ABSTRACT
OBJECTIVE: To examine the range and responsiveness to change of clinical outcome measures and study predictors of clinical response in patients with diffuse cutaneous systemic sclerosis (dcSSc) in the context of clinical trials. METHODS: Data were combined from 629 patients with dcSSc who participated in 7 multicenter clinical therapeutic trials. Trials used common outcome measures: modified Rodnan skin thickness score (MRSS), Health Assessment Questionnaire disability index (HAQ DI), patient's global assessment of disease activity, pulmonary function tests (forced vital capacity, diffusing capacity for carbon monoxide), hand span, and oral aperture. RESULTS: The combined database included 629 patients (82% women, mean ± SD age 46.5 ± 11.8 years, mean ± SD disease duration 19.4 ± 15.9 months). Outcomes tended to improve during trials for patients with more severe disease at study entry and to worsen for patients with less severe disease at entry. Disease duration was mildly negatively predictive of change in MRSS at 6 months (r = -0.27, P < 0.001), and substantial bidirectional variation in change in MRSS and HAQ DI score was seen across the spectrum of disease duration. Sixty-three percent of patients with "early" disease (disease duration <18 months) had a decline in MRSS, and 37% had an increase in MRSS. Eighty-one percent of patients with "late" disease (disease duration ≥ 18 months) had a decline in MRSS, and 19% had an increase in MRSS. Multivariate mixed models did not demonstrate that any baseline variables were strongly predictive of subsequent outcome. CONCLUSION: Among patients with dcSSc enrolled in clinical trials, standard outcome measures tend to improve in those with more severe disease at study entry and to worsen in those with less severe disease at entry. Overall, the MRSS improves during trials, while HAQ DI scores and lung function are mostly static. None of these variables, including disease duration, reliably identifies groups of subjects whose MRSS will predictably increase or decrease in the course of a clinical trial. These findings have important implications for clinical trial design in scleroderma.
Subject(s)
Clinical Trials as Topic , Scleroderma, Diffuse/drug therapy , Adult , Female , Humans , Male , Middle Aged , Outcome Assessment, Health Care , Treatment OutcomeABSTRACT
OBJECTIVE: Antiphospholipid (aPL) antibodies are present in patients with systemic lupus erythematosus (SLE) and/or antiphospholipid antibody syndrome (APS) and are associated with recurrent thromboses, thrombocytopenia, and pregnancy losses. The presence of aPL antibodies is routinely tested using a standardized ELISA that utilizes cardiolipin as antigen (aCL ELISA). This test, although sensitive, is frequently positive in patients with nonrelated autoimmune disorders and some infectious diseases, making the test less specific. Thus there is a need for more specific tests for aCL with equivalent sensitivity to the standard assay. We evaluated the diagnostic utility of a new aPL antibody test kit with a unique phospholipid mixture designed to be more specific than the standard anticardiolipin ELISA. METHODS: aPL antibodies (IgG, IgM) were measured by both a standard ELISA and a new ELISA kit (APhL ELISA Kit, Louisville APL Diagnostics, Inc., Louisville, KY, USA) in the baseline serum from patients enrolled in a 5 year inception cohort, prospective study of early rheumatoid diseases: rheumatoid arthritis (N = 70), SLE (70), scleroderma (45), inflammatory myositis (36), and early undifferentiated connective tissue disease (CTD) (165). Diagnosis was based on standardized criteria and determined at the last study visit. A nested group of patients with Sjogren's syndrome (44) was also defined. Serum from 200 blood donors (BD) served as controls. Patients with known APS (33) and antinuclear cytoplasmic antibody positive renal vasculitis (52) were also studied. Laboratory personnel were blinded to sample diagnostic group. RESULTS: The kit was 90.9% sensitive for detecting APS. Seven patients missed by the kit all had standard aCL values < 40 PL units. Assuming controls do not have APS, the kit was 99.5% specific vs 96.0% for the standard assay. For the patients with CTD, the kit never detected a patient that was not also detected by the standard aCL assay. CONCLUSION: The APhL ELISA Kit appears to be more specific than the standard aCL ELISA without adding potential false positive results. The new test may be useful for followup study for patients found to be aCL positive by standard assays to increase specificity for aCL screening.
Subject(s)
Antibodies, Anticardiolipin/analysis , Antibodies, Antiphospholipid/analysis , Antiphospholipid Syndrome/diagnosis , Reagent Kits, Diagnostic , Rheumatic Diseases/diagnosis , Cohort Studies , Diagnosis, Differential , Enzyme-Linked Immunosorbent Assay , Evaluation Studies as Topic , False Positive Reactions , Female , Humans , Immunoglobulin G/blood , Immunoglobulin M/blood , Male , Prospective Studies , Sensitivity and SpecificityABSTRACT
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.
