Antinuclear antibody testing: discordance between commercial laboratories.

Antinuclear antibody (ANA) test results frequently affect the course of patients' evaluations, diagnosis, and treatment, but different laboratory centers may yield conflicting results. This study investigated the degree of agreement between laboratory results in a group of subjects who had ANA testing performed at two commercial laboratories. This was a chart review study, in which all ANA tests ordered by the authors from one commercial laboratory over a 4-year period were queried. Corresponding patient charts were reviewed, and if ANA testing had also been performed at the second commercial laboratory, subjects were entered into the study. The primary measurement was agreement between paired ANA results, and we performed sensitivity analysis using varying criteria defining agreement (criteria A to criteria D [strictest to most lenient definition of agreement]). Other data captured included relevant data obtained through the course of evaluation (e.g., presenting complaints, exam findings, other laboratory data) and final diagnoses. Of 101 paired ANA tests, there was 18 % agreement according to the strictest criteria and 42 % according to the most lenient. Of the seven subjects with ANA-associated rheumatic disease, none of the paired tests were in agreement according to criteria A (two agreed according to criteria D). Our findings demonstrate poor agreement between paired ANA tests performed at two commercial laboratories. The low level of agreement may have far-reaching clinical implications. Specifically, this finding calls into question the reliability of ANA testing as it is currently performed and suggests that results may in part depend upon the laboratory center to which patients are referred.

Thromboangiitis obliterans successfully treated with phosphodiesterase type 5 inhibitors.

Thromboangiitis obliterans, or Buerger's disease, is a non-atherosclerotic, segmental, inflammatory disease affecting the small- and medium-sized vessels of the distal extremities. Other than discontinuation of tobacco, there is no standard-of-care treatment. Although two randomized trials have demonstrated a role for intravenous iloprost, no oral drug has yet been demonstrated to be effective in treating thromboangiitis obliterans. We present the first three reported cases of thromboangiitis obliterans successfully treated with phosphodiesterase type 5 inhibitors, followed by a discussion of the rationale for the use of these agents in thromboangiitis obliterans.

The clinical utility of a positive antinuclear antibody test result.

BACKGROUND: This retrospective study investigated the clinical utility of a positive antinuclear antibody (ANA) test performed outside of the rheumatology setting. Prior studies have investigated the frequency of ANA positivity within the general population. The purpose of this investigation was to evaluate the clinical utility of a positive ANA test result in a real-world setting by reviewing the final diagnoses of patients who were referred to a tertiary rheumatology clinic for evaluation of a positive ANA test result. METHODS: We reviewed the records of patients presenting to the authors between July 2007 and July 2009. Patients were included in the evaluation if they were referred for a positive ANA test result. All relevant descriptive and laboratory data were collated, as were the initial reasons for ordering ANA testing and the ultimate diagnoses reached. Positive predictive values for a "positive ANA test result" were calculated for all antinuclear antibody-associated rheumatic diseases and for lupus specifically. RESULTS: A total of 232 patients were referred for a positive ANA test result. The positive predictive value of a positive ANA test result in this cohort was 2.1% for lupus and 9.1% for any antinuclear antibody-associated rheumatic disease. No antinuclear antibody-associated rheumatic disease was identified in patients with an ANA<1:160. The most common reason for ordering ANA testing was widespread pain (54/232, 23.2%). CONCLUSIONS: In this retrospective study, more than 90% of patients who were referred to a tertiary rheumatology clinic for a positive ANA test result had no evidence for an ANA-associated rheumatic disease. The poor predictive value of a positive ANA in this cohort was largely attributable to unnecessary testing in patients with low pretest probabilities for ANA-associated rheumatic disease.

Use of a medication control officer to reduce bias in a clinical trial: lessons learned from the scleroderma lung study.

