International consensus for a definition of disease flare in lupus.

The Lupus Foundation of America (LFA) convened an international working group to obtain a consensus definition of disease flare in lupus. With help from the Paediatric Rheumatology International Trials Organization (PRINTO), two web-based Delphi surveys of physicians were conducted. Subsequently, the LFA held a second consensus conference followed by a third Delphi survey to reach a community-wide agreement for flare definition. Sixty-nine of the 120 (57.5%) polled physicians responded to the first survey. Fifty-nine of the responses were available to draft 12 preliminary statements, which were circulated in the second survey. Eighty-seven of 118 (74%) physicians completed the second survey, with an agreement of 70% for 9/12 (75%) statements. During the second conference, three alternative flare definitions were consolidated and sent back to the international community. One hundred and sixteen of 146 (79.5%) responded, with agreement by 71/116 (61%) for the following definition: "A flare is a measurable increase in disease activity in one or more organ systems involving new or worse clinical signs and symptoms and/or laboratory measurements. It must be considered clinically significant by the assessor and usually there would be at least consideration of a change or an increase in treatment." The LFA proposes this definition for lupus flare on the basis of its high face validity.

Pre-treatment affinity for LJP 394 influences pharmacodynamic response in lupus patients.

Five prospective clinical studies in lupus patients have shown that LJP 394 can reduce circulating anti-dsDNA antibody levels without causing generalized immunosuppression. The compound is currently being evaluated in a phase III clinical trial for the prevention of renal flares in patients with high-affinity antibodies to LJP 394 and a history of lupus nephritis. The current study analyzed the affinity of patient IgG for LJP 394 prior to and following 4 months of treatment with LJP 394 to determine if pretreatment affinity influenced pharmacodynamic response. Patient serum samples from a multicenter, double-blind, placebo-controlled trial were evaluated prior to and following 4 months of weekly, biweekly or monthly treatment with placebo (n = 9) or weekly treatment with 10 mg LJP 394 (n = 6) or 50 mg LJP 394 (n = 4). After treatment there was a dose-dependent reduction in affinity in the 10 mg/week and 50 mg/week groups (P < 0.05 and P < 0.01, respectively), whereas the placebo group was unchanged. This study demonstrates that weekly treatment with LJP 394 produces a dose-dependent reduction in titer-weighted average affinity. These results suggest it may be possible to use an affinity assay to define prospectively patients that are most likely to exhibit the desired pharmacodynamic response to LJP 394.

Treatment of systemic lupus erythematosus with LJP 394.

OBJECTIVE: LJP 394 is a novel therapy under development for the treatment of systemic lupus erythematosus (SLE). We investigated the optimal LJP 394 dosing regimen required to maximally reduce serum dsDNA antibodies. We also evaluated the safety and tolerability of repeated doses of LJP 394 as well as the effects of therapy on SLE related disease activity and health related quality of life. METHODS: This was a multicenter, partially randomized, placebo controlled, double blind, dose-ranging trial. Study drug or placebo was administered at weekly, biweekly, or monthly intervals for a total of 17, 9, or 5 doses, respectively. Fifty-eight patients were randomly assigned to receive 1, 10, or 50 mg LJP 394 or placebo. After a 2 month pretreatment period, dosing visits continued for 16 weeks, after which there was a 2 month posttreatment period. RESULTS: The greatest reductions in mean dsDNA antibody titers were observed in the group of patients who received 50 mg LJP 394 weekly (38.1% and 37.1 % at Weeks 16 and 24, respectively). A reduction (29.3%) in dsDNA antibody titers was also observed at Week 24 in the group of patients who received 10 mg LJP 394 weekly. The frequencies of adverse events were comparable in the placebo and active treatment groups. CONCLUSION: This clinical trial, in which a large number of patients with SLE were treated with LJP 394, expanded the safety profile of LJP 394 and demonstrated its capacity to reduce dsDNA antibodies.

Hepatic angiosarcoma occurring after cyclophosphamide therapy: case report and review of the literature.

A 54-year-old man with polyarteritis nodosa developed acute onset of right upper quadrant abdominal pain associated with a large liver mass. Transvenous liver biopsy revealed hepatic angiosarcoma, a rare liver tumor classically associated with environmental toxins. He had been treated with oral cyclophosphamide for 13 years. A review of the literature revealed two other cases of hepatic angiosarcoma in patients after long-term cyclophosphamide treatment. We propose that cyclophosphamide be added to the list of exposures potentially associated with hepatic angiosarcoma.

A life skills approach to mathematics instruction: preparing students with learning disabilities for the real-life math demands of adulthood.

