Michael P. LaValley

Bone Marrow Edema and Its Relation to Progression of Knee Osteoarthritis

Context Bone marrow edema on magnetic resonance imaging (MRI) correlates with pain in patients with knee osteoarthritis, but its association with progression of joint changes is unknown. Contribution Among 223 patients with knee osteoarthritis, bone marrow edema on MRI was associated with radiographic progression in the same compartment over the following 15 to 30 months after adjustment for age, sex, body mass index, and limb malalignment (another predictor of progression). Cautions While this study shows that bone marrow edema is associated with the progression of knee osteoarthritis, we do not know whether it is causal or an epiphenomenon. These findings do not define a role for MRI in the routine evaluation of knee osteoarthritis. The Editors Osteoarthritis, the most common form of arthritis, is the leading cause of mobility-related disability in elderly persons (1). With the aging of the population, the prevalence of osteoarthritis is increasing. Loss of hyaline articular cartilage is a central pathologic event in osteoarthritis, but the pathogenesis of cartilage loss is poorly understood. Specifically, there is a paucity of information about what factors identify joints at high risk for progression. Identification of such factors might permit better understanding of the disease process. While cartilage loss is a major pathologic feature of osteoarthritis, abnormal bone has been documented as another important element. Bone scan studies of persons with osteoarthritis have reported late-phase uptake of tracer in subchondral bone, signifying accelerated bone turnover. This increase in tracer has been associated with joint pain (2) and with a markedly increased risk for radiographic progression in osteoarthritis of the knee (3) and hand (4). The study in knees, however, was limited by the use of outdated radiographic techniques (5). Increased uptake on bone scan has a parallel finding on magnetic resonance imaging (MRI): bone marrow edema (6, 7). Bone marrow edema is indicated by focally increased signal in the marrow on fat-suppressed T2-weighted images. McAlindon and colleagues (7) found that of 12 knees with bone scan lesions, 11 had bone marrow edema lesions in the same location. The question of whether bone marrow edema lesions on MRI affect structural change in the osteoarthritic joint has not been longitudinally evaluated. We previously reported that among persons with radiographic knee osteoarthritis, those with bone marrow edema lesions more often had knee pain than those without (8). In patients without osteoarthritis, these edema lesions have been associated with bone trauma (9, 10). Like lesions on bone scans, limb malalignment has also been reported as a potent risk factor for structural progression of osteoarthritis. In a recent longitudinal study (11), patients with varus alignment were at high risk for subsequent medial progression of knee osteoarthritis, while limbs with valgus alignment were at commensurately high risk for lateral progression. The accepted mechanism for the effect of malalignment is that increased stress on one side of the joint leads to cartilage loss. We performed a natural history study of knee osteoarthritis using MRIs and knee radiography. One goal of our study was to examine the effect of bone marrow edema lesions on structural deterioration of the joint, as indicated by joint space loss on radiographs. Previous work (12) documented the correlation between joint space width and articular cartilage thickness, and other studies (11, 13) have used joint space loss as a proxy for cartilage loss. Our ob jectives were to investigate the relation of bone marrow edema lesions to joint space loss in patients with osteoarthritis, to evaluate whether these lesions were associated with malalignment, and to determine whether some of the relation of marrow lesions to progression could be explained by their association with malalignment. In addition, if bone marrow edema lesions were associated with malalignment, we postulated that they had a local effect and that the contralateral side of the joint was protected. Methods Patients were recruited to participate in a natural history study of symptomatic knee osteoarthritis. All patients in the current study are a subset of patients whose recruitment has been described in detail elsewhere (8). Briefly, patients were recruited from two prospective studies, one in men and one in women, of quality of life among veterans; from clinics at Boston Medical Center in Boston, Massachusetts; and from advertisements in local newspapers. Potential participants were asked two questions: Do you have pain, aching, or stiffness in one or both knees on most days? and Has a doctor ever told you that you have knee arthritis? For patients who answered yes to both questions, we conducted a follow-up interview in which we asked about other types of arthritis that could cause knee symptoms. If no other forms