Serologic changes during induction of lupus-like disease by procainamide

Procainamide-induced lupus is a well-recognized syndrome, but the events leading up to clinical symptoms are obscure. In the present study, serologic changes in a 69-year-old man were monitored during his treatment with procainamide and after discontinuation of procainamide because of symptoms of drug-induced lupus. Antihistone antibodies of unique specificity and in vivo complement activation were detected after one year of procainamide therapy during a period prior to development of significant clinical symptoms. Antihistone antibodies and complement activation substantially increased during a full-blown episode of lupus-like symptoms. Progressive return to normal laboratory findings occurred after procainamide was discontinued. The antihistone/complement profile may be useful in the diagnosis of drug-induced lupus and warn of impending clinical deterioration in patients with minimal symptoms.     

Antibodies to cytoplasmic antigens in lupus erythematosus

Seven patients with classic cutaneous lupus ery-thematosus are described. Three of these patients had features satisfying four of the American Rheumatism Association (ARA) preliminary criteria for the diagnosis of systemic lupus erythematosus (SLE). Their sera, however, lacked antinuclear antibodies but demonstrated precipitating antibodies reactive against cytoplasmic RNP (La) and non-nucleic acid (Ro) antigens. Four additional ANA-negative patients lacking significant skin disease but having a lupus-like multisystem disease were found to have antibodies to soluble cytoplasmic antigens. Thirty-three of 130 ANA-positive SLE patients, but none of 16 discoid lupus patients, possessed these anticytoplasmic antibodies. These findings suggest that antibodies to Ro and La may be a marker for systemic disease in ANA-negative patients with 1) cutaneous lupus and 2) a distinct sub-population of patients with a lupus-like syndrome without skin disease.     

Transverse myelitis as the first manifestation of systemic lupus erythematosus or lupus-like disease: good functional outcome and relevance of antiphospholipid antibodies

OBJECTIVE: Transverse myelitis (TM) is a rare complication of systemic lupus erythematosus (SLE). Although usually a late manifestation of SLE, it can occur at presentation. We investigated the clinical presentation, treatment and outcome of 15 patients with TM as the presenting manifestation of SLE or lupus-like disease. METHODS: All patients received corticosteroids, while 13 also received immunosuppressive therapy. Five patients were fully anticoagulated with warfarin. RESULTS: A sensory level with spastic lower limb weakness and sphincter disturbance was the most common presentation: 14/15 patients had a thoracic or cervical sensory level. Cerebrospinal fluid examination showed high protein concentrations in 3 patients and oligoclonal bands in 8. Eleven of the 15 (73%) had antiphospholipid antibodies (aPL). Of the 15 patients, 3 had complete resolution of the symptoms, 6 had good functional improvements, 5 had good to fair outcome with some functional deficit, and one patient who received corticosteroids alone later died from pneumonia. CONCLUSION: We describe 15 patients with TM as the presenting manifestation of SLE or lupus-like disease with a high prevalence of aPL. Our data support the view that early diagnosis and immunosuppressive therapy may be superior to corticosteroids alone in improving functional outcome. In those patients with aPL, antiplatelet agents and/or warfarin should also be considered.     

Lymphocytotoxic antibodies in systemic lupus erythematosus and clinically related diseases.

Sera from patients with systemic lupus erythematosus (SLE) and clinically related diseases were examined for cold-reactive lymphocytotoxic antibodies (LCA). The incidence of LCA was significantly increased in SLE (93%), discoid lupus (50%), and "lupus-like" syndromes associated with congenital complement deficiencies (63%) as compared to normal controls (3%) and patients with drug-induced lupus (11%), mixed connective tissue disease (MCTD) (17%), and necrotizing vasculitis (19%). The diagnostic and pathogenetic implications of these differences are discussed.     

Pulmonary silicosis and disseminated lupus erythematosus

In a 59-year old sand-blaster, histologically proven silicosis was complicated by systemic lupus erythematosus (SLE) and focal glomerulonephritis with IgG, IgA and ClQ deposits. Nothing likely to facilitate SLE was detected by investigating the familial background, the HLA phenotype and the complement system. This type of SLE differs from drug-induced lupus-like syndromes by a high level of anti-double helix DNA antibodies and by the renal lesions observed. The connection between silicosis and SLE lies in changes in humoral immunity, i.e. polyclonal activation and production of antinuclear antibodies. A decrease in the number of suppressor T-cells may also be held responsible.     