Subject(s)
Connective Tissue Diseases/diagnosis , Arthritis/diagnosis , Arthritis/mortality , Cohort Studies , Connective Tissue Diseases/mortality , Disease Progression , Follow-Up Studies , Humans , Lupus Erythematosus, Systemic/diagnosis , Lupus Erythematosus, Systemic/mortality , Prognosis , Raynaud Disease/diagnosis , Raynaud Disease/mortality , Rheumatic Diseases/diagnosis , Rheumatic Diseases/mortality , Scleroderma, Systemic/diagnosis , Scleroderma, Systemic/mortalityABSTRACT
OBJECTIVE: Heterotopic ossification (HO) is a disorder characterized by the formation of new bone in tissue that does not ossify under normal conditions. We report a series of 6 cases in which HO occurred in the setting of adult respiratory distress syndrome (ARDS). We wished to show that HO can occur after neuromuscular blockade and that these cases might provide additional evidence that HO is influenced by neural mechanisms. METHODS: Cases of HO were selected from the consultation services at the Massachusetts General Hospital and the Brigham and Women's Hospital. Affected patients all had ARDS and had been treated with a neuromuscular blocking agent. Patients with a history of stroke, burn, head trauma, spinal cord injury, or joint replacement were excluded from this study. RESULTS: Heterotopic bone appeared around large joints in a pattern identical to that seen in patients with paralysis, traumatic brain injury, severe burns, or trauma. New bone formation was self-limited over a period of 1-2 years. Alkaline phosphatase and technetium bone scan were sensitive ways of detecting early disease and monitoring disease activity. Medical therapies had limited benefit. Surgical excision of mature new bone appeared to be the only definitive therapy. CONCLUSION: Neuromuscular blockade in the setting of ARDS appears to be an important risk factor for the development of HO. The similarity of these cases of HO occurring in patients with brain or spinal cord injury raises the possibility that neural mechanisms may be important in the pathogenesis of this disease. Whether the type of neuromuscular blocking agent and the duration of use are important determinants of disease severity remains to be determined.
Subject(s)
Joint Diseases/etiology , Neuromuscular Blockade , Ossification, Heterotopic/etiology , Adult , Aged , Alkaline Phosphatase/blood , Bone and Bones/diagnostic imaging , Bone and Bones/pathology , Calcium/blood , Elbow/pathology , Female , Hip Joint/diagnostic imaging , Humans , Joint Diseases/diagnostic imaging , Knee Joint/diagnostic imaging , Male , Middle Aged , Ossification, Heterotopic/diagnostic imaging , Pulmonary Ventilation , Radiography , Radionuclide Imaging , Respiratory Distress Syndrome/therapy , Shoulder Joint/diagnostic imaging , TechnetiumABSTRACT
BACKGROUND: Two types of antineutrophil cytoplasmic antibodies (ANCA), antiproteinase 3 antibodies (anti-PR3) and antimyeloperoxidase antibodies (anti-MPO), are useful in the diagnosis of such types of vasculitis as Wegener granulomatosis and microscopic polyangiitis. Connective tissue diseases frequently appear in the differential diagnosis of this spectrum of vasculitis. OBJECTIVE: To determine the prevalence of ANCA in patients with connective tissue disease. DESIGN: Blinded, controlled study of a 5-year inception cohort. SETTING: Tertiary-care university teaching hospitals. PATIENTS: 70 patients with rheumatoid arthritis, 70 patients with systemic lupus erythematosus, 45 patients with scleroderma, 36 patients with inflammatory myositis, 44 patients with the sjögren syndrome, 33 patients with the antiphospholipid syndrome, and 165 patients with early undifferentiated connective tissue disease (EUCTD). Serum was taken from 200 blood donors and 52 patients who had known vasculitis and positive results on tests for anti-PR3 or anti-MPO; these patients served as controls. MEASUREMENTS: The presence of anti-PR3 and anti-MPO was determined by combining the results of indirect immunofluorescence tests for cytoplasmic (C-ANCA) and perinuclear (P-ANCA) patterns with the results of enzymelinked immunosorbent assays (ELISAs) directed to measure antigen. RESULTS: Cytoplasmic ANCA was not detected in any study or control patient. Perinuclear ANCA was commonly detected among patients with lupus (31%) but was uncommon among patients in other groups (0% to 5%). In all cases, P-ANCA was associated with the presence of antinuclear antibodies. Atypical ANCA immunofluorescence patterns were fairly common in all groups (11% to 39%). Antiproteinase 3 was detected by ELISA in study patients (1 patient with rheumatoid arthritis, 1 with lupus, 1 with polymyositis, and 6 with EUCTD). Antimyeloperoxidase was detected by ELISA in 2 study patients (1 with rheumatoid arthritis and 1 with lupus). None of the patients with positive ELISA results had evidence of renal vasculitis during follow-up. When an ANCA scoring system that combines immunofluorescence and ELISA was used, the test specificity for vasculitis was 99.5% among patients with connective tissue disease. CONCLUSIONS: Patients with connective tissue disease are known to develop multiple autoantibodies; positivity for anti-PR3 and anti-MPO ANCA in such patients is highly specific for anti-PR3. However, P-ANCA immunofluorescence, which may have positive results because of the presence of antinuclear antibodies, is not a specific marker of anti-MPO. A rigorous ANCA testing system that combines the results of immunofluorescence with those of ELISA is highly specific for Wegener granulomatosis and related vasculitides even in patients with connective tissue disease.