of arthritis were identified, then the individual was eligible for recruitment. A series of knee radiographs were obtained for each patient to determine whether radiographic osteoarthritis was present. If patients had a definite osteophyte on any view in the symptomatic knee, they were eligible for the study. Because they had frequent knee symptoms and radiographic osteoarthritis, all patients met American College of Rheumatology criteria for symptomatic knee osteoarthritis (14). For the natural history study, we enrolled patients who were interested in participating and who could walk with or without a cane. Of 351 patients from the cross-sectional study (8), 324 met these criteria. Of these, 193 men and 19 women received care from the Veterans Administration Health Care System and were recruited from the outpatient clinics there. Eight men and 104 women were recruited from the community. The study included a baseline examination and follow-up examinations at 15 and 30 months. At baseline, patients who did not have contraindications to MRIs had MRI of the more symptomatic knee. At all examinations, patients had knee radiography and answered questionnaires about the severity of knee symptoms, including the Western Ontario McMaster Osteoarthritis (WOMAC) questionnaire. Patients were also weighed, with shoes off, on a balance-beam scale, and height was assessed. At the first follow-up visit, long-limb films were obtained with a 14 51 cassette, using methods described elsewhere (15). Our study focuses on baseline MRI findings as predictors of change in radiographs over follow-up. The institutional review boards of Boston University Medical Center and the Veterans Administration Boston Health Care System approved the baseline and follow-up examinations. Assessments Magnetic Resonance Imaging All studies were performed with a Signa 1.5T MRI system (General Electric Corp., Milwaukee, Wisconsin) using a phased-array knee coil. A positioning device was used to ensure uniformity among patients. Coronal, sagittal, and axial images were obtained. Coronal spin-echo fat-saturated proton density and T2-weighted fat-saturated images (repetition time, 2200 milliseconds; echo time, 20/80 milliseconds) with a slice thickness of 3 mm, a 1-mm interslice gap, one excitation, a field of view of 11 to 12 cm, and a matrix of 256 128 pixels were obtained. To evaluate bone marrow lesions, we used the coronal T2-weighted fat-saturated images. As previously reported (8), each femur and tibia were divided into medial, central, and lateral quadrants, resulting in six potential sites of lesions for each knee. We defined lesions as areas of increased signal adjacent to the subcortical bone; a single radiologist, blinded to patient characteristics and radiographs, graded lesions from 0 to 3 on the basis of their size. Because previous work (8) demonstrated that lesions of grade 2 or greater were more strongly associated with the presence of knee pain (grade 1 lesions were common in those with and without knee pain), we focused on lesions that were grade 2 or larger. Such lesions encompassed at least one quarter of the width of the compartment on two or more slices (Figure 1). For intraobserver agreement for reading of these lesions, the value was 0.66 (P < 0.001). We defined a lesion as occurring in either the medial or lateral compartment if it was present in the femur or tibia of that compartment. Figure 1. Bone marrow edema lesion ( B ) on magnetic resonance imaging. Radiography Patients underwent weight-bearing posteroanterior radiography using the protocol of Buckland-Wright (16). Using fluoroscopic positioning, we aligned the beam relative to knee center, and the knee was flexed so that the anterior and posterior lips of the medial tibial plateau were superimposed. Feet were rotated until the tibial spines were centered in the notch, and outlines of foot rotation were then made on foot maps so that the foot rotation would be the same for subsequent films. Fluoroscopic positioning has been shown to more accurately assess joint space compared with nonfluoroscopic acquisition and to improve reproducibility of joint space assessment. Other films obtained at baseline included weight-bearing skyline (17) and weight-bearing semi-flexed lateral films; the latter were obtained according to the Framingham Study protocol. For evaluation of progression, we focused on the width of the joint space in medial and lateral compartments, since that has been found to correlate with cartilage thickness (12). Films were read by using the Osteoarthritis Research Society International Atlas (18), in which each medial and lateral tibiofemoral joint space is graded from 0 (normal) to 3 (bone on bone). We defined progression of joint space narrowing in a knee compartment as progression by at least one grade. A reader unfamiliar with the MRI findings read all films. All films were read unblinded to sequence; however, films for a subsample of patients were also read blinded to sequence to test the reproducibi