Current mathematics instruction does not address the day-to-day needs of many students with learning disabilities. Although the vast majority of students with learning disabilities are not college bound, much of mathematics instruction provides college preparation. Too often, classes in mathematics ignore the skills needed in home and community and on the job. The present article examines the ways in which general mathematics instruction, focused on daily living skills, can easily be integrated into the classrooms of students with learning disabilities.

Life skills curricula for students with learning disabilities: a review of the literature.

This article presents a review of the current literature on life skills curricula and instruction as they relate to students with learning disabilities. The review of life skills literature is organized into two sections: intervention and follow-up, follow-along studies. Based on the available research, several suggestions for designing research programs that address life skills curricula and instruction for students with learning disabilities are outlined.

Learning disabilities, employment discrimination, and the ADA.

The Americans with Disabilities Act (ADA) of 1990 was intended to prohibit discrimination against individuals with disabilities. Although the scope of this legislation is broad, there are aspects of Title I and Title II of the ADA that may be of particular interest to persons with learning disabilities who are preparing for employment. This article discusses those aspects and presents case studies to demonstrate how the ADA could potentially be applied to typical situations. Suggestions are given for individuals with learning disabilities, their parents, and teachers with regard to employment preparation in secondary and postsecondary settings.

Controlled trial of plasma exchange and leukapheresis in polymyositis and dermatomyositis.

BACKGROUND: The therapeutic options for patients with polymyositis or dermatomyositis that is resistant to corticosteroids are limited, unproved, and often toxic. Uncontrolled trials concluded that both plasma exchange and leukapheresis are beneficial, but despite the considerable use of these approaches, proof of their efficacy is lacking. METHODS: Thirty-nine patients with definite polymyositis or dermatomyositis were randomly assigned to receive plasma exchange (replacement of one volume of plasma with 5 percent albumin in saline), leukapheresis (removal of 5 x 10(9) to 10 x 10(9) lymphocytes), or sham apheresis in a double-blind manner, with 12 treatments given over a one-month period. Muscle strength, functional capacity, and serum levels of muscle-associated enzymes were measured before and after the 12 procedures. RESULTS: In each group 3 of 13 patients had improvements in strength and functional capacity. The condition of 3 patients treated with leukapheresis and 1 treated with plasma exchange deteriorated, and it was unchanged in the other 26 patients. Adverse effects of apheresis included the need for a central venous catheter (9 patients), major vasovagal episodes (3 patients), and severe citrate reactions (2 patients). Despite the occurrence of significant reductions in the serum levels of muscle enzymes with plasma exchange (P less than 0.001) and significant decreases in lymphocyte counts with leukapheresis (P = 0.002), there were no significant differences among the three treatment groups in the final muscle strength or functional capacity of the patients. CONCLUSIONS: As treatments for corticosteroid-resistant polymyositis or dermatomyositis, leukapheresis and plasma exchange are no more effective than sham apheresis.

Idiopathic inflammatory myopathies.

The idiopathic inflammatory myopathies are a heterogeneous group of uncommon diseases. The incidence rate of IIM is approximately 5 cases per million population, but there appears to be an increase in the rate over the last two decades, particularly in black females. This may be a true increase or due to renewed interest and awareness of the disease and improvement in our ability to diagnose mild disease. There has also been progress in decreasing the mortality rate in IIM perhaps secondary to better treatment and/or the diagnosis of mild disease. The discovery of anti-Jo-1 antibodies has renewed the investigation of a possible viral etiology of IIM. Studies of quantitative slot blot hybridization with coxsackievirus probes and RNA from IIM muscle biopsies and in situ hybridization of biopsies with a Theiler's virus probe have revealed a few positive hybridizations in each study. Although there are some fundamental problems with these studies, these intriguing results bear confirmation. These results continue to implicate picornaviruses as the primary suspects in the pathogenesis of IIM. HIV has now been associated with a number of rheumatologic syndromes, including a polymyositis that is indistinguishable from IIM, and we can expect additional changes in the epidemiology of this family of disorders in coming years. Study of these patients may provide insight into the etiopathogenesis of IIM.

WISC-R stability and re-evaluation of learning-disabled students.

This study investigated the temporal stability of WISC-R IQ scores for learning-disabled subjects (N = 113). All study subjects were administered the WISC-R for an initial evaluation (M age = 8 years, 3 months) and a follow-up re-evaluation (M age = 11 years, 7 months). Pearson product-moment correlations yielded coefficients that were considerably lower than those previously reported: r = .55, p less than .001 for the Verbal IQs; r = .63, p less than .001 for the Performance IQs; and r = .58, p less than .001 for the Full Scale IQs. Results of t-test analyses indicated that only the Verbal IQ scores were significantly different when the initial evaluation (M = 89.4) was compared to the re-evaluation (M = 85.3), p less than .001. The results suggest that the WISC-R may be less stable for the learning-disabled population than for other groups and that the average 3-year test-retest time lapse was an influential factor in the reduced reliability of this instrument.

