Application of explicit process of care measurement to rheumatoid arthritis: Moving from evidence to practice.

OBJECTIVE: To construct quality measures with measurement validity and meaning for clinicians. METHODS: We conducted a prospective cohort study of rates of change in disease-modifying antirheumatic drug (DMARD) and/or systemic corticosteroid drug or dose for 568 patients with rheumatoid arthritis (RA) across 6,159 clinical encounters within 12 months to examine how changes in clinical specifications change adherence. RESULTS: Rates of DMARD change were sensitive to specifications regarding the intensity of disease activity (severe or moderate), duration of specified disease activity, and length of the observation period. Over 12 months, the proportions of 377 patients with severe disease activity observed for 1-month, 2-month, and 3-month time blocks who had a change in DMARD drug or dose were 36%, 57%, and 74%, respectively. Over 12 months, a change in DMARD drug or dose was observed for 44%, 50%, and 68% of 377 patients with severe disease within 3 months, 6 months, and 12 months, respectively, of the patient meeting criteria for severe disease activity. A change in DMARD drug or dose was observed for 21%, 23%, and 34% of 149 patients with moderate disease activity within 3, 6, and 12 months, respectively, of the patient meeting criteria for moderate disease activity. CONCLUSION: Rates of pharmacologic interventions for patients with moderate and severe RA disease activity vary substantially by intensity and duration of disease activity and by duration of period for observing change. Lack of precision in explicit process criteria could substantially mislead comparisons of quality of care across comparison groups.

Long-term safety and efficacy of etanercept in patients with rheumatoid arthritis.

OBJECTIVE: Patients with rheumatoid arthritis (RA) treated with etanercept (Enbrel) in controlled studies of 3 to 6 months' duration had rapid and sustained improvement of their disease, with minimal safety issues. In this study, we examine safety and clinical benefit after longer term treatment with etanercept. METHODS: All adult patients with RA with a previously inadequate response to one or more disease modifying antirheumatic drugs, and who received at least one dose of etanercept as monotherapy in controlled or open label clinical trials were evaluated for safety and clinical benefit. Adverse event rates were compared as was evidence of continued benefit over time. RESULTS: Etanercept continued to be safe and well tolerated in 628 adult patients treated for a median of 25 mo (maximum 43 mo; 1109 patient-years). Nine percent of patients withdrew due to lack of efficacy and 7% due to adverse events. Most adverse events were mild, and no statistically significant increases in frequency of events were seen when patients received etanercept over longer periods of time. Clinical benefit was maintained with longterm therapy. A 100% improvement in individual disease activity measures was achieved by 17% to 28% of the patients. Fifty-five percent of patients who were taking corticosteroids (mean dose at baseline 6.6 mg/day) decreased or discontinued corticosteroid therapy while maintaining control of their arthritis symptoms. CONCLUSION: Etanercept continued to be safe and well tolerated, and its clinical benefit was sustained for a median of 25 mo and for as long as 43 mo in patients with RA.

Treatment with a consensus peptide based on amino acid sequences in autoantibodies prevents T cell activation by autoantigens and delays disease onset in murine lupus.