Hyperuricemia and incident hypertension: A systematic review and meta‐analysis

A novel rodent model and a recent randomized trial of hyperuricemic adolescents with hypertension suggest a pathogenetic role of uric acid in hypertension, but it remains unknown whether these findings would be applicable to adult populations where the larger disease burden exists. We conducted a systematic review and meta‐analysis to determine if hyperuricemia was associated with incident hypertension, particularly in various demographic subgroups.

HLA–B51/B5 and the risk of Behçet's disease: A systematic review and meta‐analysis of case–control genetic association studies

OBJECTIVE To quantify by meta-analysis the genetic effect of the HLA-B5 or HLA-B51 (HLA-B51/B5) allele on the risk of developing Behçets disease (BD) and to look for potential effect modifiers. METHODS Relevant studies were identified using the PubMed Medline database and manual searches of the literature. Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated by using the random-effects model. Subgroup meta-analyses and meta-regression analyses were undertaken to investigate the effects of selected study-level parameters on the pooled OR. Heterogeneity was assessed using the I2 statistic. Pooled results were used to calculate population-attributable risks (PAR) for BD in relationship to HLA-B51/B5. RESULTS A total of 4,800 patients with BD and 16,289 controls from 78 independent studies (published 1975-2007) were selected. The pooled OR of HLA-B51/B5 allele carriers to develop BD compared with noncarriers was 5.78 (95% CI 5.00-6.67), with moderate between-study heterogeneity (I2 = 61%). The subgroup analyses stratifying studies by geographic locations (Eastern Asia, Middle East/North Africa, Southern Europe, Northern/Eastern Europe) yielded consistent OR ranges (5.31-7.20), with I2 ranges of 52-70%. Univariate random-effects meta-regression indicated the percentage of male BD cases (P = 0.008) as a source of heterogeneity. The PAR within the various geographic areas were estimated at 32-52%. CONCLUSION The strength of the association between BD and HLA-B51/B5, and its consistency across populations of various ethnicities, lends further support to this allele being a primary and causal risk determinant for BD. Variations according to sex support an interaction of this allele with BD characteristics.

Evidence for a Mendelian gene in a segregation analysis of generalized radiographic osteoarthritis the Framingham Study

OBJECTIVE To investigate the inheritance of generalized osteoarthritis (OA). METHODS OA was identified on hand and knee radiographs obtained from members of the Framingham Study cohort (the parents) in 1967-1970 and 1992-1993, and from their adult children in the Framingham Offspring Study in 1993-1994. All hand and knee radiographs evaluated for OA were graded using the Kellgren and Lawrence (K/L) scale. A measure of generalized OA was defined as the count of the number of hand and knee joints affected, as determined by the proportion of joints with a K/L grade > or =2. The OA count, treated as a continuous variable, was adjusted for age, body mass index, and a measure of physical activity for each joint area (hand or knee). Calculations were made separately for each generation and each sex, and correlations were analyzed against the standardized residual of OA. Segregation analysis was used to test whether OA aggregated in families, and if its transmission fit a Mendelian pattern. RESULTS A total of 337 nuclear families with 2 parents and at least 1 biologic offspring were studied. In parents, the mean age was 61.2 years at the time of hand radiographs and 72.8 years at the time of knee radiographs, which were mostly obtained at a later examination. The mean age at the time of radiographs in offspring was 53.9 years. Using standardized residuals, parent-offspring and sibling-sibling correlations ranged from 0.115 to 0.306. In segregation analyses, models testing the hypotheses of no familial aggregation, no familial transmission, or a Mendelian gene alone were all rejected (P < 0.001 for each of these models). The best-fitting models were mixed models with a Mendelian mode of inheritance and a residual multifactorial component. The Mendelian recessive model provided the best fit. CONCLUSION These analyses support a significant genetic contribution to OA, with evidence for a major recessive gene and a multifactorial component, representing either polygenic or environmental factors.