The failure of intravenous cyclophosphamide therapy in refractory idiopathic inflammatory myopathy.

Eleven patients with idiopathic inflammatory myopathy refractory to treatment with corticosteroids and other immunosuppressive agents were treated with monthly intravenous cyclophosphamide (0.75-1.357 g/m2). Six patients completed a full course of 7 infusions at which point only one patient met predefined criteria for improvement in both strength and function. Five had modest improvement in strength but did not meet the criteria for improvement. All patients have subsequently required treatment with other medications. Major complications observed during therapy included serious infections in 2 patients (streptococcal endocarditis and disseminated Mycobacterium avium intracellulare) and death in one patient in which the contribution of cyclophosphamide cannot be excluded. We conclude that intravenous cyclophosphamide as used in our study cannot be recommended for the treatment of patients with refractory inflammatory myopathy.

Immunoglobulin deficiency in patients with systemic lupus erythematosus.

Hypergammaglobulinemia is a common laboratory finding in patients with active systemic lupus erythematosus; in contrast, immunoglobulin deficiency, except for immunoglobulin A, is unusual. We report 18 patients who developed low immunoglobulin G levels 4 months to 22 years (median = 4 years) following the diagnosis of systemic lupus erythematosus. This phenomenon was transient in 10 patients (median duration 10.5 months). Eight patients had received cytotoxic drugs prior to the development of hypogammaglobulinemia, while all had received prednisone. The nadir levels of serum IgG were 132-550 mg/dl (median = 363 mg/dl). The presence and degree of immunoglobulin G deficiency did not correlate, in general, with the type or dose of medication. None of the patients had renal failure. Only 4 patients developed recurrent infections. Urinary loss of protein was not a cause of this disorder. Study of the in vitro cellular immune responses of peripheral blood lymphocytes in 5 patients showed that excessive 'suppressor' T cell activity and decreased numbers of B cells may be responsible for the development of immunoglobulin deficiency. Serum immunoglobulin levels should not be employed as an indication of disease activity in systemic lupus erythematosus, as all 18 patients continued to have significant clinical disease. Deficiencies of immunoglobulins are often transient and may not require treatment.

Current concepts in the idiopathic inflammatory myopathies: polymyositis, dermatomyositis, and related disorders.

Idiopathic inflammatory myopathy, a category encompassing polymyositis, dermatomyositis, and a number of other disorders, is very uncommon, but has been the focus of intense study in the Arthritis and Rheumatism Branch of the National Institute of Arthritis and Musculoskeletal and Skin Diseases for the past several years. We describe the clinical picture, stressing the need for biopsy to ensure correct diagnosis. It is especially important to recognize the treatment-resistant variant, inclusion body myositis. The extraskeletal manifestations, particularly the cardiopulmonary, oropharyngeal, gastrointestinal, and endocrine involvement, are described. The cardiopulmonary involvement, especially interstitial lung disease, arrhythmias, and cardiac failure, may dominate the clinical picture. The known causes are varied, and include drugs, toxins, and some infectious agents, however, in most cases a cause cannot yet be identified. Circumstantial evidence suggests that picornaviruses may initiate some cases in humans, and a very similar disease in mice caused by a picornavirus is actively under study. Studies of autoantibodies and cellular immune function support a central role for disordered immunity in the pathogenesis. The myositis-specific autoantibodies, especially those directed at certain enzymes important in protein synthesis (the aminoacyl-transfer RNA synthetases), are found in a clinically distinct subset of patients. Although most patients respond initially to corticosteroids, cytotoxic drugs are sometimes added when steroid toxicity or refractoriness develops. We describe several newer therapies under study for such cases and outline future directions in research.

Simultaneous use of multiple serologic tests in assessing clinical activity in systemic lupus erythematosus.

Ten technics for quantifying and qualifying anti-DNA antibodies were correlated with manifestations of disease activity in sera from 27 patients with systemic lupus erythematosus (SLE) using both a simple and a stepwise regression. In the stepwise analysis, a panel consisting of four of these tests provided maximal correlation (r = 0.68) with clinical status. Low IgM anti-DNA was a significant correlate of nephritis in stepwise discriminant function analysis. Multivariate analysis can offer distinct advantages over simple correlation in understanding the role of serological abnormalities in disease expression in SLE.