OBJECTIVE: To test the hypothesis that an artificial peptide, based on an algorithm describing T cell stimulatory sequences from the VH regions of murine IgG antibodies to DNA, is an effective tolerogen in vivo in the (NZB/NZW)F1 (BWF1) mouse model of systemic lupus erythematosus. METHODS: Using proliferative T cell responses to 439 Ig peptides, an algorithm was constructed that describes the amino acid sequences likely to stimulate BWF1 T cells. Stimulatory (pConsensus [pCONS]) or nonstimulatory (pNegative [pNEG]) peptides were synthesized. Groups of 10-week-old (healthy) or 20-week-old (diseased) BWF1 mice received monthly intravenous injections of 1,000 microg of peptide or saline. Ex vivo splenic T cell responses and in vivo clinical effects were measured. RESULTS: Tolerance was induced by pCONS, but not by pNEG, with respect to ex vivo T cell proliferation and T cell help for antibodies to DNA. T cell help for IgG anti-DNA was impaired not only after T cell stimulation by pCONS but also after stimulation by some peptides from nucleosomal and Ro antigens. Treatment with pCONS significantly delayed the onset of nephritis and inhibited increases in the plasma levels of total IgG, IgG antibodies to DNA, nucleosome, cardiolipin, interferon-gamma, and interleukin-4. In contrast, antibody responses to an exogenous antigen were not impaired. Survival was significantly prolonged in both healthy and diseased mice treated with pCONS. CONCLUSION: Induction of immune tolerance in response to treatment with pCONS in autoreactive T cell helper populations is highly effective in delaying the appearance of multiple autoantibodies, cytokine increases, and nephritis in BWF1 mice, and dramatically prolongs survival. A striking effect is the ability of the peptide to tolerize T cell help for anti-DNA that is induced by multiple, structurally unrelated self antigens.

Direct and indirect costs associated with the onset of seropositive rheumatoid arthritis. Western Consortium of Practicing Rheumatologists.

OBJECTIVE: To examine the direct and indirect costs of rheumatoid arthritis (RA) during the first year of disease. METHODS: As part of a longitudinal observational study, 150 patients with seropositive RA of 5.9 +/- 2.9 mo duration were recruited through the Western Consortium of Practicing Rheumatologists. Subjects completed questionnaires about health care services and resources utilized and about the number of days of usual activity lost as a result of RA during the 6 month period prior to enrolment. RESULTS: Study participants had active RA as evidenced by mean tender and swollen joint counts of 24.9 +/- 13.5 and 20.6 +/- 11.6, respectively, and moderate functional impairment reflected by a mean Health Assessment Questionnaire (HAQ) score of 1.24 +/- 0.7. The average total direct cost of RA was $200/month. Health care visits, medications, and radiographs accounted for 78% of the total direct cost, while expenditures for hospitalizations accounted for only 3.5% of the total. The average number of days of usual activity lost per month because of RA was 3.8 +/- 7.7, translating into an average indirect cost of $281/month. Of the 95 subjects who were gainfully employed prior to disease onset, 12 were disabled and 5 were on sick leave as a result of RA, corresponding to a work disability rate of 18%. Work disabled subjects reported significantly lower total household incomes and higher HAQ disability and global disease activity scores than subjects who continued working. CONCLUSION: In this group of patients with seropositive RA substantial costs, both direct and indirect, were incurred during the first year of disease.

Relative contributions of the components of the American College of Rheumatology 20% criteria for improvement to responder status in patients with early seropositive rheumatoid arthritis.

OBJECTIVE: To evaluate factors that influence the responses defined by the American College of Rheumatology (ACR) 20% criteria for improvement in rheumatoid arthritis (RA). METHODS: ACR 20% and 50% response rates were calculated from data collected for the intervals 0-6, 0-12, and 0-24 months for 180 RA patients participating in the Western Consortium of Practicing Rheumatologists long-term observational study of early seropositive RA (mean +/- SD duration of RA at study entry 6.0 +/- 3.4 months). Analyzable cases were patients with paired data for tender and swollen joint counts plus at least 3 of the following criteria: physician's and patient's global assessments of disease activity and patient's score for pain (by visual analog scale), physical function score on the Health Assessment Questionnaire (HAQ), and levels of an acute-phase reactant. Response rates were then recalculated by 3 different methods: 1) using only cases with complete paired data for all criteria, 2) sequentially assuming no improvement in each of the 5 secondary criteria, and 3) substituting grip strength for HAQ scores. RESULTS: Using 464 paired observations for all analyzable cases, ACR 20% (50%) improvement rates were 52.6% (33.0%), compared with 55.6% (34.8%) for 365 paired observations from the cases with complete data. Decreases in ACR response rates when secondary criteria were sequentially set at "no improvement" ranged from 11.7% (pain at 0-6 months) to 1.2% (C-reactive protein at 0-12 months), but these were not statistically different by the kappa statistic. Overall numerical rankings of the relative contributions of the secondary criteria to the ACR 20% or 50% response rates were physician's global assessment, pain, HAQ, patient's global assessment, and acute-phase reactant. Only 7.8% of paired grip strength observations showed > or =20% improvement, compared with 71% of paired HAQ observations. CONCLUSION: The use of all "analyzable" cases (paired data for tender and swollen joint counts plus > or =3 of the 5 secondary criteria) increases the number of subjects and only slightly decreases the ACR response rate compared with analyses limited to cases with complete data. The contributions of the secondary criteria are not statistically different, supporting their equal weighting in the ACR definition of improvement. The ACR 20% response rates are higher when the HAQ, rather than grip strength, is used to measure physical function.