Should imporvement in rheumatoid arthritis clinical trials be defined as fifty percent or seventy percent improvement in core set measures, rather than twenty percent?

OBJECTIVE To determine whether improvement of more than 20% in core set parameters should be required before patients are characterized as improved in rheumatoid arthritis (RA) clinical trials. METHODS Data from 6 RA trials were reanalyzed to evaluate the discriminant validity (ability to differentiate active treatment from control) of 4 proposed definitions of improvement: the current American College of Rheumatology (ACR) definition (a 20% threshold for core set parameters [ACR 201), a 50% threshold (ACR 50), a 70% threshold (ACR 70), and an ordinal definition in which a patient could be classified in any of 3 categories (unimproved, ACR 20, or ACR 50). To evaluate the discriminant validity of these 4 definitions of improvement, we characterized each patient in each trial as improved or not, based on each definition, and computed a chi-square value differentiating the active treatment group from the control group, with the corresponding P value. RESULTS With an increase in the threshold for improvement, the percentage of placebo-treated patients who were classified as experiencing response dropped dramatically in all trials, as did the percentage of patients receiving active therapy (second-line drug, combination therapy, tumor necrosis factor p75-Fc fusion protein) who were classified as experiencing response. Generally, the drop in active treatment response rates was greater than the drop in placebo response rates, leaving the difference between the 2 groups less at the higher thresholds. Therefore, chi-square values fell as the threshold for response was raised. The ordinal definition of improvement yielded chi-square values similar to those obtained using ACR 20 alone. CONCLUSION Adopting a definition of efficacy in RA trials that requires 50% or 70% improvement in core set parameters would likely compromise statistical power and make it more difficult to distinguish between 2 treatments with different efficacy. ACR 20 should continue to be the primary measure of efficacy in RA trials, with higher thresholds for improvement being determined and reported as secondary efficacy measures.

Effect of Vitamin D Supplementation on Progression of Knee Pain and Cartilage Volume Loss in Patients With Symptomatic Osteoarthritis: A Randomized Controlled Trial