Subject(s)
Antibodies, Antineutrophil Cytoplasmic/blood , Autoantigens/immunology , Connective Tissue Diseases/immunology , Peroxidase/immunology , Serine Endopeptidases/immunology , Connective Tissue Diseases/diagnosis , Enzyme-Linked Immunosorbent Assay , Fluorescent Antibody Technique, Indirect , Follow-Up Studies , Humans , Myeloblastin , Prospective StudiesABSTRACT
Despite their propensity to cause toxicity, nonsteroidal anti-inflammatory drugs (NSAIDs) are routinely prescribed for older patients for painful musculoskeletal conditions, many of which are noninflammatory in nature. In some settings, simple analgesia with paracetamol (acetaminophen) or tramadol may be just as effective as NSAIDs. The benefits of therapy with NSAIDs must be weighed against their potential risks. With the anticipated growth of the elderly population, the economic implications of NSAID use in older patients are staggering. Estimates of the total cost of prescribing NSAIDs to the elderly must include the additional costs of gastroprotective agents, prophylaxis, laboratory monitoring, physician evaluations and interventions for adverse effects. Misoprostol may be cost effective as primary prophylaxis of NSAID-induced ulcer disease in some elderly patients. NSAIDs may reduce disability and improve quality of life, thereby offsetting their costs. To date, the direct, indirect and intangible cost of NSAIDs and cost offsets have not been systematically evaluated in the elderly. At this juncture, NSAIDs may be used judiciously in older patients, and misoprostol should be considered in high risk patients. Further studies to assess the economics of NSAIDs in the elderly population are warranted.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Anti-Inflammatory Agents, Non-Steroidal/economics , Aged , Anti-Ulcer Agents/therapeutic use , Costs and Cost Analysis , Female , Gastrointestinal Diseases/chemically induced , Gastrointestinal Diseases/prevention & control , Humans , Kidney Diseases/chemically induced , Kidney Diseases/physiopathology , Kidney Diseases/prevention & control , Male , Misoprostol/therapeutic use , Risk FactorsABSTRACT
The differentiation of articular from nonarticular complaints and inflammatory from noninflammatory disorders can usually be made by clinical evaluation. Laboratory and radiographic studies serve as adjuncts in the evaluation of musculoskeletal complaints; however, before ordering these studies, it is important to consider how the findings will affect diagnosis, prognosis, and treatment. An effective clinical evaluation is frequently sufficient to establish a differential diagnosis, focus further confirmatory testing, and consider appropriate treatment.
Subject(s)
Musculoskeletal Diseases/diagnosis , Diagnosis, Differential , Humans , Inflammation , Joint Diseases/diagnosis , Medical History Taking , Muscular Diseases/diagnosis , Musculoskeletal Diseases/metabolism , Physical ExaminationABSTRACT
PURPOSE: To determine the prevalence and clinical associations of anticardiolipin antibodies (aCL) in a blinded, controlled study of patients with a variety of connective tissue diseases (CTD) using a standardized aCL testing system. PATIENTS AND METHODS: Anticardiolipin antibodies (IgG, IgM, and IgA) were measured by direct enzyme-linked immunosorbent assay (ELISA) in the baseline serum samples of patients enrolled in a Cooperative Study of Systematic Rheumatic Diseases (CSSRD), National Institutes of Health (NIH) supported, 5-year inception-cohort, prospective study of early rheumatic diseases: rheumatoid arthritis (RA, n = 70), systemic lupus erythematosus (SLE, n = 70), scleroderma (PSS, n = 45), myositis (PM/DM, n = 36), and early undifferentiated connective tissue disease (EUCTD, n = 165). Diagnosis was based on standardized criteria and determined at the last study visit. A nested group of patients with Sjögren's syndrome (SJ, n = 44) was also defined. Serum from 200 blood donors (BB) served as controls. Additional patients with known antiphospholipid syndrome (APS, n = 33) and ANCA-related renal vasculitis (ANCA, n = 52) were also studied. Laboratory personnel were blinded to sample diagnostic group. RESULTS: The prevalence of either IgG or IgM aCL among each diagnostic group was RA 15.7%, SLE 15.76%, PSS 6.7%, PM/DM 8.3%, EUCTD 9.1%, SJ 6.8%, ANCA 3.8%, and BB controls 4.0%. Prevalence of aCL was significantly different for both the RA and SLE groups versus BB controls (P < 0.01) but not among other diagnostic groups. Only 2 study patients had positive tests for IgA aCL (1 with PM/DM and 1 with EUCTD) versus 15% of APS with positive IgA aCL. Study patients positive for IgG or IgM aCL were significantly more likely to have hemolytic anemia or a positive serologic test for syphilis and less likely to have Raynaud's phenomenon. However, no associations were found between aCL positivity and thrombocytopenia, seizures, renal insufficiency, presence of a positive antinuclear antibody or rheumatoid factor, subcutaneous nodules or digital ulcers. CONCLUSIONS: Based on results from this large CSSRD inception cohort, anticardiolipin antibodies are present in approximately 16% of patients with RA or SLE but are less common in patients with PSS, PM/DM, EUCTD, SJ, and ANCA vasculitis, where their prevalence approaches that in the normal population. Few consistent clinical association can be found among patients with CTD who are aCL positive. The complete diagnostic and prognostic importance and specificity of these antibodies remains to be fully determined.
Subject(s)
Antibodies, Anticardiolipin/blood , Connective Tissue Diseases/immunology , Antibodies, Antineutrophil Cytoplasmic/blood , Arthritis, Rheumatoid/immunology , Case-Control Studies , Cohort Studies , Enzyme-Linked Immunosorbent Assay , Humans , Immunoglobulin A/blood , Immunoglobulin G/blood , Immunoglobulin M/blood , Lupus Erythematosus, Systemic/immunology , Myositis/immunology , National Institutes of Health (U.S.) , Prevalence , Prospective Studies , Research Support as Topic , Scleroderma, Systemic/immunology , Single-Blind Method , Sjogren's Syndrome/immunology , United States , Vasculitis/immunologyABSTRACT
OBJECTIVE: To evaluate the associations of soluble serum interleukin-2 receptor (sIL-2R) levels in patients with rheumatoid arthritis (RA) with clinical and laboratory measures of disease activity and the predicted response to therapy. METHODS: sIL-2R levels were determined by ELISA in 137 patients with RA, not previously treated with 2nd line therapy. Patients were enrolled in a prospective, randomized, placebo controlled trial of sulfasalazine (SSZ) versus gold sodium thiomalate (GSTM), sponsored by the Cooperative Systematic Studies of Rheumatic Diseases. Using correlation analysis and regression modeling, the clinical utility of sIL-2R as a measure of disease activity and predictor of outcome was assessed. RESULTS: 91 women and 46 men with a mean age of 51 +/- 13 years and mean duration of disease of 64 +/- 78 months participated in this study. The mean sIL-2R level in all patients with RA was markedly elevated (980 +/- 589 U/ml) compared with that in healthy control subjects (446 +/- 196 U/ml; p = < 0.0001). There was no correlation between the sIL-2R levels and the joint pain/tenderness count, either at study entry or completion. There were significant positive correlations between the baseline sIL-2R and baseline erythrocyte sedimentation rate (ESR) and between the change in sIL-2R and the change in ESR. Both a multiple linear regression model and a multiple logistic regression model showed that baseline sIL-2R levels were not predictive of clinical outcome. CONCLUSION: sIL-2R levels are significantly elevated in patients with active RA and correlate positively with ESR. However, these results indicate that in patients with early RA, sIL-2R levels are neither associated with standard disease activity criteria nor predictive of the response to therapy with SSZ or GSTM, even after controlling for the simultaneous effects of other important clinical variables.