Patient self-report tender and swollen joint counts in early rheumatoid arthritis. Western Consortium of Practicing Rheumatologists.

OBJECTIVE: To determine the correlation between patient self-report joint counts and standard physician joint counts, and to compare pictorial (Mannequin) and text (Rapid Assessment of Disease Activity in Rheumatology, RADAR) formats for obtaining patient self-reports. METHODS: Baseline patient self-report joint counts were mailed and completed by 60 patients with early rheumatoid arthritis (RA) one day before and one day after being examined by a physician. Twenty-seven were randomized to the Mannequin tender and Mannequin swollen joint counts; 33 were randomized to the RADAR tender and swollen joint counts. Agreement between patient and physician self-report joint counts, diagnostic characteristics, and test-retest reliability of patient self-report joint counts was computed. Stepwise regression analyses were performed to identify predictors of patient-physician differences in total joint count. RESULTS: Means and standard deviations of paired patient and physician total joint counts were not different for Mannequin or RADAR forms. Spearman correlations were moderate (0.58 to 0.69 for Mannequin, 0.37 to 0.58 for RADAR). Agreement (intraclass correlations) was 0.65 for the Mannequin and 0.56 for the RADAR forms. Patient test-retest reproducibility was moderate for RADAR tenderness (0.58) and high (r>0.90) for RADAR swollen and both Mannequin forms. Level of patient education predicted patient-physician differences on the RADAR swollen joint counts (p = 0.003), but was not significant in Mannequin forms, suggesting that education was not a factor in accurate completion of Mannequin forms. CONCLUSION: Both pictorial and text format patient self-report joint counts are significantly correlated with physician joint counts. In addition to moderately high patient test-retest reproducibility, this suggests that patient self-reports in both formats may yield accurate measures of improvement in disease activity.

Equivalence of the acute phase reactants C-reactive protein, plasma viscosity, and Westergren erythrocyte sedimentation rate when used to calculate American College of Rheumatology 20% improvement criteria or the Disease Activity Score in patients with early rheumatoid arthritis. Western Consortium of Practicing Rheumatologists.

OBJECTIVE: In an additive cohort of patients with early rheumatoid arthritis (RA), to determine the effect of substituting one acute phase reactant for another on the number of patients satisfying the American College of Rheumatology (ACR) 20% preliminary criteria for improvement, and on calculated Disease Activity Scores (DAS). METHODS: A total of 251 patients with 6.4 months average disease duration had detailed clinical assessments at entry and 6, 12, and 24 months in a multicenter prospective longterm observational study. Matched erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and plasma viscosity (PV) assays were done at 366 time points. Disease modifying antirheumatic drugs were not started until after the baseline evaluation. RESULTS: After 6, 12, and 24 months, 50%, 53%, and 57% of patients were responders, as defined by the ACR 20% improvement criteria. The difference in response rates when ESR, CRP, or PV was used as the acute phase reactant ranged from 0.4% at 12 months to 3% at 24 months. Percentile distributions of the 366 matched CRP, ESR, and PV values were used to prepare a nomogram that can be used to calculate the other acute phase reactant values if the value of one is known. When the nomogram was used to impute ESR values from observed PV or CRP values, average DAS scores calculated with the actual ESR values were not different from average DAS scores calculated from the imputed ESR values. CONCLUSION: ESR, CRP, and PV are equally useful in calculating ACR 20% response rates in patients with active early RA. A nomogram can be used to impute ESR values from CRP or PV values; use of the imputed ESR values is as accurate as use of the actual ESR values to calculate average DAS.