IMPORTANCE Knee osteoarthritis (OA), a disorder of cartilage and periarticular bone, is a public health problem without effective medical treatments. Some studies have suggested that vitamin D may protect against structural progression. OBJECTIVE To determine whether vitamin D supplementation reduces symptom and structural progression of knee OA. DESIGN, SETTING, AND PATIENTS A 2-year randomized, placebo-controlled, double-blind, clinical trial involving 146 participants with symptomatic knee OA (mean age, 62.4 years [SD, 8.5]; 57 women [61%], 115 white race [79%]). Patients were enrolled at Tufts Medical Center in Boston between March 2006 and June 2009. INTERVENTION Participants were randomized to receive either placebo or oral cholecalciferol, 2000 IU/d, with dose escalation to elevate serum levels to more than 36 ng/mL. MAIN OUTCOME MEASURES Primary outcomes were knee pain severity (Western Ontario and McMaster Universities [WOMAC] pain scale, 0-20: 0, no pain; 20, extreme pain), and cartilage volume loss measured by magnetic resonance imaging. Secondary end points included physical function, knee function (WOMAC function scale, 0-68: 0, no difficulty; 68, extreme difficulty), cartilage thickness, bone marrow lesions, and radiographic joint space width. RESULTS Eighty-five percent of the participants completed the study. Serum 25-hydroxyvitamin D levels increased by a mean 16.1 ng/mL (95% CI, 13.7 to 18.6) in the treatment group and by a mean 2.1 mg/mL (95% CI, 0.5 to 3.7) (P < .001) in the placebo group. Baseline knee pain was slightly worse in the treatment group (mean, 6.9; 95% CI, 6.0 to 7.7) than in the placebo group (mean, 5.8; 95% CI, 5.0 to 6.6) (P = .08). Baseline knee function was significantly worse in the treatment group (mean, 22.7; 95% CI, 19.8 to 25.6) than in the placebo group (mean, 18.5; 95% CI, 15.8 to 21.2) (P = .04). Knee pain decreased in both groups by a mean -2.31 (95% CI, -3.24 to -1.38) in the treatment group and -1.46 (95% CI, -2.33 to -0.60) in the placebo group, with no significant differences at any time. The percentage of cartilage volume decreased by the same extent in both groups (mean, -4.30; 95% CI, -5.48 to -3.12 vs mean, -4.25; 95% CI, -6.12 to -2.39) (P = .96). There were no differences in any of the secondary clinical end points. CONCLUSION AND RELEVANCE Vitamin D supplementation for 2 years at a dose sufficient to elevate 25-hydroxyvitamin D plasma levels to higher than 36 ng/mL, when compared with placebo, did not reduce knee pain or cartilage volume loss in patients with symptomatic knee OA. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00306774.

Effect of Therapeutic Exercise for Hip Osteoarthritis Pain: Results of a Meta-Analysis

OBJECTIVE Recommendations for lower extremity osteoarthritis (OA) and exercise have been primarily based on knee studies. To provide more targeted recommendations for the hip, we gathered evidence for the efficacy of exercise for hip OA from randomized controlled trials. METHODS A bibliographic search identified trials that were randomized, controlled, completed by >or=60% of subjects, and involved an exercise group (strengthening and/or aerobic) versus a non exercise control group for pain relief in hip OA. Two reviewers independently performed the data extraction and contacted the authors when necessary. Effect sizes (ES) of treatment versus control and the I(2) statistic to assess heterogeneity across trials were calculated. Trial data were combined using a random-effects meta-analysis. RESULTS Nine trials met the inclusion criteria (1,234 subjects), 7 of which combined hip and knee OA; therefore, we contacted the authors who provided the data on hip OA patients. In comparing exercise treatment versus control, we found a beneficial effect of exercise with an ES of -0.38 (95% confidence interval [95% CI] -0.68, -0.08; P = 0.01), but with high heterogeneity (I(2) = 75%) among trials. Heterogeneity was caused by 1 trial consisting of an exercise intervention that was not administered in person. Removing this study left 8 trials (n = 493) with similar exercise strategy (specialized hands-on exercise training, all of which included at least some element of muscle strengthening), and demonstrated exercise benefit with an ES of -0.46 (95% CI -0.64, -0.28; P < 0.0001). CONCLUSION Therapeutic exercise, especially with an element of strengthening, is an efficacious treatment for hip OA.

The role of vitamin D in corticosteroid-induced osteoporosis: A meta-analytic approach

