The effect of low dose methotrexate on bone density.

OBJECTIVE: High dose methotrexate (MTX) has been linked with bone loss in oncology patients. However, it is unclear whether longterm low dose MTX used in the treatment of inflammatory arthritis is associated with bone loss. We compared the effect of low dose MTX on bone density in prospectively recruited patients with rheumatoid arthritis (RA) and psoriasis/psoriatic arthritis (Ps/PsA). METHODS: Thirty RA patients and 30 Ps/PsA patients taking MTX were compared to controls not taking MTX (30 with RA, 27 Ps/PsA). Bone mineral density (BMD) of the radius, lumbar spine, trochanter, and femoral neck was measured using Lunar dual energy x-ray absorptiometry. Student t tests were used to detect differences in bone density (using Z scores) of the MTX group versus controls for both the RA and Ps/PsA groups. Analysis of covariance was used to examine for confounders including disease duration, disease activity, age, and sex. RESULTS: BMD of the radius/femoral neck/trochanter did not differ significantly between the MTX treated groups and controls when analyzed by Z scores. The mean difference between the MTX group and controls of the femoral neck was 0.040 (95% CI -0.40, 0.12) and 0.060 (95% CI -0.30, 0.15) for the RA and Ps/PsA groups, respectively. The absolute BMD of the lumbar spine (L2-L4) was higher in the RA MTX group than in controls. Analysis of covariance did not reveal an effect of study group on bone density. CONCLUSION: This study suggests that low dose MTX does not have a negative effect on bone density, at either cortical or trabecular sites.

Does the site of postgraduate family medicine training predict performance on summative examinations? A comparison of urban and remote programs.

BACKGROUND: The location of postgraduate medical training is shifting from teaching hospitals in urban centres to community practice in rural and remote settings. We were interested in knowing whether learning, as measured by summative examinations, was comparable between graduates who trained in urban centres and those who trained in remote and rural settings. METHODS: Family medicine training programs in Ontario were selected as a model of postgraduate medical training. The results of the 2 summative examinations--the Medical Council of Canada Qualifying Examination (MCCQE) Part II and the College of Family Physicians of Canada (CFPC) certification examination--for graduates of the programs at Ontario's 5 medical schools were compared with the results for graduates of the programs in Sudbury and Thunder Bay from 1994 to 1997. The comparability of these 2 cohorts at entry into training was evaluated using the results of their MCCQE Part I, completed just before the family medicine training. RESULTS: Between 1994 and 1997, 1013 graduates of family medicine programs (922 at the medical schools and 91 at the remote sites) completed the CFPC certification examination; a subset of 663 completed both the MCCQE Part I and the MCCQE Part II. The MCCQE Part I results for graduates in the remote programs did not differ significantly from those for graduates entering the programs in the medical schools (mean score 531.3 [standard deviation (SD) 69.8] and 521.8 [SD 74.4] respectively, p = 0.33). The MCCQE Part II results did not differ significantly between the 2 groups either (mean score 555.1 [SD 71.7] and 545.0 [SD 76.4] respectively, p = 0.32). Similarly, there were no consistent, significant differences in the results of the CFPC certification examination between the 2 groups. INTERPRETATION: In this model of postgraduate medical training, learning was comparable between trainees in urban family medicine programs and those in rural, community-based programs. The reasons why this outcome might be unexpected and the limitations on the generalizability of these results are discussed.

The remarkable spectrum of methotrexate toxicities.

This article outlines a general scheme for categorizing medication-related adverse events. This is followed by a review of the less well-recognized adverse events attributed to low-dose methotrexate therapy. Known and suspected risk factors are described and causative mechanisms are suggested. Ultimately, this article aims at increasing the readers awareness of uncommon or underreported methotrexate-associated adverse events so that prescribing and monitoring practices can be tailored to enhance the safe use of this valuable antirheumatic agent.

Progression of rheumatoid arthritis following bone marrow transplantation. A case report with a 13-year followup.

