[Merkel cell carcinoma during treatment with TNF-alpha inhibitors: coincidence or warning?]. / Merkelcel-carcinoom bij gebruik van TNF-α-blokkers. Toeval of waarschuwing?

BACKGROUND: Increasing numbers of patients are being treated with TNF-alpha inhibitors. Two patients in our outpatient clinic developed Merkel cell carcinoma during treatment with TNF alpha inhibitors. Since this is a very rare malignancy, this is a remarkable observation. CASE DESCRIPTION: A 70-year-old male with rheumatoid arthritis had been treated with etanercept for two years when he discovered a nodule on his elbow that started growing rapidly. It was diagnosed as Merkel cell carcinoma. Despite treatment, the patient died 2 years later. CONCLUSION: Merkel cell carcinoma is an aggressive malignancy with a clinically benign aspect. Patients treated with TNF-alpha inhibitors possibly have an increased risk of developing this malignancy.

Trends in economic consequences of rheumatoid arthritis over two subsequent years.

OBJECTIVE: To examine changes in direct costs and in working status over 2 yrs in patients with rheumatoid arthritis (RA). PATIENTS AND METHODS: In both 1999 and 2000, RA patients (n = 461) filled out a questionnaire retrospectively regarding utilization of health care, other RA-related direct costs and working status. Patients were categorized into four disease duration groups: 0-2 yrs, 2-6 yrs, 6-10 yrs and >10 yrs. At the same time points, disease activity was assessed. Logistic regression analyses were performed to identify a possible association between disease activity (high >66th percentile) measured at start of the second year and high direct costs (high >66th percentile) in the second year. RESULTS: Compared with the first year, a significant decrease in the costs for contacts with health care workers and for costs for laboratory tests was observed in the second year for the <2 yrs group. In the 2-6 yrs group and the >10 yrs group, we found a significant decrease in costs for devices and adaptations, but medication costs increased in the <2 yrs and the >10 yrs group in the second year. In the >10 yrs group, this was mainly due to an increasing number of patients who started to use biological agents during the second year. In all four disease duration groups, worse Visual Analogue Scale (VAS) disease activity and VAS general well-being were significantly associated with high direct costs. Of 97 patients working without disability at time of the first assessment, 12 (12%) patients became (partial) work disabled during follow-up. CONCLUSION: In particular, costs for devices/adaptations and for medication changed during follow-up. The latter was probably due to an increase in the use of biological agents. Hopefully a decrease in direct costs and a reduced percentage of patients getting work disabled by better disease control will outweigh the high costs of biological drugs in the future.

Joint surgery in the Utrecht Rheumatoid Arthritis Cohort: the effect of treatment strategy.

OBJECTIVE: To investigate the prevalence and prognostic factors of joint surgery in a large cohort of patients with rheumatoid arthritis, whose treatment, clinical and radiographic data have been assessed at predefined points in time since disease onset. METHODS: Data on surgical interventions were retrospectively obtained from 482 patients with rheumatoid arthritis whose follow-up data for at least 2 years were available, including treatment and response to treatment during the first 2 years. Survival time until the first surgical intervention and until the first major surgical intervention was determined for the total study population by Kaplan-Meier survival curves. Three separate Cox regression analyses were carried out to determine which variables measured at baseline, during the first year and during the first 2 years were predictors for joint surgery. RESULTS: 27% of the patients underwent surgical interventions. Mean survival time until the first surgical intervention was 10.4 years. The percentage of patients with a surgical intervention was 10% lower in the group with response to treatment when compared with the non-response group. Next to a delayed start with disease-modifying antirheumatic drugs, fast radiographic progression during the first year and first 2 years was a predictor of joint surgery in the multivariate regression analyses. CONCLUSION: Treatment with disease-modifying antirheumatic drugs immediately after diagnosis results in less joint surgery when compared with a delayed start. Furthermore, joint surgery is carried out more often in patients who do not respond to treatment.

A good response to early DMARD treatment of patients with rheumatoid arthritis in the first year predicts remission during follow up.