Subject(s)
Arthritis, Rheumatoid/drug therapy , Gold Sodium Thiomalate/therapeutic use , Receptors, Interleukin-2/blood , Sulfasalazine/therapeutic use , Adult , Aged , Blood Sedimentation/drug effects , Female , Humans , Joints/drug effects , Linear Models , Logistic Models , Male , Middle Aged , Treatment OutcomeABSTRACT
OBJECTIVE: To evaluate the acute toxicity, potential efficacy, and effects on the soluble interleukin 2 receptor (sIL-2R) of recombinant human interferon gamma (rIFN-gamma) in patients with systemic sclerosis (SSc). METHODS: A multicentered, pilot clinical trial of rIFN-gamma was performed on 20 patients (15 women, 5 men, mean age 45 years) with active cutaneous SSc (mean disease duration 36 months) to evaluate it potential as a novel therapy for this untreatable disorder. After one week of rIFN-gamma 0.01 mg/m2/day, subjects self-administered rIFN-gamma 0.1 mg/m2/day intramuscularly for a total of 18 weeks. The major outcome variable was a modified skin score (0 = normal skin, 3 = hidebound skin) measured and summed from 15 anatomic areas of the body. sIL-2R levels were measured by ELISA at entry and exit from the study. RESULTS: The clinical results were modest at best. Nine of 20 patients achieved at least a 20% reduction in skin score, with one patient showing almost total remission of all skin abnormalities. The mean skin score at entry for all subjects was 22.8 +/- 8.9 and over the course of the trial improved marginally compared to baseline (mean change -4.72 +/- 6.62; p = 0.008). However, 8 subjects did not change appreciably while in the trial. Antibodies to Scl-70 were observed in only 5 patients (all with diffuse scleroderma) and were not associated with either response to or complications from therapy. The adverse reactions were frequent and occasionally severe. Ten subjects were withdrawn because of exacerbation of Raynaud's symptoms (n = 5), constitutional symptoms (n = 2), development of renal crises (n = 2), and mild pancytopenia (n = 1). Minor laboratory abnormalities were common and included elevation of cholesterol, triglycerides, hepatic transaminases, and reduction in white blood cell count. Compared to controls, mean sIL-2R was markedly elevated at entry (1309 +/- 495 U/ml; p = 0.0001) and did not change appreciably at exit. Spearman correlation analysis showed a trend but no statistically significant association of skin score with sIL-2R (R = 0.408; p = 0.074). However, sIL-2R was significantly correlated with erythrocyte sedimentation rate (R = 0.542; p = 0.0165). A subset analysis revealed that skin score (p = 0.0001) and sIL-2R (p = 0.00170) were significantly higher at baseline for patients with diffuse scleroderma compared to patients with limited disease. CONCLUSION: rIFN-gamma may be beneficial for some patients with SSc, but the benefit appears marginal for most individuals and the side effects frequent. Although sIL-2R was elevated in many of the patients with SSc, it did not appear to be correlated with activity of cutaneous disease or response to therapy.
Subject(s)
Interferon-gamma/therapeutic use , Receptors, Interleukin-2/metabolism , Scleroderma, Systemic/therapy , Skin/pathology , Adult , Aged , Autoantibodies/blood , Blood Sedimentation , DNA Topoisomerases, Type I , Enzyme-Linked Immunosorbent Assay , Female , Fibrosis/blood , Fibrosis/pathology , Fibrosis/therapy , Humans , Injections, Intramuscular , Interferon-gamma/administration & dosage , Interferon-gamma/adverse effects , Leukocyte Count , Male , Middle Aged , Nuclear Proteins/immunology , Pilot Projects , Receptors, Interleukin-2/drug effects , Recombinant Proteins , Remission Induction , Scleroderma, Systemic/blood , Scleroderma, Systemic/pathology , Skin/drug effects , Skin/metabolism , Treatment OutcomeABSTRACT
OBJECTIVES: This analysis evaluated the clinical and demographic risk factors for a suspected, serious nonsteroidal anti-inflammatory drug (NSAID)-induced gastrointestinal (GI) complication in everyday clinical practice and calculated the risk reduction associated with misoprostol therapy in these "at-risk" patients. METHODS: Using logistic regression analysis, the data set from a randomized, parallel, placebo-controlled trial of misoprostol in 8,843 rheumatoid arthritis patients taking NSAIDs (the Misoprostol Ulcer Complications Outcomes Safety Assessment trial) was modeled to identify risk factors for GI adverse events. The dependent variable was defined as a "suspected serious GI complication," and the independent variables included demographic features, level of functional disability, presence of co-morbid diseases, use of certain drugs, and treatment arm. RESULTS: Two hundred forty-two suspected serious GI complications were observed; 102 occurred in the misoprostol treatment group (risk: 2.32%) and 140 in the placebo group (risk: 3.15%). Overall risk reduction due to misoprostol therapy was 26.6% (confidence interval 5.5%-42.9%, P < .05). However, in patient groups with identified risk factors, misoprostol use decreased the risk for an adverse GI event by 38.3%-87.3%. Specifically, those who benefitted significantly from therapy with misoprostol were patients with a history of peptic ulcer disease (risk reduction 52.4%), history of previous GI bleeding (risk reduction 50%), history of significant cardiovascular disease (risk reduction 38.3%), significant functional disability (risk reduction 87.2%), and patients whose symptoms required concomitant antacid use (risk reduction 48.3%). CONCLUSION: We conclude that in everyday practice, patients who require chronic NSAID therapy and who have specific clinical risk factors may benefit from misoprostol co-therapy.