A series of patients on anti-TNF therapy referred to a multidisciplinary lung cancer service.

BACKGROUND: Biological therapies have significantly improved the quality of life of patients with aggressive collagen vascular diseases. Blocking TNF activity may potentially confer a higher malignant potential for patients. AIMS: To identify patients to whom anti-TNF therapies were recently prescribed and were referred to a multidisciplinary lung cancer service. METHODS: Retrospective review of patients over an 18-month period who were referred to a multidisciplinary lung cancer service. RESULTS: Three patients who underwent recent anti-TNF therapies and presented with solid organ tumours. All had significant additional risks for cancer including smoking and family history and active connective tissue diseases with a past history of immunosuppressive therapies. CONCLUSIONS: Our series highlights the potential malignant risk of anti-TNF theraphy to a general medical audience.

Is the development of drug-related lupus a contraindication for switching from one TNF alpha inhibitor to another?

The use of TNF alpha (TNFalpha) inhibitors has made a strong impact on the management of rheumatoid and psoriatic arthritis, ankylosing spondylitis and Crohn disease. Side effects of these agents include the development of autoantibodies and a lupus-like syndrome (drug-related lupus, DRL). Here, a case of a patient who developed DRL while receiving infliximab therapy which resolved spontaneously upon discontinuation of the agent and did not recur with subsequent institution of adalimumab is described. A discussion on the possible pathogenic mechanisms involved in the development of drug-related autoimmunity and differences between the agents is also included.

Disease outcomes and ovarian function of childhood-onset systemic lupus erythematosus.

The objective of this study was to determine the medical outcomes including the ovarian function childhood-onset SLE (cSLE). The medical records of all patients diagnosed with cSLE in the Greater Cincinnati area between 1981 and 2002 were reviewed. Patient interviews were performed to obtain additional information on current medication regimens, disease activity [SLE Disease Activity Index (SLEDAI-2k)], and damage [Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI)]. The occurence of premature ovarian failure (POF) and reduction of the ovarian reserve was assessed by timed gonadotropin levels. There were 77 patients (F : M = 70 : 7, 53% Caucasian, 45% African-American and 2% Asian) with a mean age at diagnosis of 14.6 years. Nine patients died (88.3% survival) during the mean follow-up of 7.1 years (standard deviation [SD] 5.6) and 88% of the patients continued to have active disease (SLEDAI-2k mean/SD: 6.6/6.7), with 42% of them having disease damage (SDI mean/SD: 1.62/2.1); Non-Caucasian patients had higher disease activity (mean SLEDAI-2k: 10 versus 3.4; P < 0.0001) and more disease damage (mean SDI : 2.1 versus 1.2; P < 0.02) than Caucasian patients. Cyclophosphamide was given to 47% of the patients during the course of their disease and associated with the presence of significantly reduced ovarian reserve (RR = 2.8; 95% CI: 1.7-4.8; P = 0.026). Patient mortality and disease damage with cSLE continue to be high. Although overt POF with cyclophosphamide exposure is rare, it is a risk factor for significantly decreased ovarian reserve cSLE.

In vitro production of antibodies to histones in patients receiving chronic procainamide therapy.

OBJECTIVE: Procainamide related autoimmunity is characterized by the production of antibodies to histones and, in particular, to the H2A-2B dimer. We evaluated in vitro production of antibodies to total histones and the H2A-2B dimer by peripheral blood mononuclear cells (PBMC) from patients chronically exposed to procainamide and related this to in vivo production, and assessed possible immunostimulatory response by the postulated reactive metabolite procainamide hydroxylamine (PAHA) using PAHA conjugated autologous erythrocytes. METHODS: We evaluated in vitro spontaneous and mitogen induced production of histone antibodies by PBMC from 26 asymptomatic patients, who were chronically receiving procainamide, in the presence and absence of PAHA conjugated autologous erythrocytes. Correlations with in vivo production were sought. RESULTS: PBMC from 9 patients revealed significant spontaneous production of histone antibodies, of whom 2 developed procainamide related lupus within 2 mo of the evaluation. There was a significant increase in in vitro production of antibodies to total histones by PBMC that had been cultured in the presence of PAHA-autologous erythrocyte conjugates, but in the absence of mitogens, from 15 (65%) of 23 patients, and of antibodies to H2A-2B by cells from 10 (42%) of 24 patients. Patients' cells that were co-cultured with PAHA-erythrocyte conjugates produced significantly greater amounts of antibodies to both total histones (p = 0.03) and the H2A-2B dimer (p = 0.009) compared with those cultured alone. Co-culture with similarly pretreated erythrocytes also resulted in a significant increase in the production of antibodies to total histones (p < 0.001), but not to the H2A-H2B dimer, by cells from controls. CONCLUSION: Some patients receiving chronic procainamide therapy have spontaneous production of histone antibodies. Co-culture with PAHA-erythrocyte conjugates resulted in significantly greater production, suggesting an immunomodulating effect by this metabolite.

Unusual presentation of polyarteritis nodosa.