OBJECTIVE To determine if vitamin D is more effective than no therapy or calcium alone in the management of corticosteroid-induced osteoporosis, and to determine how vitamin D compares with other osteoporosis therapies, e.g., bisphosphonates, calcitonin, or fluoride, for this condition. METHODS We evaluated all formulations of vitamin D, including its active metabolites and analogs. A systematic search for published and unpublished studies was conducted using MEDLINE (1966-December 1997), bibliographic references, abstracts from proceedings of recent national meetings, and contact with pharmaceutical companies and content experts. We included all randomized controlled trials lasting at least 6 months (and reporting extractable results), of patients receiving oral corticosteroids, that compared vitamin D with either 1) no therapy or calcium alone, or 2) bisphosphonates, calcitonin, or fluoride. The primary outcome measure of interest was change in lumbar spine bone mineral density. RESULTS We found a moderate beneficial effect of vitamin D plus calcium versus no therapy or calcium alone (9 trials) (effect size 0.60; 95% confidence interval [95% CI] 0.34, 0.85; P < 0.0001). In comparisons of vitamin D with other osteoporosis therapies, bisphosphonates were more effective than vitamin D (6 trials) (effect size 0.57; 95% CI 0.09, 1.05). Calcitonin was similar in efficacy to vitamin D (4 trials) (effect size 0.03; 95% CI -0.39, 0.45). Fluoride was more effective than vitamin D, but there were only 2 trials. CONCLUSION Vitamin D plus calcium is superior to no therapy or calcium alone in the management of corticosteroid-induced osteoporosis. Vitamin D is less effective than some osteoporosis therapies. Therefore, treatment with vitamin D plus calcium, as a minimum, should be recommended to patients receiving long-term corticosteroids.

The Comparative Efficacy of Drug Therapies Used for the Management of Corticosteroid-Induced Osteoporosis: A Meta-Regression

We determined the comparative efficacy of vitamin D, calcitonin, fluoride, and bisphosphonates for the management of corticosteroid‐induced osteoporosis using meta‐regression models. A systematic search for trials was conducted using MEDLINE, bibliographic references, abstracts from national meetings, and contact with pharmaceutical companies and content experts. We included all randomized controlled trials, lasting at least 6 months, of adult patients on oral corticosteroids that evaluated treatment comparisons between vitamin D, calcitonin, bisphosphonates, or fluoride either with no therapy/calcium or with each other and that reported extractable results. The outcome measure of interest was change in lumbar spine bone mineral density (BMD). We identified 45 eligible trials, which provided 49 eligible treatment comparisons (some trials had three arms or more). Our results indicated that bisphosphonates were the most effective class (effect size 1.03; 95% CI: 0.85, 1.17); results were similar even when newer generations of nitrogen‐containing bisphosphonates were excluded from analysis. We found the efficacy of bisphosphonates was enhanced further when used in combination with vitamin D (effect size, 1.31; 95% CI: 1.07, 1.50). Vitamin D and calcitonin were more effective than no therapy/calcium (effect size, 0.46; 95% CI: 0.27, 0.62; and effect size, 0.51; 95% CI: 0.33, 0.67, respectively) and were of similar efficacy, but both were significantly less effective than bisphosphonates. Fluoride appeared effective, but there were too few studies (n = 5) to draw robust conclusions regarding its efficacy compared with the other three therapies. In summary, bisphosphonates are the most effective of evaluated agents for managing corticosteroid‐induced osteoporosis. The efficacy of bisphosphonates is enhanced further with concomitant use of vitamin D.

Effect of Dose-Intensive Intravenous Melphalan and Autologous Blood Stem-Cell Transplantation on AL Amyloidosis–Associated Renal Disease

