug, the risk of adverse reaction was clinically significant. Received: April 24, 2002 / Accepted: September 11, 2002 RID="*"     

The best cardiovascular risk calculator to predict carotid plaques in rheumatoid arthritis patients

Clinical Rheumatology - Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death in patients with rheumatoid arthritis (RA). Chronic inflammation and traditional risk factors...     

HLA antigens and adverse drug reactions to sodium aurothiomalate and D-penicillamine in patients with rheumatoid arthritis

Summary The association between HLA antigens and adverse drug reactions (ADR), (e.g. proteinuria, haematological abnormalities, stomatitis, diarrhoea and dermatitis) in rheumatoid arthritis (RA) to sodium aurothiomalate (gold) and to Dpenicillamine (PA) were studied in 32 patients. Thirtyeight RA patients treated with gold and PA, and with no ADR to these drugs, were used as controls. The frequency of HLA B8 was significantly (p<0.05) increased among RA patients with ADR compared to plasma donors. DR3 was also significantly increased (p<0.05) in RA patients with haematological ADR compared to plasma donors. Haematological ADR occured significantly (p<0.05) more often in DR3 positive patients (55%) than among DR3 negative RA patients (27%).     

Antibodies to DNA in patients with rheumatoid arthritis and juvenile rheumatoid arthritis.

Antibodies to double-stranded DNA (DSDNA) were found in 18 patients with RA, in 5 patients with JRA, and in 5 patients with undiagnosed connective tissue disease. Five patients had clinical features consistent with both RA and SLE, 11 with only RA, and 5 with only JRA. Based on these observations, the presence of serum anti-DSDNA antibodies should not be used as a sole criterion in the diagnosis of SLE.