We describe an unusual presentation of a localized form of polyarteritis nodosa (PAN) manifested by acute onset of severe calf pain. Biopsies of the gastrocnemius muscle and fascia revealed an acute necrotizing arteritis with fasciitis. The lumens of affected vessels were occluded by thrombi. PAN localized to calf muscles is extremely rare. To our knowledge this is the first report of evidence of fascial involvement believed to contribute to the severity of the clinical features of PAN. The occurrence of multiple intraluminal thrombi in conjunction with anticardiolipin antibodies suggested the possibility of a coexisting coagulopathy, and they were also likely contributors to the severity of the pain.

Acetylation status is associated with serological changes but not clinically significant disease in patients receiving procainamide.

OBJECTIVE: Autoantibodies occur in the majority of patients receiving procainamide (PA) for more than one year. Slow acetylator status has been proposed to predispose to their development. We previously reported the results of serological evaluation of 52 asymptomatic patients receiving PA. The aims of this study were to follow these patients to determine the incidence of drug related lupus (DRL) and serologic changes in patients receiving longterm PA therapy; and to evaluate the possible effect of acetylator status on the development of PA autoimmunity. METHODS: Fifty-two patients receiving PA were reevaluated after a mean of 31.5 months. Antinuclear antibodies and antibodies to histones, dsDNA, and polyadenylic acid (PolyA) were assayed. Acetylator status was determined by phenotyping and genotyping methods. Five additional patients referred with a diagnosis of DRL were also evaluated. RESULTS: Autoantibodies were detected in the majority of patients still receiving PA and in some patients in whom PA had been discontinued. Slow acetylator status correlated with IgG antibodies to the H2A-2B dimer complex. Acetylator status did not correlate with PA dose. Seven of the 9 patients with PA related lupus were fast acetylators. CONCLUSION: Most patients receiving PA have autoantibodies that may persist after discontinuation of PA. Despite persistently high frequency of autoantibodies the majority of these patients did not develop DRL. Slow acetylator status correlated with IgG antibodies to H2A-2B but was not a risk factor for the development of PA related lupus.

Genetic and immunologic studies of patients on procainamide.

Forty (40) patients with cardiac arrhythmias receiving procainamide (PA) therapy and 24 patients who were receiving other drugs for their cardiac disorders were investigated for class II HLA phenotypes and their DRB1*04 and DQB1*03 subtypes. Other genetic marker evaluations in the PA patients included: 1) class III MHC C4A and C4B null alleles of complement; and, 2) acetylation phenotype. Twenty (20) of the PA patients were also tested for the ability of their stimulated cells to secrete Interleukin-1 (IL-1 beta) and tumor necrosis factor (TNF alpha). We also examined the spontaneous production of these cytokines by peripheral blood leukocytes (PBL) from patients who were receiving chronic PA treatment. The results revealed no association of acetylation phenotypes with the class II HLA phenotypes nor class III MHC C4 allotypes in these patients. The results did show a significant increase in class III C4 complement allotypes in the PA patients when compared to the controls. The results also showed a significant increase in autoantibodies and DQw3 phenotypes in the PA patient group when compared to control populations. Results of spontaneous IL-1 and TNF production suggested there may be an association of select class II HLA phenotypes in some patients and this may be relevant to host responsiveness to PA treatment.

High prevalence of antiphospholipid antibodies in patients taking procainamide.

OBJECTIVE: To determine whether antiphospholipid antibodies (aPL) are more prevalent in cardiac patients taking procainamide than in a control population of similar elderly cardiac patients and to determine whether these antibodies react in an ELISA in which the primary antigen is beta 2-glycoprotein I (beta 2-GPI). METHODS: aPL and antibodies to beta 2-GPI were measured in 66 patients taking procainamide from a Veterans Administration Medical Center population and a control group of 30 similar cardiac patients not taking procainamide. RESULTS: 21% of the patients taking procainamide and no control patients were found to have moderate to high aPL. There were similar results in an assay that measured anti-beta 2-GPI in the absence of exogenous phospholipids. aPL were associated with antinuclear antibodies and antihistone antibodies but not with diabetes or clinical manifestations of drug related lupus. There was no increase in cholesterol or past thrombotic history associated with aPL, but there was a frequent history of noncardiac thrombosis in patients taking procainamide (25.7%). CONCLUSION: The predictive significance of procainamide induced aPL remains unknown but beta 2-GPI dependent aPL may be of some concern in this elderly population already at high risk for thrombosis.

Role of genetic factors in drug-related autoimmunity.

Although there is evidence to suggest that genetic factors play a major role in the pathogenesis of many of the rheumatic diseases, far less is known of their role in the induction and expression of human autoimmunity resulting from long-term exposure to drugs, chemicals and environmental agents. Pharmacogenetic factors represent an important source of interindividual variation in response to drugs; most research to date has focused on genetic polymorphism of drug metabolism via N-acetylation, S-methylation or cytochrome P-450-catalyzed oxidation. In drug-related autoimmunity, there is limited evidence that the host's genetic background plays a major role beyond the expression of autoantibodies. More recent prospective studies have concentrated on the association of MHC-genes in the expression of autoimmunity and the susceptibility of patients to develop drug-related clinical syndromes.

