Daniel O. Clegg

Psoriatic arthritis: epidemiology, clinical features, course, and outcome

Psoriatic arthritis (PsA) has been defined as a unique inflammatory arthritis associated with psoriasis. Its exact prevalence is unknown, but estimates vary from 0.3% to 1% of the population. The clinical features described initially are recognised by most experienced clinicians, although they are most distinct in early disease. Initially, PsA typically presents as an oligoarticular and mild disease. However, with time PsA becomes polyarticular, and it is a severe disease in at least 20% of patients. Patients with PsA who present with polyarticular disease are at risk for disease progression. In addition to progression of clinical and radiological damage, health related quality of life is reduced among patients with PsA. It important to note that patients included in recent drug trials resemble patients followed prospectively in a clinic.

A Genomewide Screen in Multiplex Rheumatoid Arthritis Families Suggests Genetic Overlap with Other Autoimmune Diseases

Rheumatoid arthritis (RA) is an autoimmune/inflammatory disorder with a complex genetic component. We report the first major genomewide screen of multiplex families with RA gathered in the United States. The North American Rheumatoid Arthritis Consortium, using well-defined clinical criteria, has collected 257 families containing 301 affected sibling pairs with RA. A genome screen for allele sharing was performed, using 379 microsatellite markers. A nonparametric analysis using SIBPAL confirmed linkage of the HLA locus to RA (P < .00005), with lambdaHLA = 1.79. However, the analysis also revealed a number of non-HLA loci on chromosomes 1 (D1S235), 4 (D4S1647), 12 (D12S373), 16 (D16S403), and 17 (D17S1301), with evidence for linkage at a significance level of P<.005. Analysis of X-linked markers using the MLOD method from ASPEX also suggests linkage to the telomeric marker DXS6807. Stratifying the families into white or seropositive subgroups revealed some additional markers that showed improvement in significance over the full data set. Several of the regions that showed evidence for nominal significance (P < .05) in our data set had previously been implicated in RA (D16S516 and D17S1301) or in other diseases of an autoimmune nature, including systemic lupus erythematosus (D1S235), inflammatory bowel disease (D4S1647, D5S1462, and D16S516), multiple sclerosis (D12S1052), and ankylosing spondylitis (D16S516). Therefore, genes in the HLA complex play a major role in RA susceptibility, but several other regions also contribute significantly to overall genetic risk.

Comparison of sulfasalazine and placebo for the treatment of axial and peripheral articular manifestations of the seronegative spondylarthropathies: A Department of Veterans Affairs Cooperative Study

OBJECTIVE To determine if the peripheral articular manifestations of the seronegative spondylarthropathies (SNSA) respond differently than the axial manifestations to treatment with sulfasalazine (SSZ). METHODS This is a reanalysis of a previously reported series of randomized, double-blind, placebo-controlled, multicenter trials comparing the effects of SSZ, 2,000 mg/day, and placebo on the axial and peripheral articular manifestations of ankylosing spondylitis (AS), psoriatic arthritis (PsA), and reactive arthritis (ReA; Reiters syndrome). Patients were classified as treatment responders on the basis of meeting predefined improvement criteria in 4 outcome measures: namely, patient and physician global assessments in all patients, morning stiffness and back pain in patients with axial manifestations, and joint pain/tenderness scores and joint swelling scores in patients with peripheral articular manifestations. RESULTS Six hundred nineteen SNSA patients (264 AS, 221 PsA, and 134 ReA) were studied. One hundred eighty-seven of these patients had only axial manifestations of their disease, while 432 patients had peripheral articular manifestations. Of the patients with axial disease, 40.2% of the SSZ group and 43.3% of the placebo group met the predefined response criteria (P = 0.67). Of the peripheral articular group, 59.0% of the SSZ-treated patients and 42.7% of the placebo-treated patients showed a response (P = 0.0007). CONCLUSION In a large group of affected individuals, the response of SNSA patients to SSZ appears to be related to the articular manifestations of their disease. These data demonstrate that the axial and peripheral articular manifestations of SNSA respond differently to treatment with SSZ. In SNSA patients with persistently active peripheral arthritis, SSZ is safe, well tolerated, and effective.