Early undifferentiated connective tissue disease (CTD). VI. An inception cohort after 10 years: disease remissions and changes in diagnoses in well established and undifferentiated CTD.

OBJECTIVE: (1) To review the diagnoses after 10 years in patients who were identified within 12 months of the onset of well established and undifferentiated connective tissue diseases (CTD). (2) To examine the death rates and disease remissions in these patients. METHODS: This inception cohort of 410 patients had less than one year of signs and/or symptoms of CTD. Diagnoses of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and poly/dermatomyositis (PM/DM) were made in 197 patients using accepted diagnostic and classification criteria. Diagnoses of undifferentiated CTD were made in 213 patients. These latter patients were placed in 3 categories: isolated Raynaud's phenomenon (RP), unexplained polyarthritis (UPA), and undifferentiated CTD (UCTD), defined as meeting at least 3 of 11 specific manifestations of CTD. The diagnoses and remissions in all patients after 10 years were determined. RESULTS: Patients with well established CTD tended to remain with the original diagnosis. The 10 year survival was at least 87% in all diagnostic categories, with the exception of SSc, in which it was 56%. The progression of UPA to RA occurred infrequently. The presence of antinuclear antibodies suggested that UPA may develop additional symptoms and/or a specific diagnosis, and RP in these patients increased the likelihood of progressing to UCTD or a specific well established CTD. Ten percent of patients with RP progressed to SSc. In patients with UCTD, joint pain/tenderness and swelling counts were associated with progression to other diagnoses including RA, while either serositis, malar rash, or discoid lupus suggested the eventual diagnosis of SLE. CONCLUSION: The survival of patients with SSc was poor, with most dying early in the course of their disease. Remissions were seen in all groups of patients except SSc. The remissions were sometimes transient in SLE. Undifferentiated disease at initial examination within 12 months of onset usually remains undifferentiated.

Etanercept therapy in rheumatoid arthritis. A randomized, controlled trial.

BACKGROUND: In a phase II study, etanercept (recombinant human tumor necrosis factor receptor [p75]:Fc fusion protein) safely produced rapid, dose-dependent improvement in rheumatoid arthritis over 3 months. OBJECTIVE: To confirm the benefit of etanercept therapy of longer duration and simplified dosing in patients with rheumatoid arthritis. DESIGN: Randomized, double-blind, placebo-controlled trial with blinded joint assessors. SETTING: 13 North American centers. PATIENTS: 234 patients with active rheumatoid arthritis who had an inadequate response to disease-modifying antirheumatic drugs. INTERVENTION: Twice-weekly subcutaneous injections of etanercept, 10 or 25 mg, or placebo for 6 months. MEASUREMENTS: The primary end points were 20% and 50% improvement in disease activity according to American College of Rheumatology (ACR) responses at 3 and 6 months. Other end points were 70% ACR responses at 3 and 6 months and other measures of disease activity at 3 and 6 months. RESULTS: Etanercept significantly reduced disease activity in a dose-related fashion. At 3 months, 62% of the patients receiving 25 mg of etanercept and 23% of the placebo recipients achieved 20% ACR response (P < 0.001). At 6 months, 59% of the 25-mg group and 11% of the placebo group achieved a 20% ACR response (P < 0.001); 40% and 5%, respectively, achieved a 50% ACR response (P < 0.01). The respective mean percentage reduction in the number of tender and swollen joints at 6 months was 56% and 47% in the 25-mg group and 6% and -7% in the placebo group (P < 0.05). Significantly more etanercept recipients achieved a 70% ACR response, minimal disease status (0 to 5 affected joints), and improved quality of life. Etanercept was well tolerated, with no dose-limiting toxic effects. CONCLUSIONS: Etanercept can safely provide rapid, significant, and sustained benefit in patients with active rheumatoid arthritis.