BACKGROUND: Scleroderma Lung Study (SLS) was designed to evaluate the efficacy and safety of oral cyclophosphamide (CYC) versus placebo taken for 1 year for scleroderma-associated interstitial lung disease. An independent medication control officer (MCO), usually a physician, at each center was assigned to monitor laboratory and clinical toxicity of study medication and regulate its dosing based on these results. By having an MCO who watched and managed toxicity, the study investigators were free to care for study patients and to assess study outcomes without the potential bias of knowing toxicity data (toxicity from cyclophosphamide is distinctive - cytopenias and hematuria in particular). PURPOSE: To assess the usefulness of an MCO, whose chief role was to maintain safety while retaining the blinding in the clinical trial. METHODS: Patients had safety laboratory testing every 2-4 weeks and results were sent directly to the MCO within 2 days of the test. Other clinical adverse events (AEs) were reported by the patient to a nurse coordinator who reported them to the MCO who then managed the AEs to preserve the blinding of investigators caring for the patients. The MCO was provided pre-determined algorithms for dose adjustments of test medication based on the presence and severity of laboratory abnormalities. RESULTS: Safety monitoring by the MCO was effective in the early detection of drug toxicity with provision of appropriate medical intervention on a timely basis. At the same time, investigator blinding appeared to be maintained. LIMITATIONS: The testing of MCO effectiveness in maintaining blinding and consistency was not defined as an a priori hypothesis and thus complete data relating to the efficacy of the MCO were not collected in a prospective fashion. CONCLUSION: An MCO and pre-specified monitoring and dosing guidelines, coupled with uniform pre-specified responses to AEs, may be used effectively to preserve investigator blinding and provide consistency in response to AEs in a clinical trial setting, even when AEs of the test medication are distinctive.

Update on fibromyalgia therapy.

Primary fibromyalgia, a poorly-understood chronic pain syndrome, is characterized by widespread musculoskeletal pain, nonrestorative sleep, fatigue, psychological distress, and specific regions of localized tenderness, all in the absence of otherwise apparent organic disease. While the etiology of fibromyalgia is unclear, accumulating data suggest that disordered central pain processing likely plays a role in the pathogenesis of symptoms. Although various pharmacological treatments have been studied and espoused for treating fibromyalgia, no single drug or group of drugs has proved to be particularly useful in treating fibromyalgia patients as a whole, and only one drug to date has earned U.S. Food and Drug Administration approval for treating the syndrome in the United States. This review critically and systematically evaluates clinical investigations of medicinal and nonmedicinal treatments for fibromyalgia dating from 1970 to 2007.

Narrative review: the pathophysiology of fibromyalgia.

Primary fibromyalgia is a common yet poorly understood syndrome characterized by diffuse chronic pain accompanied by other somatic symptoms, including poor sleep, fatigue, and stiffness, in the absence of disease. Fibromyalgia does not have a distinct cause or pathology. Nevertheless, in the past decade, the study of chronic pain has yielded new insights into the pathophysiology of fibromyalgia and related chronic pain disorders. Accruing evidence shows that patients with fibromyalgia experience pain differently from the general population because of dysfunctional pain processing in the central nervous system. Aberrant pain processing, which can result in chronic pain and associated symptoms, may be the result of several interplaying mechanisms, including central sensitization, blunting of inhibitory pain pathways, alterations in neurotransmitters, and psychiatric comorbid conditions. This review provides an overview of the mechanisms currently thought to be partly responsible for the chronic diffuse pain typical of fibromyalgia.

A 58-year-old man with anti-Jo-1 syndrome and renal cell carcinoma: a case report and discussion.

The association of inflammatory myopathies with malignancy and interstitial lung disease has been well accepted. Polymyositis can be associated with interstitial lung disease or malignancy, although it is rare for all three entities to occur simultaneously at the initial presentation. We report a patient who was found to have concurrent polymyositis, interstitial lung disease, with anti-Jo-1 antibody, and renal cell carcinoma.

Diagnosis, treatment, and prognosis of erythema migrans and Lyme arthritis.

Most patients with erythema migrans, the pathognomonic rash of Lyme disease, do not recall a deer tick bite. The rash is classically 5 to 68 cm of annular homogenous erythema (59%), central erythema (30%), central clearing (9%), or central purpura (2%). Serologic testing is not indicated for patients with erythema migrans, because initially, the result is usually negative. Successful treatment of a patient with erythema migrans can be accomplished with 20 days of oral doxycycline, amoxicillin, or cefuroxime axetil. Patients with Lyme arthritis usually present with a mildly painful swollen knee. Patients with Lyme arthritis have markedly positive serology and can usually be successfully treated with 28 days of oral doxycycline or amoxicillin. Some patients may have persistent effusion despite 4 to 8 weeks of antibiotics and may need synovectomy. Persistent effusion is not due to persistent infection. Antibiotic therapy for more than 8 weeks for patients with Lyme disease is not indicated. Chronic Lyme disease due to antibiotic resistant infection has not been demonstrated.