The effect of glucosamine and/or chondroitin sulfate on the progression of knee osteoarthritis: A report from the glucosamine/chondroitin arthritis intervention trial

OBJECTIVE Osteoarthritis (OA) of the knee causes significant morbidity and current medical treatment is limited to symptom relief, while therapies able to slow structural damage remain elusive. This study was undertaken to evaluate the effect of glucosamine and chondroitin sulfate (CS), alone or in combination, as well as celecoxib and placebo on progressive loss of joint space width (JSW) in patients with knee OA. METHODS A 24-month, double-blind, placebo-controlled study, conducted at 9 sites in the United States as part of the Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT), enrolled 572 patients with knee OA who satisfied radiographic criteria (Kellgren/Lawrence [K/L] grade 2 or grade 3 changes and JSW of at least 2 mm at baseline). Patients with primarily lateral compartment narrowing at any time point were excluded. Patients who had been randomized to 1 of the 5 groups in the GAIT continued to receive glucosamine 500 mg 3 times daily, CS 400 mg 3 times daily, the combination of glucosamine and CS, celecoxib 200 mg daily, or placebo over 24 months. The minimum medial tibiofemoral JSW was measured at baseline, 12 months, and 24 months. The primary outcome measure was the mean change in JSW from baseline. RESULTS The mean JSW loss at 2 years in knees with OA in the placebo group, adjusted for design and clinical factors, was 0.166 mm. No statistically significant difference in mean JSW loss was observed in any treatment group compared with the placebo group. Treatment effects on K/L grade 2 knees, but not on K/L grade 3 knees, showed a trend toward improvement relative to the placebo group. The power of the study was diminished by the limited sample size, variance of JSW measurement, and a smaller than expected loss in JSW. CONCLUSION At 2 years, no treatment achieved a predefined threshold of clinically important difference in JSW loss as compared with placebo. However, knees with K/L grade 2 radiographic OA appeared to have the greatest potential for modification by these treatments.

Treatment of rheumatoid arthritis with oral type II collagen: Results of a multicenter, double‐blind, placebo‐controlled trial

OBJECTIVE Oral administration of cartilage-derived type II collagen (CII) has been shown to ameliorate arthritis in animal models of joint inflammation, and preliminary studies have suggested that this novel therapy is clinically beneficial and safe in patients with rheumatoid arthritis (RA). The present study was undertaken to test the safety and efficacy of 4 different dosages of orally administered CII in patients with RA. METHODS Two hundred seventy-four patients with active RA were enrolled at 6 different sites and randomized to receive placebo or 1 of 4 dosages (20, 100, 500, or 2,500 microg/day) of oral CII for 24 weeks. Efficacy parameters were assessed monthly. Cumulative response rates (percentage of patients meeting the criteria for response at any time during the study) were analyzed utilizing 3 sets of composite criteria: the Paulus criteria, the American College of Rheumatology criteria for improvement in RA, and a requirement for > or = 30% reduction in both swollen and tender joint counts. RESULTS Eighty-three percent of patients completed 24 weeks of treatment. Numeric trends in favor of the 20 microg/day treatment group were seen with all 3 cumulative composite measures. However, a statistically significant increase (P = 0.035) in response rate for the 20 microg/day group versus placebo was detected using only the Paulus criteria. The presence of serum antibodies to CII at baseline was significantly associated with an increased likelihood of responding to treatment. No treatment-related adverse events were detected. The efficacy seen with the lowest dosage is consistent with the findings of animal studies and with known mechanisms of oral tolerance in which lower doses of orally administered autoantigens preferentially induce disease-suppressing regulatory cells. CONCLUSION Positive effects were observed with CII at the lowest dosage tested, and the presence of serum antibodies to CII at baseline may predict response to therapy. No side effects were associated with this novel therapeutic agent. Further controlled studies are required to assess the efficacy of this treatment approach.

Pulmonary disease during the treatment of rheumatoid arthritis with low dose pulse methotrexate

Methotrexate therapy has been effective in the treatment of RA with short term experience suggesting little serious adverse reactions. Our review of 168 patients receiving methotrexate has identified nine patients with probable or possible methotrexate-induced pulmonary toxicity, giving a prevalence of 5% and an incidence of 3.9 per 100 patients per year. No clinical or laboratory features showed an association that could potentially predict the development of pulmonary disease. All patients experienced complete recovery with supportive care and/or corticosteroid therapy. Clinical monitoring for this complication is warranted in all patients receiving long term methotrexate therapy for RA.