A prospective study of neurophysiologic, neurologic and immunologic abnormalities in systemic lupus erythematosus.

OBJECTIVE: To describe neurologic and neurophysiologic (NP) outcome in patients with systemic lupus erythematosus (SLE) followed prospectively and to determine predictors of change in NP status. METHODS: Clinical examination, laboratory and NP tests (brain stem auditory and visual evoked responses, peripheral nerve conduction studies) were performed in 18 unselected patients with SLE attending a general rheumatology clinic at enrollment into the study (baseline) and after a 2-year (mean) period of followup. RESULTS: Fifty percent (9/18) and 83% (15/18) of patients had neurological abnormalities at baseline and followup, respectively, the most common of which were headache and peripheral neuropathy. NP abnormalities were found in 56% (10/18) and 61% (11/18) of patients at baseline and followup. The most frequent abnormalities at both visits were of peripheral nerve conduction [33% (6/18) and 56% (10/18), respectively] and abnormalities of brainstem and/or visual evoked responses were found in 28% (5/18) and 22% (4/18) of patients at both visits. At baseline, vasculitis was significantly increased in patients with NP abnormalities (p = 0.04). NP status deteriorated between visits in 8 patients (44%), 6 of whom acquired peripheral abnormalities. Improvement in NP status was only noted in patients (2/18, 11%) who had NP abnormalities restricted to the central nervous system. Associations were seen between elevated dsDNA antibodies, vasculitis, and lymphopenia, and the risk of acquiring new NP abnormalities. CONCLUSION: Patients with SLE had many neurological and NP abnormalities. NP deficits acquired were most often of peripheral nerve conduction. The ability to identify and classify clinical and subclinical neurological abnormalities in patients with SLE using NP tests may enhance our understanding and management of their neurological disease.

Genetic, immunologic and biotransformation studies of patients on procainamide.

This report represents follow-up observations of a unique long-term study of patients on procainamide (PA) for various cardiac arrhythmias. Serologic and clinical evaluations associated with drug-related autoimmunity were assessed and patients were characterized for factors postulated to influence susceptibility to autoimmunity, including acetylator phenotype, oxidative metabolism of PA, HLA class profile, and production of interleukin-1 (IL-1) and tumor necrosis factor (TNF). Fifty-two percent had IgM and 70% IgG antibodies to total histones; 67% had IgG antibodies to histone H2A/H2B. Patients were equally divided between fast and slow acetylators. N-oxidative metabolism of PA was indicated by the presence of urinary nitroprocainamide, which correlated with elevated titers of antihistone antibodies. There was a significant incidence of the DQw7 split of DQw3 in PA patients when compared to controls, and the frequency of antibodies to total histones and H2A/H2B was significantly increased in the DQw7 patients. C4A*QO and C4B*QO alleles were more frequent in the PA patients than in controls. IL-1 and TNF production was not different in patients compared to controls. These data suggest that certain genetic factors may serve as markers for PA-related autoimmunity.

Serologic evaluation of patients receiving procainamide.

This controlled study examined the characteristics of serologic abnormalities in 52 patients receiving procainamide for cardiac arrhythmias, who had no symptoms of a connective tissue disease. Antinuclear antibodies occurred in 43 patients (83%). Significant elevation of antibody binding to single-stranded DNA (mean +/- SEM 30 +/- 2.6%), double-stranded DNA (13 +/- 1.1%), Z-DNA (optical density 0.54 +/- 0.06), and poly A (7.2 +/- 0.6%) was seen (P less than 0.001). Thirty-four patients (65.4%) had antibodies to total histones, most frequently, the H2A/2B dimer. IgG antibodies to H2A/2B correlated with the cumulative procainamide dose. One patient subsequently developed drug-related lupus.

Determination of metabolically derived nitroprocainamide in the urine of procainamide-dosed humans and rats by liquid chromatography with electrochemical detection.

The N-oxidized metabolites of the antiarrhythmic procainamide have previously been implicated as inciting agents in the autoimmune condition drug-related lupus. Although much data have been collected with respect to the in vitro behavior of these metabolites, relatively little has been accomplished in vivo because of their extreme reactivity. The determination of nitroprocainamide (NPA), a stable decomposition product of the reactive hydroxylamine and nitroso species, in the urine of rats dosed with procainamide is reported here using the sensitive and selective method of HPLC with electrochemical detection. For orally and i.v.-dosed animals, up to microgram amounts of NPA were excreted over 24 hr from an initial dose of 66-100 mg procainamide/kg body weight. Also, the apparent elimination of microgram quantities of NPA in the urine specimens of 9 of 11 patients undergoing treatment with procainamide was observed. This suggests that N-oxidation of the aromatic ring of procainamide is occurring at sufficient levels to result in the formation of significant amounts of the reactive hydroxylamine and nitroso metabolites in vivo, and may have direct implications in the diverse and widespread symptomatology associated with procainamide-induced drug-related lupus.