Primary (AL) amyloidosis is a plasma cell dyscrasia in which clonal plasma cells in the bone marrow produce a monoclonal immunoglobulin protein (M protein). The M protein light chains or light-chain fragments form insoluble fibrils with -pleated sheet configurations, rendering them avid for Congo red dye. The deposition of amyloid fibrils into the extracellular matrix of a variety of tissues results in severe organ dysfunction and poor patient survival. The kidney is one of the most common sites of amyloid deposition in AL amyloidosis, with clinically evident renal disease occurring in 48% to 82% of patients (1-5). Renal disease associated with AL amyloidosis is usually characterized by the nephrotic syndrome, often with massive proteinuria and refractory peripheral edema (6). The natural history of renal disease associated with AL amyloidosis is persistence of the nephrotic syndrome and progressive decrease in glomerular filtration rate (5, 7). In one series, one third of patients presenting with renal involvement began long-term dialysis therapy at a median of 13.8 months after diagnosis (2). Randomized, controlled trials have shown that cyclic oral melphalan and prednisone can prolong the life of patients with AL amyloidosis (1, 4). However, response to this treatment is limited: Serum or urine monoclonal protein levels decrease in only 20% of patients, and the median survival is only 16 to 18 months. Since 1994, we have been using dose-intensive intravenous melphalan with autologous blood stem-cell support to treat selected patients with AL amyloidosis. The goal of this treatment is to eliminate the clonally expanded plasma cells that produce the amyloidogenic light chains, thereby preventing further amyloid deposition into vital organs. In previous studies of this treatment approach, we found that complete remission of the plasma cell dyscrasia occurred in more than 50% of patients who received 200 mg/m2 of intravenous melphalan and in more than 40% of patients who received 100 to 140 mg/m2 of intravenous melphalan followed by autologous stem-cell transplantation (8-10). The objective of the present study was to investigate the effect of this treatment on AL amyloidosisassociated renal disease. Methods Patients In our analysis, we included patients with AL amyloidosis and renal involvement who were treated with dose-intensive intravenous melphalan and autologous blood stem-cell transplantation at Boston University (Boston, Massachusetts) between 1 July 1994 and 30 June 1998. We excluded patients who were dialysis dependent before treatment. Persons who underwent stem-cell mobilization and collection but did not receive intravenous melphalan because of inability to tolerate the former or death before melphalan administration were included in the analysis of treated patients. The diagnosis of AL amyloidosis required both tissue demonstration of amyloid by Congo red staining and evidence of monoclonal immunoglobulin protein in serum, urine, bone marrow, or tissue amyloid deposits. Patients were considered to have renal involvement if urinary protein excretion exceeded 1 g/24 h. The hematologic outcomes of the first 23 of these patients have been reported elsewhere (9, 10), and a brief description of the renal outcome was provided for 13 of the patients (9). To be eligible for intravenous melphalan with autologous blood stem-cell transplantation, patients needed to be at least 18 years of age, have a Southwest Oncology Group performance status score of 0 to 3, have a left ventricular ejection fraction greater than 0.4, and have supine systolic blood pressure greater than 85 mm Hg. Approximately 40% of patients with AL amyloidosis evaluated at our center during the study period met these eligibility criteria and elected to undergo stem-cell transplantation. The institutional review board of Boston University Medical Center approved the study. Treatment Blood stem cells were mobilized and collected as described elsewhere (9, 10). We used granulocyte colony-stimulating factor (Filgrastim, Amgen, Thousand Oaks, California), 10 to 16 g/kg of body weight, as the sole mobilizing agent in 59 patients and in combination with granulocyte-macrophage colony-stimulating factor (Sargramostim, Immunex, Seattle, Washington), 250 g/m2, in 6 patients (10). Seven patients received CD34-selected stem cells (Isolex 300, Baxter Biotech, Irving, California). All other patients received unselected stem cells. Melphalan was administered intravenously during 2 consecutive days at a total dose of 100 to 200 mg/m2. Stem cells were infused 24 to 72 hours after completion of melphalan administration. The dose of melphalan given before autologous stem-cell transplantation was determined on the basis of patient age and clinical status. Eligibility criteria for the highest dose of melphalan (200 mg/m2) included age younger than 61 years, left ventricular ejection fraction of at least 0.45, pulmonary diffusion capacity at least 50% of the