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Anti-Ulcer Agents/therapeutic use , Gastrointestinal Diseases/prevention & control , Misoprostol/therapeutic use , Aged , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Anti-Ulcer Agents/administration & dosage , Arthritis, Rheumatoid/drug therapy , Confidence Intervals , Double-Blind Method , Drug Therapy, Combination , Female , Gastrointestinal Diseases/chemically induced , Humans , Logistic Models , Male , Middle Aged , Misoprostol/administration & dosage , Risk Factors , Treatment OutcomeABSTRACT
OBJECTIVES: To examine the musculoskeletal manifestations in a large cohort of patients (n = 410) diagnosed with either a well-established connective tissue disease (CTD) (n = 197) or an early undifferentiated CTD (n = 213) with a symptom duration of <1 year. This study was aimed at determining the predictive value of demographic, clinical, and laboratory features on outcome in patients with unexplained polyarthritis (UPA) (from the early undifferentiated CTD cohort; n = 67) or rheumatoid arthritis (RA) (from the well-established CTD cohort; n = 57), over a 5-year followup period. METHODS: Patients from both cohorts were assessed at years 1, 3, and 5. At the study visits, clinical data were collected in a standardized manner, and sera were obtained and stored. A priori criteria were established for patient ascertainment and diagnosis over the duration of the study. Standard statistics were used for comparisons of baseline characteristics in patients diagnosed as having systemic lupus erythematosus, RA, undifferentiated CTD, and UPA at entry into the cohorts. Baseline features in patients with UPA were examined according to the different subsequent outcomes (RA, CTD, or undifferentiated CTD, remission [nonpersistent], or persistent or active UPA). Baseline features in patients with RA whose disease remained active versus those in whom remission was attained were also examined. Two multivariable analyses, classification trees and polychotomous logistic regression, were performed to predict disease outcomes over time. RESULTS: The overall rate of ascertainment for the 410 patients ranged from 90 % at year 1 to 71 % at year 5. Patients with established CTDs showed a tendency for more stable diagnoses than those with early undifferentiated CTDs (90-100% versus 45-70%). Consistent baseline predictors of persistent active disease among patients with RA, in both univariate and multivariable analyses, were higher joint counts for pain and tenderness and higher erythrocyte sedimentation rate (ESR). In approximately 20% of patients who were classified as having RA when they originally entered the cohort, the disease was in remission at 5 years. Twenty percent of the patients originally classified as having UPA developed RA over the duration of the study. These patients tended to be older and to have swelling of small joints at baseline. However, a consistent pattern of predictive variables could not be identified in the multivariable analyses, other than at year 1 (higher small joint counts for swelling and higher ESR). CONCLUSION: Baseline features (joint counts, and ESR) among RA patients were variously predictive of persistently active disease at years 1-5. Consistent baseline predictors of outcome among patients with UPA only emerged at year 1. Remission occurred in approximately 20% of RA patients, whereas a similar percentage of patients with UPA developed RA. These findings have implications with regard to treatment decisions in patients with early RA and/or UPA.
Subject(s)
Connective Tissue Diseases/diagnosis , Adult , Aged , Arthritis/diagnosis , Arthritis, Rheumatoid/diagnosis , Cohort Studies , Connective Tissue Diseases/therapy , Female , Follow-Up Studies , Humans , Joint Diseases/diagnosis , Longitudinal Studies , Male , Middle Aged , Multivariate Analysis , Musculoskeletal Diseases/diagnosis , Predictive Value of Tests , Recurrence , Time Factors , Treatment OutcomeABSTRACT
PURPOSE: To quantify the activity of joint inflammation with magnetic resonance (MR) imaging and positron emission tomography (PET). MATERIALS AND METHODS: Gadolinium-enhanced MR imaging and 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG) PET of the wrist were performed prospectively in 12 patients receiving antiinflammatory therapy. Patients were studied three times: off medications for 2 weeks, after 2 weeks of treatment with prednisone or nonsteroid antiinflammatory drugs, and after 12 weeks of treatment with methotrexate. Volume of enhancing pannus (VEP) was determined from fat-suppressed MR images (12 patients). FDG uptake was calculated from PET images (11 patients). RESULTS: VEP and FDG uptake were closely correlated (r > .86, P < .0001), as were changes in VEP and standardized uptake volume (r > .91, P < .0002). VEP and FDG uptake were strongly associated with clinical findings in wrists (P < .002) but not with treatment outcomes (P > .05). CONCLUSION: Contrast material-enhanced MR imaging and PET allow quantification of volumetric and metabolic changes in joint inflammation and comparison of efficacies of antiinflammatory drugs.