OBJECTIVE: To describe the frequency and duration of remission in the Utrecht rheumatoid arthritis cohort of patients followed since diagnosis, and the clinical and treatment characteristics of patients with remission v those without. METHODS: In 1990 the Utrecht rheumatoid arthritis cohort study group started a clinical trial in which patients with recent onset of rheumatoid arthritis (<1 year) were randomised into four treatment groups: hydroxychloroquine (n = 169); intramuscular gold (n = 163); methotrexate (n = 166); and pyramid (n = 64). After two years, rheumatologists were allowed to prescribe any disease modifying antirheumatic drug. Remission was defined as: duration of morning stiffness < or =15 min, mean VAS pain < or =10 mm, Thompson joint score < or =10, and ESR < or =30 mm/h during at least six months. Cox regression analysis was used to determine baseline clinical, demographic, and treatment predictors of remission. RESULTS: Mean follow up duration was 62 months. Thirty six per cent achieved at least one period of remission. Median duration between diagnosis and the first remission period was 15 months for the intramuscular gold group, 18 months for the methotrexate and hydroxychloroquine groups, and 24 months for the pyramid group (NS). Predictors of remission were early response to initial treatment, less pain, rheumatoid factor negativity, and lower joint score at baseline. CONCLUSIONS: After a mean follow up duration of 62 months, only 36% of the patients had fulfilled the remission criteria at least once. A good response to treatment during the first year seems to be independently associated with remission rather than initial treatment alone.

Working status among Dutch patients with rheumatoid arthritis: work disability and working conditions.

OBJECTIVES: To assess work disability and variables associated with work disability among Dutch patients with rheumatoid arthritis (RA). METHODS: A questionnaire on working status was filled out by 296 patients of working age. Employment and work disability rates adjusted for age and sex from the Dutch population were determined using indirect standardization. Cox proportional hazard analysis was used to assess baseline predictors of work disability in a subgroup of patients (n = 195). RESULTS: After a mean disease duration of 4.3 yr, patients had a 0.78 (95% CI 0.67-0.88) chance of being employed and a 2.14 (95% CI 1.75-2.54) risk of being work disabled when compared with the Dutch population. Functional disability and job type at the start of the disease were predictors of future work disability. In total, 48 (37%) currently employed patients had changed their working conditions, of which reduced working hours (46%), reduced pacing of work (42%) and help from colleagues (49%) were the most important alterations. Of the 60 work disabled patients without a paid job, only 11 patients (18%) would be willing to work again. CONCLUSION: This study shows that the adjusted employment rates were lower and that work disability rates were higher in patients with RA when compared with the general Dutch population. In addition, a substantial number of employed patients had to change their working conditions due to RA. Only a minority of work disabled RA patients was willing to return to the paid labour force.

The course of radiologic damage during the first six years of rheumatoid arthritis.

OBJECTIVE: To describe the radiologic course in a large cohort of patients with early rheumatoid arthritis (RA) and to analyze individual components of damage. METHODS: Five hundred two patients with recent-onset RA (disease duration <1 year) underwent annual radiologic assessment for a maximum of 6 years in this longitudinal prospective study. The study was designed to investigate the efficacy of 3 different therapeutic strategies. For the assessment of radiologic damage, radiographs of the hands and feet were scored according to the modified Sharp/van der Heijde method (SHS; range 0-448). A mean of 2.9 (range 1-7) radiographs was read per patient. RESULTS: Stable rates of progression of the SHS, erosion score, and narrowing score were found over the course of RA: the mean rates were 8.6, 5.4, and 3.2 modified Sharp units per year, respectively. The rate of progression of newly (not previously) damaged joints declined, and the rate of progression of already damaged joints (which became more damaged) increased during followup, leading to an equal contribution to progression of the SHS at 5 years. The joints of the feet, especially the fifth metatarsophalangeal joint, generally became eroded earlier and more of them became eroded compared with the joints of the hands. CONCLUSION: Radiologic damage progresses at a constant rate. In advanced disease, monitoring the progression of previously existing damage is as important as assessing new abnormalities in previously undamaged joints. Radiographs of the feet should be included in assessments of radiologic damage that are used in clinical intervention trials and daily practice.

Aggressive treatment in early rheumatoid arthritis: a randomised controlled trial. On behalf of the Rheumatic Research Foundation Utrecht, The Netherlands.