predicted value, serum creatinine concentration less than 177 mol/L (2.0 mg/dL), and Southwest Oncology Group performance status score of 0 to 2 (9). Patients who did not meet these criteria were treated with a modified dose (100 mg/m2 or 140 mg/m2, or two cycles of 100 mg/m2 given 4 to 6 months apart). Evaluation and Outcome Measures Patients were evaluated before treatment, at 3 and 12 months after treatment, and annually thereafter. At each evaluation, 24-hour urinary protein excretion and creatinine excretion were measured and the status of the plasma cell clone was determined by bone marrow biopsy and both serum and urine immunofixation electrophoresis. Complete hematologic response was defined as absence of detectable monoclonal protein by serum and urine immunofixation and a bone marrow biopsy specimen containing less than 5% plasma cells without clonal dominance of or isotype. Patients with a partial hematologic response (for example, those who showed loss of serum monoclonal protein but persistence of urine monoclonal protein or bone marrow clonality) or no hematologic response were categorized as having persistent plasma cell disease. A renal response was defined as a greater than 50% reduction in 24-hour urinary protein excretion in the absence of a 25% or greater reduction in creatinine clearance. Statistical Analysis Comparisons were performed by using the Wilcoxon test for continuous variables and the Fisher exact test for categorical variables. All analyses used a two-tailed significance value of 0.05 and were performed by using SAS for Windows (SAS Institute, Inc., Cary, North Carolina). Confidence intervals for medians were calculated nonparametrically by using the method of Hahn and Meeker (11). Confidence intervals provided for proportions are exact 95% intervals based on the binomial distribution. Role of the Funding Sources The funding sources had no role in the collection, analysis, or interpretation of the data or in the decision to submit the paper for publication. Results Patients Seventy-two patients with AL amyloidosisassociated renal disease were treated with intravenous melphalan and autologous peripheral blood stem-cell transplantation during the 4-year study period. Seven of these patients were dialysis dependent before treatment and were therefore excluded. The median age of the remaining 65 patients was 57 years; in 88%, the monoclonal immunoglobulin light-chain isotype was (Table 1). Multiorgan involvement was common, and 40% of patients had symptomatic cardiac disease. In most patients, amyloidosis had been diagnosed less than 12 months before intravenous melphalan treatment. Approximately one third of patients had previously been treated with oral melphalan. Table 1. Baseline Clinical Characteristics of Patients with Renal Amyloidosis The dose of intravenous melphalan preceding autologous stem-cell transplantation was 200 mg/m2 in 39 patients (60%) and 100 or 140 mg/m2 in 26 patients (40%). Fifty patients (77%) survived at least 12 months after treatment and were included in the analysis of renal response to treatment. The patients who survived at least 12 months were younger, had fewer organ systems involved, received a higher intravenous melphalan dose, and had higher serum cholesterol concentration at baseline than the 15 patients who died within 12 months (Table 1). Of the 50 patients who survived at least 12 months, 40 (80%) had nephrotic-range proteinuria (>3 g/d) at baseline and 13 (26%) had a baseline serum creatinine concentration of at least 133 mol/L (1.5 mg/dL). Treatment Toxicity In 15 patients (23%), the serum creatinine concentration doubled or increased by at least 88 mol/L (1 mg/dL) during the peritransplantation period (defined as 100 days after administration of intravenous melphalan or during stem-cell mobilization or collection). Two of these patients required temporary dialysis. The creatinine concentration returned to its baseline value within 1 to 5 weeks in all but 3 patients; of these 3, 1 died of multiorgan failure 19 days after stem-cell reinfusion, 1 had stabilization of creatinine concentration during the peritransplantation period but subsequently had progressive renal insufficiency requiring initiation of long-term dialysis 13 months after treatment, and 1 had gradual improvement in renal function over the 12 months after treatment. Other treatment-related toxicities included mucositis (53%), peripheral edema (23%), bacteremia (19%), pulmonary edema (18%), elevation in liver enzyme or bilirubin levels (13%), gastrointestinal bleeding (10%), and nongastrointestinal bleeding (10%). None of the patients had sustained dependence on blood product transfusions. Six patients (9%) died during the peritransplantation period. Five of these deaths occurred in patients with symptomatic cardiac disease, and all six occurred in patients who had three or more organ systems affected by amyloid. Hematologic Response Twenty-three of the 65 patients (35%) had