A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate.

BACKGROUND: Patients treated with methotrexate for rheumatoid arthritis often improve but continue to have active disease. This study was undertaken to determine whether the addition of etanercept, a soluble tumor necrosis factor receptor (p75):Fc fusion protein (TNFR:Fc), to methotrexate therapy would provide additional benefit to patients who had persistent rheumatoid arthritis despite receiving methotrexate. METHODS: In a 24-week, double-blind trial, we randomly assigned 89 patients with persistently active rheumatoid arthritis despite at least 6 months of methotrexate therapy at a stable dose of 15 to 25 mg per week (or as low as 10 mg per week for patients unable to tolerate higher doses) to receive either etanercept (25 mg) or placebo subcutaneously twice weekly while continuing to receive methotrexate. The primary measure of clinical response was the American College of Rheumatology criteria for a 20 percent improvement in measures of disease activity (ACR 20) at 24 weeks. RESULTS: The addition of etanercept to methotrexate therapy resulted in rapid and sustained improvement. At 24 weeks, 71 percent of the patients receiving etanercept plus methotrexate and 27 percent of those receiving placebo plus methotrexate met the ACR 20 criteria (P<0.001); 39 percent of the patients receiving etanercept plus methotrexate and 3 percent of those receiving placebo plus methotrexate met the ACR 50 criteria (for a 50 percent improvement) (P<0.001). Patients receiving etanercept plus methotrexate had significantly better outcomes according to all measures of disease activity. The only adverse events associated with etanercept were mild injection-site reactions, and no patient withdrew from the study because of adverse events associated with etanercept. CONCLUSIONS: In patients with persistently active rheumatoid arthritis, the combination of etanercept and methotrexate was safe and well tolerated and provided significantly greater clinical benefit than methotrexate alone.

Biologic therapies in rheumatoid arthritis.

Our growing understanding of the immune response mechanism has created a wave of novel biologic agents for the treatment of rheumatoid arthritis. The domain of biologic agents includes: 1) Recombinant regulatory cytokines; 2) engineered molecules and monoclonal antibodies that target proinflammatory cytokines; 3) monoclonal antibodies against lymphocyte cell-surface proteins; 4) fusion proteins and monoclonal antibodies that block the second signal and induce anergy; 5) vaccines comprised of specific proteins from lymphocytes and antigen presenting cells; 6) monoclonal antibodies that block intercellular adhesion; and 6) gene therapy whereby antiarthritis genes are introduced directly into the joint. Most treatments remain under investigation; however, in 1998 two antagonists of tumor necrosis factor were approved marking the first approvals of antirheumatic biologic agents. For the first time anti-rheumatic therapies are being designed instead of borrowed.

Early undifferentiated connective tissue disease. V. An inception cohort 5 years later: disease remissions and changes in diagnoses in well established and undifferentiated connective tissue diseases.

OBJECTIVE: To review the diagnoses after 5 years in patients who were identified within 12 months of the onset of well established and undifferentiated connective tissue diseases (CTD); to examine death rates and disease remissions in these patients. METHODS: This inception cohort of 410 patients was identified in 10 academic rheumatology practices. They had less than one year of signs and/or symptoms of CTD. Diagnoses of specific well established CTD were made using accepted diagnostic and classification criteria. The diagnoses after 5 years were determined. RESULTS: Patients with well established CTD tended to remain with the original diagnosis. The progression of unexplained polyarthritis to rheumatoid arthritis occurred infrequently. Ten percent of patients with isolated Raynaud's phenomenon progressed to systemic sclerosis (SSc). The 5 year survival was over 90% in all diagnostic categories, with the exception of SSc, in which it was 64%. CONCLUSION: Patients with a well established CTD usually continued with the same diagnosis. Patients with undifferentiated CTD tended to remain undifferentiated or to remit.