OBJECTIVES: To compare three therapeutic strategies using slow acting antirheumatic drugs (SAARDs) in early rheumatoid arthritis (RA), for their disease modifying properties, toxicity, and lag time until treatment effect. METHODS: Patients with recent onset RA from six hospitals were randomly assigned to immediate initiation of one of three treatment strategies: (I) a "mild SAARD with a long lag time" (hydroxychloroquine, if necessary replaced by auranofin); (II) a "potent SAARD with a long lag time" (intramuscular gold, if necessary replaced by D-penicillamine); (III) a "potent SAARD with a short lag time" (methotrexate, if necessary replaced by sulfasalazine). Comparisons included two years of follow up. RESULTS: All SAARD strategies reduced mean disease activity. A greater percentage of patients improved clinically with strategies II and III than with strategy I: percentages of patients improved on joint score with strategies II and III (79% and 82%, respectively), which was statistically different from strategy I (66%). The same was true for remission percentages: 31% and 24% v 16%, respectively). Longitudinal analysis showed significantly less disability with strategy III, and a lower erythrocyte sedimentation rate with strategy II than with strategy I. In addition, radiological damage after one and two years, was significantly lower in strategies II and III (at two years median scores were 11 and 10 v 14 in strategy I, p<0.05). Toxicity was increased in strategy II compared with the other strategies. CONCLUSION: Strategy III, comprising methotrexate or sulfasalazine, produced the best results weighing effectiveness and toxicity. Strategy I (hydroxychloroquine or auranofin) was slightly less effective, and strategy II (intramuscular gold or D-penicillamine) was associated with increased toxicity.

Toxicity of anti-rheumatic drugs in a randomized clinical trial of early rheumatoid arthritis.

OBJECTIVE: To evaluate the toxicity of slow-acting anti-rheumatic drugs (SAARDs) and non-steroidal anti-inflammatory drugs (NSAIDs) in early rheumatoid arthritis. METHODS: Patients were randomized to receive a SAARD-hydroxychloroquine (HCQ; n=120), i.m. gold (n=114) or methotrexate (MTX; n=118)-or a NSAID only (n=67). Patients in the three SAARD groups were allowed to take NSAIDs. Follow-up included 545 patient-years (p-yr). Adverse effects were attributed to specific medications using the Naranjo scoring method. RESULTS: Fifty-five per cent of the patients suffered from adverse effect(s). Adverse effects were most common during i.m. gold therapy (87 per 100 p-yr), which led to permanent discontinuation of this treatment in 31 cases. The incidences of adverse effects that were probably attributable to NSAIDs in patients treated simultaneously with a SAARD were similar for the three SAARD groups. The mean period until the first adverse effect was longer in the MTX group (39 weeks) than in the HCQ group (27 weeks). Baseline clinical and sociodemographic parameters were not predictive of the occurrence of adverse effects. CONCLUSION: No adverse effect could be classified as definitely related to either SAARDs or NSAIDs by the Naranjo scoring method. The incidence of possible adverse effects of NSAIDs and SAARDs was 72 per 100 p-yr, and adverse effects led to permanent discontinuation of the therapy in 56 cases (13%) (31 patients receiving i.m. gold, 12 receiving MTX, 10 receiving HCQ and three receiving NSAID only).

Effects of rheumatoid arthritis on employment and social participation during the first years of disease in The Netherlands.

OBJECTIVE: To study the effect of rheumatoid arthritis (RA) on working capabilities and social participation, including non-paying jobs, during the first 6 yr of disease. DESIGN: Cross-sectional study. METHODS: In April 1996, a self-reporting questionnaire was sent to 424 participants of a population-based clinical trial of therapeutic strategies for early RA initiated in 1990. RESULTS: A total of 363 completed questionnaires were returned (response = 86%). Disease duration varied from < 1 to 6 yr (mean 2.8 yr). The employment rate was low in the RA population compared to the Dutch population. In the male 45- to 64-yr-old group, 63% of RA patients were not employed compared to 32% of the Dutch population (P < 0.01). In the female 45- to 64-yr-old group, 76% of the RA population vs 67% of the Dutch were not employed (P < 0.05). Of the employed patients, 59% reported that RA affected their working capabilities, e.g. they worked an average of 21 h per week less due to RA. Of the patients without a paying job, 41% believed that this was (partly) due to RA. In addition, fewer RA patients had non-paying jobs and they performed fewer household activities compared to the general Dutch population. CONCLUSION: RA already has a negative influence on the working capabilities, social participation and household activities of these patients during the first 6 yr of disease.

Can methotrexate be used as a steroid sparing agent in the treatment of polymyalgia rheumatica and giant cell arteritis?