The progression of rheumatoid arthritis (RA) is documented in a patient receiving a sex-mismatched, allogeneic bone marrow transplant (BMT) for gold-induced marrow aplasia. DNA typing confirmed a high probability of a full donor engraftment (complete chimerism). Although the RA was in complete remission 2 years post-BMT, clinical, laboratory, histologic, and radiologic evidence of the recurrence of synovitis from 3-13 years post-BMT is presented. Implications of these observations for theories of the pathogenesis of RA and the future of immunotherapies are discussed.

Factors influencing the emigration of physicians from Canada to the United States.

OBJECTIVE: To determine whether location of postgraduate medical training and other factors are associated with the emigration of physicians from Canada to the United States. DESIGN: Case-control study, physicians were surveyed with the use of a questionnaire mailed in May 1994 (with a reminder sent in September 1994), responses to which were accepted until Dec. 31, 1994. PARTICIPANTS: Physicians randomly selected from the CMA database, 4000 with addresses in Canada and 4000 with current addresses in the United States and previous addresses in Canada. OUTCOME MEASURES: Sex, age, location of undergraduate and postgraduate medical training, qualifications, practice location, opinions concerning residence decisions, current satisfaction and plans. RESULTS: The overall response rate was 49.6% (50.0% among physicians in the United States and 49.2% among those in Canada). Age and sex distributions were similar among the 8000 questionnaire recipients and the nearly 4000 respondents. Physicians living in the United States were more likely to be older (mean 53.2 v. 49.6 years of age), male (87% v. 75%) and specialists (79% v. 52%) than those practising in Canada. Postgraduate training in the United States was associated with subsequent emigration (odds ratio 9.2, 95% confidence interval 7.8 to 10.7). However, in rating the importance of nine factors in the decision to emigrate or remain in Canada, there was no significant difference between the two groups in the rating assigned to location of postgraduate training. Professional factors rated most important by most physicians in both groups were professional/clinical autonomy, availability of medical facilities and job availability. Remuneration was considered an equally important factor by those in Canada and in the United States. Six of seven personal/family factors were rated as more important to their choice of practice location by respondents in Canada than by those in the United States. Current satisfaction was significantly higher among respondents in the United States. Most physicians in each group planned to continue practising at their current location. Of Canadian respondents, 22% indicated that they were more likely to move to the United States than they were a year beforehand, whereas 4% of US respondents indicated that they were more likely to return to Canada. CONCLUSIONS: Factors affecting the decision to move to the United States or remain in Canada can be categorized as "push" factors (e.g., government involvement) and "pull" factors (e.g., better geographic climate in the US). Factors can also be categorized by whether they are amenable to change (e.g., availability of medical facilities) or cannot be managed (e.g., proximity of relatives). An understanding of the reasons why physicians immigrate to the United States or remain in Canada is essential to planning physician resources nationally.

Does the number of trainees in a postgraduate training program influence the pass rates on certifying examinations?

We tested the hypothesis that small training programs (3 or fewer residents) lack the "critical mass" needed for an optimal learning experience, and thus graduates of small programs will have a lower pass rate on the Royal College of Physicians and Surgeons of Canada (RCPSC) certifying exams that graduates of large (10 or more residents) training programs. Pass rates on the RCPSC certifying exams (written and oral) were compared to the training program size for each of 6 years from 1984/85 to 1989/90 within 10 of the 43 RCPSC (sub)specialties selected by meeting predefined program size requirements. These 10 specialties met the size variation requirements needed to test the hypothesis: neurology, cardiology, emergency medicine, community medicine, neurosurgery, urology, plastic surgery, dermatology, anatomical pathology, and respiratory medicine. Of these, 3 specialties had a significantly lower written exam pass rate for candidates trained in small compared to large programs. The same 3 specialties (neurology, neurosurgery, and community medicine) had a higher proportion of International Medical Graduates (IMGs) in small training programs. The significantly lower pass rate of IMGs, compared to Canadian/USA graduates, accounted for a portion of the correlation of small program size with lower pass rates in these 3 specialties. By pooling the results from the 10 specialties evaluated, candidates from small (3 or fewer residents) training programs have slightly lower pass rates (11%) on written certification examinations compared to candidates from large (10 or more residents) training programs. This small but statistically significant effect on the pooled results was due to averaging of a more marked program size effect from 3 of the 10 specialties.(ABSTRACT TRUNCATED AT 250 WORDS)

Use of magnetic resonance imaging in diagnosing eosinophilic fasciitis. Report of two cases.