The relationship between socioeconomic status and recently diagnosed rheumatoid arthritis.

OBJECTIVE: To examine the role of socioeconomic status (SES) in physical functioning, pain, and depressive symptoms among newly diagnosed rheumatoid arthritis (RA) patients with severe disease. METHODS: Data are from 118 non-Hispanic patients of European origin at baseline of a longitudinal study of early, severe RA. Outcome measures with the Health Assessment Questionnaire (HAQ) functional disability index, the HAQ visual analog pain scale, and the Center for Epidemiologic Studies Depression Scale. Hierarchical regression analyses were conducted using a health status block (disease activity and comorbidities), a non-SES related social structure block (age, sex and Lubben Social Network Scale), and indicators of SES (income and education). RESULTS: Non-SES related social structure and SES were important independent determinants of functional disability and depressive symptoms, but both they and the health status variables were unrelated to pain. Further, neither income nor education was related to disease activity or comorbidities. CONCLUSION: It cannot be argued from these data that poorer health status explains the link between SES and disability and depressive symptoms. Although, at baseline, the psychosocial effects of early RA are more severe for those with SES, the disease does not appear to be more severe. It may be that the biologic impact of status differentials will become clearer as the effects of treatment and the course of the disease unfold over time.

CAMPATH-1H in rheumatoid arthritis--an intravenous dose-ranging study.

Forty-one patients with active and refractory rheumatoid arthritis(RA) received a total of 100, 250 or 400 mg of CAMPATH-1H (CAMPATH is a trademark of Glaxo-Wellcome group companies, registered in the US Patent and Trademark Office) over 5 or 10 days in an open, uncontrolled study. Following therapy, patients were monitored for adverse effects and disease activity for 6 months. Therapy was associated with prolonged peripheral blood lymphopenia in all dosing cohorts. During the month immediately following therapy, lymphopenia was most profound in the 400 mg cohorts. The first dose of monoclonal antibody (Mab) was associated with a 'flu'-like syndrome, more pronounced at higher initial doses. One patient developed haemolytic-uraemic syndrome. There were a number of dose-related infections during the early post-treatment period and one fatal opportunistic infection which followed additional immunosuppressive therapy. Antiglobulin responses developed in 9 of 31 patients tested. The majority of patients showed symptomatic improvement following therapy and 20% of patients maintained a 50% Paulus response at 6 months, all of whom were in the 250 or 400 mg cohorts. CAMPATH-1H appears to be an effective treatment for RA. Allowing for the small number of patients treated, infections were more common with higher doses, although this was not true for adverse events overall, and therapeutic responses were more sustained at higher dosing levels. The broad specificity of CAMPATH-1H may be appropriate for the immunotherapy of RA and future studies should aim to define a dose with an optimal therapeutic ratio.

CAMPATH-1H, a humanized monoclonal antibody, in refractory rheumatoid arthritis. An intravenous dose-escalation study.

OBJECTIVE: To evaluate the biologic response, tolerability, and potential clinical effect of a humanized antilymphocyte monoclonal antibody, CAMPATH-1H, in patients with rheumatoid arthritis (RA). METHODS: Forty adult patients with active, refractory RA were treated with CAMPATH-1H, given intravenously, in a multicenter, open, single-dose-escalation study. Patients were assigned to dose groups of 1, 3, 10, 30, 60, and 100 mg CAMPATH-1H. RESULTS: There was a profound, immediate, and sustained reduction of the peripheral lymphocyte count; the most susceptible were the levels of CD4+ and CD8+ cells, which remained depressed during the study period. Sixty-three percent of patients developed antibodies to CAMPATH-1H. Side effects occurred frequently throughout the first 24 hours following infusion, and included fever, headache, nausea, vomiting, and hypotension. All of the immediate drug toxicities resolved within the initial 24-hour postdosing period. One patient developed a reactivation of Mycobacterium xenopi infection 10 weeks following infusion. Sixty-five percent of patients developed a clinical response; the mean duration of response was 2 weeks. CONCLUSION: CAMPATH-1H is a lymphocyte-depleting antibody that is biologically potent even after single-dose therapy. There was no correlation between biologic effect and clinical response. Sustained lymphocyte suppression was observed. Acute infusion toxicities were observed in most patients. The role of depleting monoclonal antibodies in the treatment of RA should be reevaluated.