Subject(s)
Arthritis, Psoriatic/diagnostic imaging , Arthritis, Psoriatic/diagnosis , Arthritis, Rheumatoid/diagnostic imaging , Arthritis, Rheumatoid/diagnosis , Contrast Media , Deoxyglucose/analogs & derivatives , Fluorine Radioisotopes , Gadolinium , Magnetic Resonance Imaging , Tomography, Emission-Computed , Wrist Joint/diagnostic imaging , Wrist Joint/pathology , Acetaminophen/therapeutic use , Adult , Aged , Arthritis, Psoriatic/drug therapy , Arthritis, Rheumatoid/drug therapy , Dextropropoxyphene/therapeutic use , Female , Fluorodeoxyglucose F18 , Humans , Image Enhancement , Male , Middle Aged , Pilot Projects , Prednisone/therapeutic use , Prospective Studies , Treatment OutcomeABSTRACT
Agents ranging from simple analgesics to antiinflammatory drugs to powerful immunomodulators have been used for the treatment of rheumatoid arthritis with varying success. Despite the availability of agents that are believed to be "second line" or "disease modifying," many patients either do not respond adequately to available agents or must discontinue their use because of intolerable or dangerous adverse reactions. For this reason, researchers continue to search for more efficacious and less toxic agents for patients with rheumatoid arthritis. This article describes pharmaceutical agents currently under investigation for use in rheumatoid arthritis, including the antiinflammatory agents, zileuton and tenidap, and the immunosuppressive agents, leflunomide, mycophenolic acid (RS-61443), tacrolimus (FK-506), sirolimus (rapamycin), amiprilose (therafectin), cladribine (2- chlorodeoxyadenosine), and azaribine.
Subject(s)
Anti-Inflammatory Agents/therapeutic use , Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/drug therapy , Drugs, Investigational/therapeutic use , Immunosuppressive Agents/therapeutic use , Animals , Anti-Inflammatory Agents/adverse effects , Anti-Inflammatory Agents/pharmacology , Antirheumatic Agents/adverse effects , Antirheumatic Agents/pharmacology , Clinical Trials as Topic , Drugs, Investigational/adverse effects , Drugs, Investigational/pharmacology , Humans , Immunosuppressive Agents/adverse effects , Immunosuppressive Agents/pharmacology , Treatment OutcomeABSTRACT
OBJECTIVE: To measure the anatomic and physiologic changes in the synovium of patients with active rheumatoid arthritis (RA) before and after the initiation of treatment with low-dose systemic glucocorticoids and methotrexate (MTX). METHODS: Two patients with RA with active synovitis involving the carpus were evaluated by imaging parameters at baseline and again after 14 weeks (of treatment with low-dose prednisone and MTX). Standard clinical parameters, laboratory measurements, and contrast-enhanced magnetic resonance imaging (MRI) (synovial volume estimate) and positron emission tomography (PET) with 18F-fluoro-2-deoxyglucose (18-FDG) (synovial metabolism estimate) were performed. RESULTS: Compared with baseline, standard clinical parameters (i.e., joint count, joint index, morning stiffness, global assessments of arthritis activity, and erythrocyte sedimentation rate) improved dramatically in both patients after treatment with low-dose prednisone and MTX. In concert with this trend, the synovial volume of the affected wrist was reduced by 60%, and 76% and the metabolism of 18-FDG was reduced by 66% and 69% in the 2 patients. CONCLUSION: These preliminary observations indicate that a volumetric estimate of inflamed synovium (using contrast-enhanced MRI) and quantification of synovial deoxyglucose metabolism (using PET) are technically feasible and, in the 2 reported cases, correlate well with standard outcome measures. These imaging modalities may provide new objective parameters to determine RA disease activity and effectiveness of antirheumatic medications; however, the potential clinical utility of these measures remains to be defined.
Subject(s)
Arthritis, Rheumatoid/metabolism , Arthritis, Rheumatoid/pathology , Glucose/metabolism , Synovial Membrane/pathology , Arthritis, Rheumatoid/drug therapy , Deoxyglucose/analogs & derivatives , Deoxyglucose/metabolism , Dose-Response Relationship, Drug , Female , Fluorine Radioisotopes , Fluorodeoxyglucose F18 , Glucocorticoids/pharmacology , Glucocorticoids/therapeutic use , Humans , Magnetic Resonance Imaging , Methotrexate/pharmacology , Methotrexate/therapeutic use , Middle Aged , Prednisone/pharmacology , Prednisone/therapeutic use , Synovial Membrane/drug effects , Synovial Membrane/metabolism , Tomography, Emission-Computed , Wrist JointABSTRACT
The long-term efficacy of methotrexate has been proved in prospective trials. With the chronic administration of methotrexate, however, concern has been raised about its safety. While side effects are common, they are seldom life threatening and rarely necessitate withdrawal of the drug. Serious side effects of methotrexate include hepatic, hematologic, and pulmonary toxicity. These toxicities are much less common, but usually result in the withdrawal of the drug. With careful monitoring of patients symptoms and laboratory test, however, these toxicities can be minimized or even prevented.