OBJECTIVE: To determine the role of magnetic resonance imaging (MRI) in the diagnosis of eosinophilic fasciitis (EF), selection of appropriate biopsy site, and followup of treatment. METHODS: MRI was used to examine 2 patients with EF at the time of their initial clinical presentation and after several months of treatment. T2-weighted axial, T2-weighted axial with fat saturation, and T1-weighted axial post-gadolinium with fat saturation scans at 1.5T were obtained. RESULTS: MRI demonstrated hyperintensity within the fascia. This defect resolved with treatment and clinical improvement. CONCLUSION: MRI is a useful noninvasive tool for diagnosing EF and for monitoring the effectiveness of therapy.

The effects of Arthritis Society fellowships on career choice.

OBJECTIVE: To find out if The Arthritis Society (TAS) fellowship grants influenced career choice or career development. METHODS: Two hundred former TAS training fellowship recipients (1975-1990 inclusive) were sent a questionnaire to evaluate the effects of TAS clinical or research fellowship support on their subsequent career development. RESULTS: One hundred and forty (70%) completed questionnaires were returned by 88 clinical and 37 research fellowship recipients--a further 17 had received both a clinical and a research fellowship. Fifty-one percent of the respondents are now academic rheumatologists, 40% in community practice and 9% still in training. Seventy-three percent of the research fellowship recipients currently receive research grant support, compared to 16% of the former clinical fellowship recipients. Seventy-one percent agreed that their TAS fellowship support had "directly or indirectly influenced or facilitated their chosen career path"--this included 100% of the research fellowship recipients, compared to 55% of the clinical fellowship recipients. The majority decided on an academic or a community based career path during their postgraduate training. Fourteen percent who trained for an academic career are now in community practice and 9% who planned on a community based career later became academic rheumatologists. Eighty-nine respondents (64%) enclosed a CV. This subset was further analyzed using career markers such as academic rank, number and size of research grants and number of publications. In this subset those who had received both a clinical and a research fellowship had the most advanced academic rank (22% full professor), largest number of publications (n = 39) and largest number of grants (5.3/year; average $40,446), compared to former research fellowship recipients: 4.0% full professor, 22 publications, 3.2 grants/year; average $25,164. Recipients of clinical fellowships in this subset had lower levels of all the academic career markers. CONCLUSION: Of 200 consecutive TAS fellowship recipients 71% of those responding (n = 140) to a career tracking study agreed that the fellowship support "directly or indirectly" influenced or facilitated their career choice. An apparent synergistic effect of providing both clinical and research fellowships on subsequent development of an academic career deserves further study.

Adverse effects of low dose methotrexate therapy in rheumatoid arthritis.

OBJECTIVE: To determine (1) the risk of treatment termination for low dose, weekly methotrexate (MTX) therapy in patients with rheumatoid arthritis (RA), and (2) the prevalence, nature and predictors of adverse effects due to longterm low dose MTX therapy. METHODS: A 13-year, retrospective survey of all patients with RA receiving low dose MTX therapy was conducted using life table, logistic regression and case control methods of analyses. Major and minor adverse effects were defined. RESULTS: Consecutive patients with RA (144) starting MTX (mean dose 8.2 mg/week) were observed to have a 75% risk of treatment termination at 60 months. Reasons for 81 patients stopping MTX were adverse effects (43), loss/lack of effect (18), other medical and nonmedical reasons (13), and lost to followup (7). Sixty-two patients experienced 83 major adverse events, including gastrointestinal symptoms (29), hepatic enzyme test abnormalities (23), pneumonitis (5) and severe leukopenia (8). Aging was the only predictor of treatment discontinuation associated with a major toxicity. Five patients developed a malignancy during the observation period. CONCLUSIONS: In our survey the risk of treatment termination was 75% in patients with RA taking MTX after 60 months. An adverse drug effect is a more common reason for treatment termination (53%), compared to loss/lack of beneficial effect (22%) or other reasons (16%) or lost to followup (9%). Increasing age is associated with an increased risk of treatment termination associated with a major toxicity.