A solid phase enzyme immunoassay (ELISA) for the detection and quantitation of anticardiolipin antibody.

A solid-phase enzyme-linked immunoabsorbent assay (ELISA) is described for the detection and quantitation of anticardiolipin antibodies (ACAs) IgG and IgM in sera. In these assays, non-specific binding was controlled by using antigen-negative wells for all serum dilutions tested. Quadruplicate 100-microliters serum samples diluted 1:20 for ACA-IgG and 1:40 for ACA-IgM were incubated for two hours, after which alkaline phosphatase-conjugated antihuman IgG or IgM was added. A standard serum was used on each plate to provide reproducibility of the assay. Upper limits of normal for ACA-IgG and IgM were established by testing 161 sera from normal persons. Sixty-one selected patients with SLE were tested; and, from these results, categories of positivity were defined from negative to 4+. All screen-positive sera (greater than or equal to 1+) were assayed in a quantitative ELISA assay for ACAs, using multiple dilutions of the unknowns. These data were fit on a standard curve generated with dilutions of a reference serum on each plate using a computerized data reduction system based on the 2 Plus 2 model. The standard curves were compared with the international standards for IgG and IgM anticardiolipin. The ability to quantitate ACA concentrations allows better definition of positive sera, as well as the opportunity to accurately evaluate and follow this antibody in a variety of patient groups.

The natural history of encephalomyocarditis virus-induced myositis and myocarditis in mice. Viral persistence demonstrated by in situ hybridization.

Picornaviruses can initiate chronic inflammation that persists after the virus can no longer be cultured from inflamed tissues. In an attempt to understand this transition we have sought evidence for viral persistence by methods that detect viral genome independent of whether or not whole competent virus is present. In mice infected with a myotropic variant of encephalomyocarditis virus, EMC-221A, virus can be cultured in high yield at 1 wk and in low yield at 2 wk from skeletal muscle, heart, and brain; a small number of plaque-forming units could be cultured from brain at 4 wk. By contrast, in situ hybridization detected viral nucleic acid at least a week or two thereafter, often in single cells. In the skeletal muscle, inflammation disappeared by 3 wk, but in heart it remained for the full 12 wk of observation. In the brain, microglial nodules, sometimes with associated viral nucleic acid, were present for a long period. Application of this technique allows a more accurate assessment of the role of viral persistence in the pathogenesis of virus-initiated but apparently autoimmune inflammation.

Musculoskeletal manifestations of systemic lupus erythematosus.

The musculoskeletal system is involved in nearly all patients with SLE. Transient arthralgias or arthritis are common and, in some patients, there is a progression to rheumatoid-like nonerosive hand deformities (Jaccoud's syndrome). The major disabling type of joint disease in lupus is articular osteonecrosis, often induced by high-dose corticosteroids. Rare forms of musculoskeletal manifestations of lupus include spontaneous tendon rupture, crystalline arthropathies, subcutaneous calcifications, and inflammatory myopathy.

IgG and IgM anticardiolipin antibodies in patients with lupus with anticardiolipin antibody associated clinical syndromes.

IgG and IgM anticardiolipin antibodies (aCL) were measured by a solid phase enzyme immunoassay in 64 patients with systemic lupus erythematosus who had one or more clinical disorders reported to be associated with aCL. We found the presence of IgG aCL was significantly associated with an increased incidence of cerebrovascular disease (p less than 0.01), a positive Venereal Disease Research Laboratories (VDRL) test (p less than 0.02) and prolonged partial thromboplastin time (PTT) (p less than 0.001). IgM aCL were associated with recurrent spontaneous abortion (p less than 0.05), thrombocytopenia (p less than 0.05) as well as a positive VDRL and prolonged PTT. The combination of high titer IgG and IgM aCL was associated with endocardial disease (p = 0.02), migraine (p less than 0.02), in addition to fetal loss (p less than 0.001).

Abnormalities of the immune system in the idiopathic inflammatory myopathies.

This brief report reviews some of the major studies presenting evidence for altered humoral and cellular immunity in the idiopathic inflammatory myopathies. Clearly, the association of these disorders with other autoimmune diseases, the myriad of myositis-associated autoantibodies, and the phenotypic and functional abnormalities of mononuclear cells from PM/DM patients, all suggest that autoimmune mechanisms are central and pervasive aspects of these diseases. Yet, the current experimental limitations in immunology, as well as the rarity and heterogeneity of the idiopathic inflammatory myopathies, combine to limit our understanding of which factors are primary, and which are only secondary epiphenomena, in the complex pathogenesis of these disorders.