Clinical efficacy and safety of glucosamine, chondroitin sulphate, their combination, celecoxib or placebo taken to treat osteoarthritis of the knee: 2-year results from GAIT

Background Knee osteoarthritis (OA) is a major cause of pain and functional limitation in older adults, yet longer-term studies of medical treatment of OA are limited. Objective To evaluate the efficacy and safety of glucosamine and chondroitin sulphate (CS), alone or in combination, as well as celecoxib and placebo on painful knee OA over 2 years. Methods A 24-month, double-blind, placebo-controlled study, conducted at nine sites in the US ancillary to the Glucosamine/chondroitin Arthritis Intervention Trial, enrolled 662 patients with knee OA who satisfied radiographic criteria (Kellgren/Lawrence grade 2 or 3 changes and baseline joint space width of at least 2 mm). This subset continued to receive their randomised treatment: glucosamine 500 mg three times daily, CS 400 mg three times daily, the combination of glucosamine and CS, celecoxib 200 mg daily, or placebo over 24 months. The primary outcome was a 20% reduction in Western Ontario and McMaster University Osteoarthritis Index (WOMAC) pain over 24 months. Secondary outcomes included an Outcome Measures in Rheumatology/Osteoarthritis Research Society International response and change from baseline in WOMAC pain and function. Results Compared with placebo, the odds of achieving a 20% reduction in WOMAC pain were celecoxib: 1.21, glucosamine: 1.16, combination glucosamine/CS: 0.83 and CS alone: 0.69, and were not statistically significant. Conclusions Over 2 years, no treatment achieved a clinically important difference in WOMAC pain or function as compared with placebo. However, glucosamine and celecoxib showed beneficial but not significant trends. Adverse reactions were similar among treatment groups and serious adverse events were rare for all treatments.

Sustained durability and tolerability of etanercept in ankylosing spondylitis for 96 weeks.

Objective: To evaluate the continued safety and durability of clinical response in patients with ankylosing spondylitis receiving etanercept. Methods: 277 patients who had participated in a previous randomised, double blind, placebo controlled 24 week trial were eligible to continue in this open label extension study. All patients who enrolled in the open label extension (n = 257) received subcutaneous etanercept 25 mg twice weekly for up to 72 weeks, for a combined 96 weeks of cumulative trial and open label experience. For the patients who had received etanercept for 24 weeks in the double blind trial, this represented almost 2 years of continuous etanercept treatment. Results: Patients continuing etanercept treatment had a sustained response for almost 2 years, with 74% achieving an ASsessments in Ankylosing Spondylitis 20% (ASAS 20) response after 96 weeks of etanercept treatment. Patients who had received placebo in the preceding double blind trial had similar responses, with 70% of patients attaining an ASAS 20 response after 24 weeks of etanercept treatment and 78% achieving an ASAS 20 response after 72 weeks. Improved spinal mobility was seen in both groups. Etanercept was well tolerated in patients treated for up to 96 weeks. Conclusion: The subcutaneous administration of twice weekly doses of etanercept provided sustained durability of response in the improvement of signs and symptoms of ankylosing spondylitis for nearly 2 years.

Evaluation of the PROMIS physical function item bank in orthopaedic patients

The patient‐reported outcomes measurement information system (PROMIS) physical function item bank v1 (PPFIB) contains 124 item response theory (IRT) calibrated items (Rose et al. 2008. J Clin Epidemiol 61:17–33). We report the psychometric properties of these items within an outpatient, orthopaedic patient population. In particular, we investigated whether a single unidimensional IRT scale can adequately define physical function of patients presenting with primarily upper or lower extremity orthopaedic complaints. We conducted a prospective study at an orthopaedic outpatient clinic to collect data from 865 adult patients with all 124 PROMIS physical function items and seven demographic items. Items were evaluated by a Rasch model. Total variance (60.6%) across the 124 items was explained by a single Rasch dimension. The variance explained by the second dimension was 7.7%, reflecting differential item functioning in the upper and lower extremity patients. The upper extremity physical function items had a pronounced ceiling effect. A single physical function dimension accounts for most of the item variance in the PPFIB, suggesting that the items are measuring predominately one single construct. Separate subscales for lower versus upper extremities, especially with additional items at the upper trait level of the upper extremity subscale, may further enhance evaluation of physical function in orthopaedic patients.