Therapeutic value of colchicine in the treatment of patients with psoriatic arthritis.

OBJECTIVE: To test the hypothesis that colchicine is an effective treatment of psoriatic arthritis. METHODS: Twenty five patients with psoriatic arthritis were entered into a two centre, double blind, crossover study of 23 weeks' duration comparing the therapeutic effect of colchicine (0.6-1.8 mg/day) with placebo. RESULTS: No significant difference was noted between colchicine or placebo treatment for the primary outcome measure (Lansbury joint count) or any of the seven secondary outcome measures. No change in the psoriasis was noted during active or placebo treatment. Adverse clinical effects were reported more often during treatment with colchicine (14 patients) than with the placebo (four patients), resulting in the early withdrawal of three patients receiving colchicine from the trial. Increased creatine kinase values, without weakness, occurred during treatment with colchicine (five patients) and placebo (four patients). CONCLUSIONS: In conclusion, our study did not provide evidence that colchicine is of therapeutic value in the treatment of psoriatic arthritis.

Pancytopenia associated with low dose methotrexate therapy. A regional survey.

OBJECTIVE: To determine which risk factors are associated with serious pancytopenia associated with low dose methotrexate (MTX) therapy. METHODS: All Ottawa area rheumatologists, hematologists and dermatologists were surveyed to obtain cases of pancytopenia associated with low dose MTX therapy between 1981 and 1991. Pancytopenia was defined as white blood cells < 3.5 x 10(9)/l and platelets < 140 x 10(9)/l and hemoglobin < 100 g/l. A case control method was used to evaluate risk factors. RESULTS: Fifteen cases of pancytopenia were identified from returned questionnaires (93% response rate) and from reviewing the medical records of 2 major teaching hospitals. All patients were hospitalized, had MTX therapy discontinued and were treated: 12 patients received transfusions, 8 leucovorin therapy, and 4 folic acid. Two patients died, only 1 directly due to MTX therapy. Identified risk factors were (1) elevated BUN or creatinine levels, (2) increasing mean corpuscular volume values, (3) increased age and (4) concomitant trimethoprim-sulfamethoxazole therapy. CONCLUSIONS: Pancytopenia associated with low dose MTX therapy is a life threatening adverse effect often associated with known risk factors. A change in monitoring guidelines and patient education are suggested as means of risk reduction.

Comparison of azathioprine, methotrexate, and the combination of both in the treatment of rheumatoid arthritis. A controlled clinical trial.

OBJECTIVE: To compare the relative safety and efficacy of azathioprine (AZA), methotrexate (MTX), and the combination of both in the treatment of active rheumatoid arthritis (RA). METHODS: Two hundred twelve patients with active RA were entered into a 24-week prospective, controlled, double-blind, multicenter trial and were randomly assigned to 1 of 3 treatment groups. RESULTS: One hundred fifty-eight patients finished 24 weeks of the study. There were no remissions seen but response rates were greater than 30% for all outcome measures. Combination therapy was not statistically superior to MTX therapy alone, but both combination therapy and MTX alone were superior to AZA alone when patients were analyzed by intent-to-treat and with withdrawals treated as therapy failures. If only patients who continued taking the therapy were analyzed, the mean improvement was greater for AZA therapy than for MTX, while the combination remained the most active. Adverse effects on the gastrointestinal tract and elevations of liver enzyme levels were the most frequent causes for discontinuations. CONCLUSION: Both combination therapy and MTX alone were superior to therapy with AZA alone for active RA but were not statistically different in their effect on outcome assessment.

Benign breast disease in systemic sclerosis (SSc). A case-control study.

