Robert F. Willkens

Pancytopenia Associated With Low Dose Pulse Methotrexate in the Treatment of Rheumatoid Arthritis

Low dose pulse MTX was associated with the development of pancytopenia in six patients with RA. Two patients died. Factors implicated in the occurrence of this complication were renal impairment in five patients, medication errors by two patients, preexisting marrow injury from occult alcoholism in one patient, and an apparent idiosyncratic reaction to the drug in another. Medication errors were associated with the use of five or more medications, and the unusual schedule of administration of low dose MTX may also have been contributory. From a consideration of the clinical pharmacokinetics of MTX, we suggest other factors that may predispose to the occurrence of marrow toxicity: the presence of hypoalbuminemia, interactions between MTX and other protein bound or weakly acidic drugs, and the repetitive dosing schedule of low dose MTX. Based on our experience, patients with impaired renal function (creatinine greater than or equal to 2.0 mg/dL) should not receive MTX. Renal function should be monitored regularly during treatment with MTX, and blood counts should be observed carefully if a new drug is added or substituted. A 5 mg test dose of MTX before initiating weekly therapy may identify patients with severe hypersensitivity to the drug. The potential risks of using MTX in a patient unwilling to accept blood products should be acknowledged and discussed with the patient. Furthermore, we recommend the use of leucovorin if pancytopenia occurs, even if low or undetectable serum levels of MTX are present.

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

The subcutaneous nodule: Its significance in the diagnosis of rheumatic disease

Summary A wide variety of cutaneous and subcutaneous nodules are seen clinically. By far the most common of these is the rheumatoid granuloma, occurring at pressure points in patients with rheumatoid arthritis. These nodules are often of long duration and generally imply severe disease. In contrast, the now uncommon rheumatic nodule is transient and does not manifest the typical trizonal architecture of central necrosis, palisading histiocytes, and surrounding fibrosis, so typical of the rheumatoid nodules. The rheumatic nodule does not correlate with severity of arthritis in rheumatic fever but is strongly associated with cardiac involvement. The rheumatoid variant arthritides are not associated with nodules, although rare patients with nodules have been reported. Patients with systemic lupus erythematosus and Jaccoud arthritis may develop typical rheumatoid nodules. It is claimed that the nodules of juvenile rheumatoid arthritis more closely resemble the rheumatic nodule than the rheumatoid nodule. Numerous reports of children without arthritis describe subcutaneous nodules with histology identical to the rheumatoid nodule. These are known as pseudorheumatoid nodules. They do not precede the onset of arthritis and are probably part of the spectrum of granuloma annulare. Necrobiosis lipoidica diabeticorum likewise shares a very similar histology with the rheumatoid nodule. The subcutaneous adiposa is the site of numerous inflammatory nodules that can be grouped together under panniculitis. In erythema nodosum, nodular panniculitis (Weber-Christian disease), lupus profundus, and the nonsystemic cutaneous vasculitides, angiitis plays a prominent role in the pathogenesis. Pancreatic disease in which direct enzymatic cytolysis occurs is an exception to this rule. The skin manifestations of the systemic angiitides are diverse, and nodules are among the least common of the dermal manifestations, with the exception of the frequent eruptions in Behcet disease. Gout, amyloidosis, and hypercholesterolemia represent metabolic disorders in which normal body materials accumulate in excess, with resultant nodular deposition in cutaneous tissue and in or around joints (tendons). The tophus can closely mimic the rheumatoid nodule clinically. Likewise, the nodules and arthropathy of amyloidosis have been confused with rheumatoid disease. Only two storage diseases, multicentric reticulohistiocytosis and Farber disease, cause both subcutaneous nodules and arthritis. The bacterial pathogens producing nodules and arthritis include the treponemal organisms, syphilis, yaws, and pinta, as well as leprosy. Erythema nodosum leprosum is probably an immune complex-mediated reaction. Among the fungi, coccidioidomycosis is a well-described cause of erythema nodosum and arthritis. Disseminated sporotricosis rarely produces juxtaarticular nodules and arthritis. Of the viruses associated with arthritis only the hepatitis B virus has been documented to produce both arthritis and subcutaneous nodules. This uncommon association may also represent an immune complex-mediated phenomenon. Finally, such miscellaneous conditions as osteoarthritis and Dupuytren contracture are common causes of nodular disease which can be clinically confusing to the uninitiated.