Early Undifferentiated Connective Tissue Disease: III. Outcome and Prognostic Indicators in Early Scleroderma (Systemic Sclerosis)

Scleroderma, or systemic sclerosis, varies widely in its presentation and course. Many patients with scleroderma have a disease course of 10 to 20 years [1-4], but some patients experience a rapidly progressive form of disease characterized by early organ failure and death. Of 91 patients studied retrospectively by Lally and colleagues [3], 16 developed renal or cardiorespiratory failure (or both) an average of 15.8 months after the onset of symptoms; 11 of these 16 patients died. Retrospective assessments are inherently weighted toward the selection of patients with a longer disease duration, and patients experiencing early death or rapidly progressive disease may be under-represented. A few clinical studies and therapeutic trials have targeted patients with a disease duration of less than 5 years [3-5]; however, additional prospective information on the course and prognosis of patients with early scleroderma is needed to make appropriate risk/benefit decisions about potentially toxic therapies. Recently, a prospective study was done in 410 patients with early undifferentiated or early defined connective tissue disease [6]. Selecting 48 patients with early scleroderma from this cohort, we analyzed short-term outcomes and identified some features occurring within the first year of disease that may be useful in distinguishing patients at high risk for an unfavorable outcome. Methods The Cooperative Systematic Studies of the Rheumatic Diseases Program is funded under a National Institute of Arthritis and Musculoskeletal Diseases contract through the Coordinating Center at the University of Utah, Salt Lake City, Utah, and includes 10 centers participating in the study of early undifferentiated connective tissue disease. Outpatients and inpatients seen at participating centers were eligible for the study if they met diagnostic criteria for rheumatoid arthritis, scleroderma, systemic lupus erythematosus, or poly/dermatomyositis [7-10] and had experienced symptoms for less than 1 year. Patients who had features of a connective tissue disease, including Raynaud phenomenon, unexplained polyarthritis, or 3 of 11 findings characteristic of connective tissue disease, but who did not meet established criteria for a specific connective tissue disease were classified as having undifferentiated connective tissue disease. Patients were evaluated at baseline and at follow-up intervals of 1, 3, and 5 years. Details on data collection and on the clinical and laboratory features of the patients with early undifferentiated connective tissue disease have been described previously [6, 11]. Enrollment for the study began in July 1982 and was completed in June 1987. Survival status was confirmed through at least 5 years after symptom onset in all cases except one (patient lost to follow-up after 1.6 years). A diagnosis of scleroderma was made in 52 patients (in 46 within 1 year of symptom onset and in 6 within 4 years of symptom onset). Four of these patients (including 2 of 6 diagnosed after the baseline evaluation) developed overlap syndromes during the 5-year follow-up period and were excluded from the study, leaving 48 patients for analysis. Deaths and causes of death were reported to the Coordinating Center; every possible effort was made to confirm the cause of death through hospital records and autopsy reports from the participating centers. Five patients died at home, on the way to the hospital, or shortly after arrival at the hospital. Sclerodermatous skin findings on physical examination were categorized as follows: sclerodactyly (involvement distal to the metacarpophalangeal joints); acrosclerosis (involvement distal to elbows and knees); or generalized or diffuse scleroderma. A skin score was not determined. Physical findings for each organ system were recorded as a yes or no response to a list of abnormal findings. Twelve cardiorespiratory signs were assessed on the baseline physical examination: These included the presence or absence of rales, wheezes, pleural or pericardial rubs, pleural effusion, systolic or diastolic murmurs, abnormal second heart sounds, cardiomegaly, arrhythmia, dependent edema, and tachycardia (pulse 100 beats/min). All patients had routine hematology and biochemical laboratory tests. Many patients also had a determination of erythrocyte sedimentation rate (Westergren method) (n = 47), pulmonary function tests (n = 43), an electrocardiogram (n = 40), a chest radiograph (n = 40), and the Schirmer test. Serum specimens from all patients were analyzed for serologic markers of rheumatic disease at the Centers for Disease Control [11]. In addition, frozen serum specimens from 45 of the 48 patients with scleroderma were analyzed at Specialty Laboratories, Inc. (Santa Monica, California): Interleukin-2 levels were assessed by enzyme-linked immunosorbent assay (ELISA); soluble interleukin-2 receptor levels by ELISA; and neopterin levels