Rheumatoid arthritis. Outcome measures.

Rheumatologists have been pioneers in the development and use of clinical measures for outcome assessment. The Lansbury Index (1958) and the Empire Rheumatism Gold Trial (1960) used sophisticated double-blind pseudo-placebo-controlled trial designs and standardized prespecified clinical outcome measures to establish the clinical usefulness of a drug whose benefit did not become evident until it was administered for several months. Since these studies, other studies have establish the clinical and statistical groundwork for rheumatoid arthritis outcome measures. In 1980, the Health Assessment Questionnaire and the Arthritis Impact Measurement Scales were added. Future development of paradigms for the decision process in the clinical management of individual rheumatoid arthritis patients will no doubt incorporate standard outcome measures to provide the data upon which management decisions can be based.

DC-ART classification: review of relevant clinical studies.

The proposed disease controlling antirheumatic therapy (DC-ART) definition requires that the therapy change the course of rheumatoid arthritis (RA) for at least 1 year, evidenced by (1) sustained improvement in physical function, (2) decreased inflammatory synovitis, and (3) slowing or prevention of structural joint damage. Selected studies are reviewed. All studies were at least 1 year in duration, but most did not include all 3 of the DC-ART requirements. In these studies, patients treated with placebo generally had no improvement in inflammatory synovitis and progressive structural joint damage, judged by serial joint radiographs. A minority of studies significantly favored one or another of the available agents (gold injections, D-penicillamine, auranofin, antimalarials, azathioprine, sulfasalazine, methotrexate), but the evidence for any one agent is not convincing. For future DC-ART clinical trials patients with early RA should be studied. A hybrid study design may be useful, combining an initial double blind randomized controlled clinical trial with continuing longterm observation of all withdrawals using specified clinical, radiographic, and self report assessments at regular intervals, and an intent-to-treat analysis comparing longterm response rates of the original control and experimental therapy groups. Responsive subgroups should be sought, their characteristics identified, and their responsiveness confirmed in additional trials limited to the identified subgroup.

Early undifferentiated connective tissue disease: III. Outcome and prognostic indicators in early scleroderma (systemic sclerosis).

OBJECTIVE: To characterize the course of early scleroderma and to delineate prognostic factors present within 1 year of disease onset that might identify patients at high risk. DESIGN: Inception cohort study. SETTING: Ten university-based rheumatology clinics participating in the Cooperative Systematic Studies of Rheumatic Diseases Program. PATIENTS: Forty-eight patients who had had scleroderma for less than 1 year. MEASUREMENTS: Fifteen patients with early scleroderma who died were compared with those still living during the initial study period (1982 to 1992). Kaplan-Meier survival estimation and Cox proportional hazards analysis were used to analyze baseline variables for their ability to predict survival duration. RESULTS: Eight of 15 deaths were due to cardiac or pulmonary system failure. The estimated 5-year survival rate was 68%. Baseline factors that were the most predictive of a poor outcome included the presence of abnormal cardiopulmonary signs and abnormal urine sediment (pyuria, hematuria). CONCLUSION: Evidence of early cardiopulmonary disease, renal disease, inflammation, or immune activation may identify a subset of patients with scleroderma who will experience rapidly progressive disease and early death.