Small-Vessel Vasculitis and Methotrexate

Excerpt To the editor: The use of chemotherapeutic agents is clearly associated with hypersensitivity reactions, including anaphylaxis and urticarial reactions when these drugs are used in moderate...

Worldwide clinical safety experience with diclofenac

Data from more than 100,000 patients in foreign and United States trials provide substantial evidence of diclofenacs safety and tolerability. Adverse experiences were infrequent and generally mild or transient. In United States short-term trials, the frequency and severity of side effects compared favorably with rates for placebo, aspirin, and other NSAIDs. The drop-out rate for therapeutic reasons (adverse effects or lack of efficacy) was lower for diclofenac than for any of the comparative treatments. In long-term trials, diclofenac has been taken safely for a year or more. The incidence of adverse experiences reported for older patients (greater than or equal to 65 years) treated with diclofenac did not generally differ from that reported for younger patients. No significant differences in the incidence of hepatic problems were detected between diclofenac and other active treatments in U.S. trials. Finally, foreign post-marketing data on adverse experiences show that diclofenac is one of the safest agents of its kind for the treatment of a broad range of rheumatic conditions.

The Treatment of Acute Gout with Naproxen

: The effectiveness of naproxen in the management of acute gouty arthritis was assessed in an open study of 20 patients. These patients were selected on the basis of their clinical presentation of characteristic acute arthritis associated in 19 with concomitant hyperuricemia. There were 17 men and three women varying in age from 35 to 89 years. The first 12 patients were treated with 600 mg naproxen initially, followed by 300 mg every 8 hours for the first 48 hours and then tapered or discontinued depending upon their clinical response. The last eight patients received a loading dose of 750 mg naproxen, followed by 250 mg every 8 hours for a duration of 72 hours before tapering the drug. The response of 15 of the 20 was either excellent or good, while the response was fair in three and poor in two. Poor responders had been failures in other regimens or were treated late in the course of their attack. The higher loading dose was associated with more rapid and satisfactory remission. No significant undesirable side effects were observed. On the basis of this study, naproxen was found effective in alleviating the inflammation of acute gout.

Forefoot Surgery in Rheumatoid Arthritis: Subjective Assessment of Outcome

Forefoot surgical outcomes were evaluated in 26 patients with rheumatoid arthritis. A total of 45 procedures were reviewed with emphasis on first ray intervention. Disease duration and aggressiveness of preceding medical therapy were combined to establish a disease severity index. Patients operated were predominantly in the midrange of disease severity. Subjective data on the relief of pain, callus, and deformity were favorable but this benefit was not long lasting inasmuch as patients were most satisfied in the period immediately following surgery and less so as time elapsed from intervention. Fusion of the first metatarsophalangeal joint seemed better than resection alone, indicating that stability should be the primary goal for surgical intervention of the rheumatoid forefoot.

RESOLVE : METHOTREXATE IS THE DRUG OF CHOICE AFTER NSAIDS IN RHEUMATOID ARTHRITIS

This article, in favor of the resolution that methotrexate (MTX) is the drug of choice after nonsteroidal antiinflammatory treatment, develops the following four points. MTX is an effective treatment of rheumatoid arthritis. MTX is easy to administer and to monitor for effectiveness and safety. MTX has demonstrated a therapeutic to toxic ratio that exceeds that of other second-line antirheumatic drugs. MTX has the potential to impair disease progression.

Zomepirac, Interstitial Nephritis, and Renal Failure

Excerpt To the editor: We report severe renal failure and nephrotic syndrome in three patients taking zomepirac sodium, a nonsteroidal anti-inflammatory drug. A 46-year-old woman who had been takin...

Prognostic staging for therapy of rheumatoid arthritis

An attempt should be made to predict the most likely course of individual disease when a patient is first diagnosed as having rheumatoid arthritis (RA). Such a prediction can be called prognostic staging for therapy. While no specific marker will accomplish this accurately, the summation of demographic, genetic, historical, physical, laboratory, radiologic, and scanning data may be used to make a reasonable estimation of outcome. The use of immunogenetic typing is the newest technique that can help identify patients likely to develop more serious disease. Once patients are identified as having probable aggressive disease, that is, beyond stage I, combination therapy should be initiated. Goals of therapy should include the prevention and/or interference of progression of radiologic erosions, as well as functional improvement as measured by life-style and productivity.