High-dose versus low-dose D-penicillamine in early diffuse systemic sclerosis trial: lessons learned.

OBJECTIVES: To review important findings, or lessons, that were learned about measures of response, design, conduct, and analysis of a randomized, controlled trial (RCT), even though the trial failed to demonstrate efficacy of d-penicillamine. METHODS: One hundred thirty-four patients with early (< or =18 months), diffuse systemic sclerosis (SSc) were entered into an RCT (high-dose [822 mg daily] vs low-dose [120 mg every other day] D-penicillamine) and were followed up regularly for up to 4 years. Because analysis failed to show efficacy for D-penicillamine in early diffuse SSc, all data were pooled for additional secondary analyses. RESULTS: This RCT showed that trials of potential disease-modifying interventions can be completed in SSc using the American College of Rheumatology guidelines. This RCT used an active control. After analysis, we were not able to tell whether either dose was effective or ineffective. That experience argues in favor of using placebo controls until such time as an active control can be found that truly modifies the disease. Skin score and the disability index of the Health Assessment Questionnaire (HAQ-DI) were valid predictors of outcome. Along with the physician global assessment, they also were valid measures of response. CONCLUSIONS: Even in studies that are therapeutically "negative," careful evaluation of the data can examine other hypotheses and thereby provide important insights into other aspects of trial design, outcome measures, patient function, and trial conduct.

Predictors and outcomes of scleroderma renal crisis: the high-dose versus low-dose D-penicillamine in early diffuse systemic sclerosis trial.

OBJECTIVE: The reported frequency of scleroderma M01-R renal crisis (SRC) in diffuse systemic sclerosis (SSc; scleroderma) is 15-20%. Early use of angiotensin-converting enzyme (ACE) inhibitors has markedly improved outcome. The present analysis reexamines the prognostic factors for and outcome of SRC in a prospective cohort of patients with early diffuse SSc. METHODS: We retrospectively evaluated the cohort of SSc patients who participated in the High-Dose Versus Low-Dose D-Penicillamine in Early Diffuse SSc trial. Patients with diffuse cutaneous scleroderma were enrolled if their disease duration was <18 months. Because the trial failed to show a difference between treatment groups, the data were pooled. RESULTS: One hundred thirty-four SSc patients entered the observation period a mean +/- SD of 0.8 +/- 0.3 years after onset of SSc. SRC occurred in 18 patients a mean +/- SD of 0.9 +/- 1.1 years after entry. During a mean +/- SD 4.0 +/- 1.1 years of followup after entry, 9 of the 18 patients died (mean +/- SD 0.6 +/- 0.9 years after SRC onset). Baseline characteristics that predicted SRC included a modified Rodnan skin thickness score of >or=20 (P < 0.01), enlarged cardiac silhouette on radiograph (P = 0.04), large joint contractures (wrist, elbow, knee) (P = 0.008), and prednisone use at entry (P = 0.01). Baseline characteristics that did not predict SRC included age, sex, race, Health Assessment Questionnaire score, fist closure, handspread, lung involvement, muscle weakness, erythrocyte sedimentation rate, and platelet count. In 5 of 10 subjects for whom at least 2 sequential skin scores were available, skin scores increased significantly (P = 0.012) in the 6 months before onset of SRC. CONCLUSION: SRC occurred in 13% of patients soon (mean 11 months) after entry into the cohort. Predictors of SRC identified in this study included higher than average skin score, prednisone use at study entry, large joint contractures, and heart enlargement. Our data suggest, however, that low-dose prednisone alone was not associated with the onset of SRC, except in the appropriate clinical setting. Although ACE inhibitors and dialysis are now readily available, SRC continues to be associated with poor survival (in this study, 50% of patients with SRC died).