by radioimmunoassay; anti-Scl-70 antibody levels by ELISA; and anticentromere antibody titer by immunofluorescence assay. Lung diffusing capacity was considered to be abnormal if it was less than 70% of the predicted diffusing capacity. Chest radiographs were considered to be abnormal if infiltrates, effusions, pleural thickening, or heart enlargement was present. Electrocardiograms were considered to be abnormal if evidence of arrhythmia, heart block, ventricular enlargement, repolarization abnormalities, significant shift in axis, or infarction was found. For the purposes of our study, nonspecific ST or T-wave abnormalities were not considered to be abnormal. Baseline clinical, laboratory, and other features of patients with early death were compared with those of survivors. Mean values were compared using the Student t-test. Comparisons between dichotomous variables were done using chi-square distribution with Yates correction. Life-table analyses using Kaplan-Meier survival estimation [12] and Mantel-Haenszel statistics [13] were done to predict survival rates for the group of patients with early scleroderma and the various subgroups generated by stratification based on selected variables. Variables were evaluated using univariate Cox proportional-hazards analysis for their ability to predict survival [14]. The variables found to be most significant, as determined by univariate Cox proportional-hazards analysis, and for which less than 10% of data were missing, were then evaluated by multivariate Cox analysis with stepwise regression modeling. We did not apply the Bonferroni correction to our results; however, because of the many variables compared, we defined statistical significance by a probability level of 0.01. Results Forty-eight patients with scleroderma were enrolled in the study. One patient was lost to follow-up 1.6 years after symptom onset, and the data gathered on her were used only in the survival and Cox analyses. During the 5-year follow-up period, 15 of the 47 evaluable patients with early scleroderma died. Kaplan-Meier estimation yielded overall survival rates at 1, 3, and 5 years after symptom onset of 92%, 75%, and 68%, respectively (Figure 1). Five patients died within 1 year of symptom onset. The cohort of patients with scleroderma accounted for 41% of all early deaths recorded for the entire study population of 410 patients. The causes of death are summarized in Table 1. Multiorgan involvement was frequently observed at the time of death, although pulmonary or cardiac system failure (or both) was thought to be the immediate cause of death in 8 of the 15 patients who died. Renal crisis was substantiated or suspected in 4 of the patients who died. The time from symptom onset to death was similar for those dying of renal causes (21 11 months) and those dying of cardiopulmonary causes (25 17 months). Table 1. Suspected Immediate Causes of Death, Average Age at Death, and Survival in Patients with Early Scleroderma* Figure 1. Cumulative survival probabilities: Kaplan-Meier survival curve with Greenwood confidence limits from onset of symptoms for the 48 early scleroderma patients. Clinical Features In Table 2, baseline characteristics of patients who died within 5 years after symptom onset are compared with those of the survivors. Twelve of the 15 (80%) patients who died had at least one abnormal cardiopulmonary sign at baseline compared with 13 of 32 (41%) survivors (P = 0.03). Among individual cardiopulmonary findings, resting heart rate was significantly different between survivors (79 13 beats/min; range, 50 to 110 beats/min) and patients who died (93 12 beats/min; range, 70 to 120 beats/min) (P = 0.001). Baseline blood pressure was similar in the subgroups (survivors: 120 17/76 12 mm Hg; patients who died: 127 27/78 16 mm Hg; P > 0.3), as was the frequency of chest radiographic, pulmonary function, and electrocardiographic abnormalities (P = 0.09). Table 2. Baseline Features of Patients with Early Scleroderma Who Survived and of Those Who Died* Chest pain, dyspnea, orthopnea, dependent edema, cough, and wheezing were common complaints; 57% of the entire group had at least one symptom. Dyspnea was the most common single cardiorespiratory complaint (36%). No significant difference in frequency of cardiopulmonary symptoms was detected between those who died and those who survived. Ninety-two percent of our patients developed skin involvement within 1 year of symptom onset, implying that patients with gradual-onset scleroderma were not included in our study. Four of the 48 patients did not have diagnosable scleroderma at their first visit, but they did develop skin disease within 3 years of follow-up (or within 4 years of disease onset). At entry, two patients had Raynaud phenomenon only and two were diagnosed with undifferentiated connective tissue disease. When baseline variables for these 4 patients with intermediate-onset scleroderma were compared with those of the remaining 44 patients with earlier-onset disease, no significant differences were