OBJECTIVE: To investigate whether methotrexate (MTX) has a steroid sparing effect in the treatment of polymyalgia rheumatica (PMR) and giant cell arteritis (GCA). METHODS: We carried out a randomised double blind, placebo controlled study in 40 patients with PMR, six of whom also had clinical symptoms of GCA. A temporal artery biopsy specimen was available from 37 patients; GCA was found in six of the specimens. Among the six patients with clinical signs of GCA, three had a positive biopsy specimen. All patients were started on prednisone 20 mg/day, irrespective of clinical signs and biopsy result, supplemented with a weekly, blinded capsule containing either MTX 7.5 mg or placebo. The prednisone dose was decreased as soon as clinical symptoms disappeared and erythrocyte sedimentation rate, C reactive protein level, or both, had normalised. RESULTS: Twenty one patients were followed for two years, or at least one year after discontinuing medication. No differences were found between the MTX group and the placebo group concerning time to achieve remission, duration of remission, number of relapses, or cumulative prednisone doses. After 21 weeks the mean daily prednisone dose was reduced by 50%. Forty percent of all patients were able to discontinue prednisone within two years. Median duration of steroid treatment was 47.5 weeks (range 3-104). No serious complications from GCA were encountered. CONCLUSIONS: With a (rapid) steroid tapering regimen, it was possible to reduce the mean daily prednisone dose by 50% in 21 weeks and to cease prednisone in 40% of the patients within two years. With this regimen, no steroid sparing effect of MTX in a dosage of 7.5 mg/week was found.

The effectiveness of early treatment with "second-line" antirheumatic drugs. A randomized, controlled trial.

OBJECTIVE: To compare two therapeutic strategies for patients with recent-onset rheumatoid arthritis. DESIGN: Open, randomized clinical trial. SETTING: Outpatient clinics of six clinical centers. PATIENTS: 238 consecutive patients with recently diagnosed rheumatoid arthritis. INTERVENTIONS: Delayed or immediate introduction of treatment with slow-acting antirheumatic drugs (SAARDs). MEASUREMENTS: Primary end points were functional disability, pain, joint score, and erythrocyte sedimentation rate at 6 and 12 months and progression of radiologic abnormalities at 12 months. RESULTS: Statistically significant advantages at 12 months for patients receiving the SAARD strategy (immediate treatment with SAARDs) with regard to all primary end points that may be clinically important are indicated by the differences in improvements from baseline and their 95% CIs. These differences were 0.3 (95% CI, 0.2 to 0.6) for disability (range, 0 to 3), 10 mm (CI, 1 to 19 mm) for pain (range, 0 to 100 mm), 39 (CI, 4 to 74) for joint score (range, 0 to 534), and 11 mm/h (CI, 3 to 19 mm/h) for erythrocyte sedimentation rate (range, 1 to 140 mm/h), all in favor of SAARD treatment. The SAARD strategy also appears to be advantageous at 6 months. Radiologic abnormalities progressed at an equal rate in the SAARD and the non-SAARD groups; the difference in progression (range, 0 to 448) was 1 (CI, -3 to 5). Analyses were based on the intention-to-treat principle and thus included 29% of patients in the non-SAARD group who discontinued the non-SAARD treatment strategy; treatment was usually discontinued because of insufficient effectiveness. The SAARD strategy including two alternative SAARDs could not be continued by 8% of patients, usually because of adverse reactions. CONCLUSIONS: Early introduction of SAARDs may be more beneficial than delayed introduction for patients with recently diagnosed rheumatoid arthritis.

Physical disability and psychological well being in recent onset rheumatoid arthritis.

OBJECTIVE: The association between self-report physical disability scores and psychological well being in patients with rheumatoid arthritis (RA) has been described in several recent publications on patients with widely varying disease durations. We describe the results of a study into these relationships in patients with RA with a disease duration of less than 1 year. METHODS: In this cross sectional study on 113 patients with recent onset RA disability was assessed with 3 self-report indices and with measurement of grip strength. Correlation coefficients between disability measures and disease activity measures (joint tenderness/swelling score, erythrocyte sedimentation rate [ESR)]), psychological well being (cheerful mood, depressive mood, and anxiety), and demographical variables were calculated; hierarchical regression analysis was done with disability measures as the dependent variables. RESULTS: All disability scales were correlated moderately strongly with the joint score and ESR, and with psychological well being. No relation was found with age, sex, marital status, or rheumatoid factor status. Regression analysis showed the variance of 9-15% in disability could be explained by psychological well being after disease activity had been controlled for. CONCLUSION: Patients with recent onset RA appear not to be obviously different with respect to the moderately strong association between physical disability and psychological well being from patients with RA of longer duration in other published reports.

Self report functional disability scores and the use of devices: two distinct aspects of physical function in rheumatoid arthritis.