We hypothesized that Systemic Sclerosis (SSc) may affect the breast in the form of Benign Breast Disease (BBD). For the purpose of this study BBD was defined as breast symptoms either detected by the patient resulting in physician consultation, or detected by a physician during the course of a routine consultation, or detected by a physician during the course of a routine physical exam. Forty-one of 47 women with SSc were matched to case controls from two disease groups (RA and OA). Case matching was done for age (+/- 5 years), disease duration (+/- 3 years) and gender. A structured telephone interview was administered to all subjects and controls to determine the frequency of BBD and associated risk factors. The SSc group had a higher prevalence of BBD compared to the RA group (12/41 versus 4/41, p less than 0.04). However, a similar proportion of the SSc patients and OA case controls had BBD (7/28 versus 9/28). These differences could not be attributed to any of the evaluated risk factors. The RA group had a higher frequency and longer duration of NSAID use, suggesting that the increased use of NSAIDs in the RA patients may account for the lower prevalence of BBD, although genetic, hormonal or undetermined factors may be operative. Without an age-matched, "healthy" general population control group it is impossible to determine if the observed difference in prevalence of BBD represents a less than normal prevalence in RA or a greater than normal prevalence in SSc and OA.

Giant cell arteritis (temporal arteritis) affecting the breast: report of two cases and review of published reports.

The breast is an infrequently recognised site of primary giant cell arteritis. Two cases of giant cell arteritis affecting the breast are described and 11 previously described cases are reviewed. All cases presented with single or multiple breast masses, leading to a diagnosis before biopsy of suspected breast carcinoma. Symptoms similar to those of polymyalgia rheumatica occurred in about half of these patients, though the significance of these symptoms was only appreciated in retrospect. Clinical or pathological evidence of giant cell arteritis outside the breast (temporal artery, thyroid artery) was noted in a minority of cases. Seven patients received corticosteroid treatment, and all patients recovered without complications. Two patients had an adenocarcinoma of the breast contiguous with the giant cell arteritis. Giant cell arteritis affecting the breast may be underrecognised and should be considered in older women with polymyalgia rheumatica-like symptoms and tender breast mass(es).

Azathioprine and methotrexate as combination chemotherapy in rheumatoid arthritis.

Azathioprine or methotrexate (MTX) are each established, and comparably effective, therapies for rheumatoid arthritis (RA). An ongoing, still double blind, 3-arm, 24-week study comparing azathioprine or MTX, or azathioprine and MTX in RA is described. With 146 (of 210 total) patients enrolled, it is apparent that all 3 treatment groups demonstrate clinically significant improvement at Week 24. One treatment arm (Group 1) showed a greater degree of improvement in raw mean scores for most outcome variables. Another treatment arm (Group 2) had an adverse effect dropout rate exceeding the sum of adverse effect dropouts from Group 1 and Group 2. Most adverse effects were due to gastrointestinal intolerance.

International study of ketanserin in Raynaud's phenomenon.

PURPOSE: The effects of ketanserin on primary or secondary Raynaud's phenomenon due to connective tissue disease were studied in a large, international group of patients. PATIENTS AND METHODS: The study population consisted of 222 patients from 10 countries. After a run-in period of one month of placebo therapy, patients were randomly assigned in a double-blind manner to receive ketanserin 40 mg three times daily (n = 113) or placebo (n = 109) for three months. Total finger blood flow was measured in 41 patients in a warm and cool room before and during treatment. Vasospastic episodes were assessed by diaries and global evaluations. RESULTS: A significant reduction of 34% in frequency of episodes occurred with ketanserin, compared to 18% with placebo (p = 0.011). There was a 1% reduction in duration of episodes with ketanserin therapy, compared to a 2% increase with placebo therapy, but this finding was not statistically significant (p = 0.29). No difference was observed in severity of attacks. Global evaluations by investigators (p = 0.03) and patients (p less than 0.01) showed an overall benefit with ketanserin compared to that seen with placebo. Patients with primary or secondary Raynaud's phenomenon responded similarly to treatment. No changes in total finger blood flow were found. CONCLUSION: Ketanserin significantly improves the subjective symptoms of patients with primary or secondary Raynaud's phenomenon and is an appropriate agent to use in this disease when conservative measures fail.