Subject(s)
Methotrexate/adverse effects , Arthritis, Rheumatoid/drug therapy , Chemical and Drug Induced Liver Injury , Hematologic Diseases/chemically induced , Humans , Lung Diseases/chemically inducedABSTRACT
OBJECTIVE: To evaluate the association of the level of soluble serum interleukin-2 receptor (sIL-2R) with disease activity and response to therapy in patients with rheumatoid arthritis (RA). METHODS: The sIL-2R levels of 148 patients with refractory RA were determined by enzyme-linked immunosorbent assay. This parameter was correlated with other clinical observations obtained during a prospective, randomized, placebo-controlled trial of methotrexate, sponsored by the Cooperative Systematic Studies of Rheumatic Diseases consortium. Using statistical modeling, the usefulness of sIL-2R as a measure of disease activity and a predictor of outcome was evaluated. RESULTS: The mean sIL-2R level in all RA patients was markedly elevated compared with that in normal control subjects, and decreased significantly during the trial. There was no correlation of the sIL-2R level and the joint pain/tenderness count either at study entry or study end. There was a significant correlation of the sIL-2R level and the erythrocyte sedimentation rate, both at study entry and study end. A multiple linear regression model showed that treatment with methotrexate, but not the sIL-2R level or the change in sIL-2R level, predicted a change in joint count. A stepwise multiple logistic regression model defined no significant predictive information for outcome for the level of sIL-2R at study entry. CONCLUSION: After controlling for the simultaneous effects of other important clinical variables, the level of sIL-2R does not appear to predict the response to methotrexate in patients with refractory RA. Further analysis of cohorts of patients with earlier RA needs to be performed.
Subject(s)
Arthritis, Rheumatoid/blood , Arthritis, Rheumatoid/drug therapy , Methotrexate/therapeutic use , Receptors, Interleukin-2/analysis , Adult , Aged , Female , Humans , Linear Models , Male , Middle Aged , Regression AnalysisABSTRACT
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.
Subject(s)
Scleroderma, Systemic/mortality , Adult , Analysis of Variance , Female , Heart Diseases/mortality , Humans , Lung Diseases/mortality , Male , Middle Aged , Prognosis , Proportional Hazards Models , Prospective Studies , Receptors, Interleukin-2/analysis , Scleroderma, Systemic/metabolism , Scleroderma, Systemic/physiopathology , Survival Analysis , Time FactorsABSTRACT
We identified a cohort of 410 patients with connective tissue disorders (CTD) of less than or equal to 1 year duration among the participating clinics of the Cooperative Systematic Studies of the Rheumatic Diseases Program. Fifty-seven had rheumatic arthritis (RA), 57 systemic lupus erythematosus, 37 poly/dermatomyositis, 46 scleroderma, and 213 early undifferentiated CTD, including patients with Raynaud's phenomenon, unexplained polyarthritis or at least 3 CTD manifestations such as rashes, myalgias, etc. Baseline clinical data are now being reported. The followup of these patients may prove to be valuable in understanding these diseases. To our knowledge no similar cohort of patients is available for further investigation.
Subject(s)
Connective Tissue Diseases/epidemiology , Adolescent , Adult , Aged , Arthritis, Rheumatoid/epidemiology , Cohort Studies , Dermatomyositis/epidemiology , Female , Humans , Lupus Erythematosus, Systemic/epidemiology , Male , Middle Aged , Raynaud Disease/epidemiology , Scleroderma, Systemic/epidemiologyABSTRACT
The presence of antinuclear antibodies (ANA) in the serum is a common finding in various connective tissue disorders, but usefulness of these antibodies in making diagnoses or prognoses is not known. We report the results of a panel of ANA determinations including ANA, anti-dsDNA, Sm, RNP, SSA, SSB, Jo-1, Scl-70 and PM-1 in 410 patients in a 5-year descriptive study of 410 patients with rheumatic disease symptoms of less than one year's duration. While some patients met diagnostic criteria for a specific rheumatologic diagnosis, others were classified as undifferentiated connective tissue disease (UCTD) and were subclassified by a constellation of symptoms. Our results show that ANA is sensitive in systemic lupus erythematosus (SLE) and progressive systemic sclerosis even in early disease but is not specific. Other "specific" autoantibodies were seen most frequently in SLE but were relatively insensitive and were seen in low frequency in UCTD. ANA have limited diagnostic value in patients with early disease. The prognostic value of these tests will be assessed as the prospective study of these cohorts progresses.