OBJECTIVES: Self report scores of physical disability and the use of devices or assistance in performing activities are sometimes integrated in one index of physical function, although they are aimed at measuring different dimensions of physical disability. The properties of both parameters were evaluated in two groups of patients with rheumatoid arthritis (RA). METHODS: A group of patients with RA of recent onset was compared with a group with established disease on four parameters of disability: use of devices, use of personal assistance, and scores on a validated Dutch version of the Health Assessment Questionnaire Disability Index, with and without integrating the use of devices or assistance. Correlation coefficients among disability parameters were calculated. In multiple regression analysis the influence of disease duration on the disability parameters was determined after disease activity, psychological wellbeing, and demographical characteristics had been controlled. RESULTS: Functional disability scores were mainly related to inflammatory activity and psychological wellbeing, whereas the uses of devices had a strong relation with disease duration, independent of current disease activity. Integrating these parameters of disability yielded a parameter that was still mainly associated with disease activity. CONCLUSION: Self report scores of functional disability and the use of devices represent distinct dimensions of physical function in RA. Integrating both parameters into one measure of physical disability does not provide an index adequately reflecting both dimensions. The use of both parameters to measure outcome in long term clinical studies is recommended.

Reflex sympathetic dystrophy syndrome of one finger.

Reflex sympathetic dystrophy syndrome (RSDS) is a common but often unrecognized syndrome. It usually affects a leg or arm but may also be limited to parts of the extremity. We report a case of a 48-year-old patient who developed RSDS of only one finger. Especially, a limited form may delay recognition and therapy of a disease which can be treated successfully in an early phase.

Atrioventricular conduction disturbance as an early feature of Reiter's syndrome.

Atrioventricular (A-V) conduction disturbances in Reiter's syndrome are usually described in longstanding disease. This report deals with two male patients with Reiter's syndrome who developed an A-V block early in the course of the disease. One of these patients developed a second degree A-V block, Wenckebach type, which has not been described before at an early stage of this syndrome.

IgA containing immune complexes and hematuria in ankylosing spondylitis. A prospective longitudinal study.

The occurrence of circulating immune complexes containing IgA (IgA-IC) was studied in groups of patients with ankylosing spondylitis (AS) selected for the presence or absence of hematuria. In studies done with 4 kinds of assays, IgA-IC were found more frequently and in higher titers in the 18 patients with AS with hematuria than in the 40 patients with AS without hematuria. Comparison of clinical indices of disease activity in these patient groups showed that the disease was more active in patients with AS with hematuria. Our findings confirm those made in a previous retrospective study on the relation between hematuria and circulating IgA-IC in AS and suggest that circulating IgA-IC play a role in the pathogenesis of hematuria in AS.

Frequency of infection among patients with rheumatoid arthritis versus patients with osteoarthritis or soft tissue rheumatism.

We compared the frequencies and types of infections that occurred in 448 patients with rheumatoid arthritis (RA) versus those occurring in 185 control patients who had osteoarthritis or soft tissue rheumatism. At least 1 infection developed in 23% of the RA patients and in 27% of the control patients. Using a series of risk factors, we found no substantial difference in the risk of infection in RA patients compared with that in control patients. Some of these factors, such as being female, having poor functional capacity, and receiving glucocorticoid treatment, were associated with different levels of risk for infection, but the levels were similar in RA patients and control patients.

Human parvovirus B19 DNA in synovial fluid.

We describe a 33-year-old woman with a serologically proven human parvovirus B19 infection, who developed synovitis. Using a dot-blot hybridization technique, we detected B19 DNA in her synovial fluid. To our knowledge, this is the first report of the isolation of B19 from synovial fluid.

Coronary arteritis complicating rheumatoid arthritis.

The case is described of a patient with rheumatoid arthritis (RA) who developed heart failure and vasculitis and died of a myocardial infarction. Autopsy showed vasculitis of several major epicardial coronary arteries. Coronary arteritis in a patient with RA is seldom diagnosed during their lifetime but should be suspected when such a patient develops ischaemic heart disease.

Acute pancreatitis in systemic lupus erythematosus.

Lethal acute pancreatitis developed in a 16-year-old Caucasian woman suffering from systemic lupus erythematosus. Until the time of onset of pancreatitis, the patient's medications included prednisone, furosemide, ethacrynic acid and chlorthalidone, all of which have been related to pancreatitis. At autopsy, no specific signs of autoimmune activity were found in the diseased pancreatic tissue. A review of the literature shows that information on the association of pancreatitis and SLE is scarce. This case illustrates the dilemma of pathogenesis and therapy of acute pancreatitis in SLE and the need for further investigation.