The "primary" antiphospholipid syndrome: major clinical and serological features

The antiphospholipid syndrome--the association of venous and/or arterial thromboses, often accompanied by thrombocytopenia in the presence of the antiphospholipid antibodies ("lupus anticoagulant" antibodies to cardiolipin)--is seen mainly in patients with systemic lupus erythematosus (SLE) and the closely related "lupus-like" disease, i.e., lupus patients not conforming to the 1982 revised American Rheumatism Association classification for SLE. It is also seen in a group of patients who do not manifest any of the major clinical or serologic features of SLE, the majority of whom do not appear to progress to classical lupus. A multicenter study of 70 of these patients is documented and their major clinical and serologic characteristics examined: They have been characterized as suffering from a "primary" antiphospholipid syndrome and present typically with a history of deep vein thromboses, often accompanied by pulmonary thromboembolism, which in a few is complicated by thromboembolic pulmonary hypertension, arterial occlusions (most commonly strokes), or fetal loss. The events are often recurrent and may be accompanied by hemocytopenias (thrombocytopenia and less frequently Coombs positivity and/or hemolytic anemia). They are often antinuclear antibody-negative and are always negative for antibodies to dsDNA and to ENA, typical serologic features of SLE. There may be a family history of SLE or a familial clotting tendency in a minority. The group of patients presented appears to be closely related, but distinctly separate from SLE.     

Drug-induced lupus erythematosus

Drug-induced lupus is a syndrome which share symptoms and laboratory characteristics with the idiopathic systemic lupus erythematosus (SLE). The list of medications implicated as etiologic agents in drug-induced lupus continues to grow. The terms used for this condition are lupus-like syndrome, drug-induced lupus erythematosus (DILE) and drug related lupus. More than 80 drugs have been associated with DILE. The first case of DILE was reported in 1945 and associated with sulfadiazin. In 1953 it was reported that DILE was related to the use of hydralazine. Drugs responsible for the development of DILE can divided into three groups, but the list of these drugs is quite long because new drugs are included yearly in the list. The syndrome is characterised by arthralgia, myalgia, pleurisy, rash and fever in association with antinuclear antibodies in the serum. Recognition of DILE is important because it usually reverts within a few weeks after stopping the drug.     

SULPHASALAZINE-INDUCED AUTOIMMUNE ABNORMALITIES IN PATIENTS WITH RHEUMATIC DISEASE

Sulphasalazine is a commonly used second line agent in rheumatoidarthritis (RA) and other inflammatory joint diseases and isreported to be one of the least toxic of this group of drugs.Recently a severe allergic reaction and cases of lupus-likedisease have been described in patients with RA after treatmentwith sulphasalazine. We describe five patients, all with inflammatoryarthropathy who developed cutaneous vasculitis, lupus-like diseaseor atypical serology after exposure to sulphasalazine. Threeof four cases investigated were found to have the slow acetylatorphenotype. These reactions can complicate the diagnosis anddelay discontinuation of the drug. Moreover, present guidelinesfor the diagnosis of drug-induced lupus do not apply to themajority of patients with sulphasalazine-induced lupus. KEY WORDS: Sulphasalazine-induced lupus, Rheumatoid arthritis, dsDNA antibodies, Vasculitis     

Drug-induced systemic lupus erythematosus associated with etanercept therapy

Specific antagonists of tumour necrosis factor (TNF)-alpha have rapidly gained popularity for the treatment of rheumatoid arthritis. The monoclonal antibody against TNF-alpha, infliximab, has been associated with induction of systemic lupus erythematosus (SLE); however, there have been no published reports of drug-induced SLE associated with the soluble TNF-alpha receptor etanercept. We describe four female patients who developed signs and symptoms of SLE during treatment with etanercept; in two SLE was unambiguous. On diagnosis of SLE, etanercept was discontinued and the SLE-related symptoms promptly resolved. Etanercept should be considered in the list of agents associated with drug-induced SLE.     

Anti-SSA/Ro and anti-SSB/La antibodies. What's new?

Anti-SSA/Ro and anti-SSB/La autoantibodies recognize different epitopes on polypeptides associated with small RNAs called scYRNA situated mostly in the cytoplasmic compartment (70%) and few in the nuclear compartment (30%). These hYRNPs (h=human) can be found on the cytoplasmic membrane or in small blebs during apoptosis after various stimuli such as UVB, 17-beta-estradiol, viral infection, TNF alpha and other cellular apoptosis inducing molecules. At least two major different proteins are called SSA/Ro: a 52 kDa Ro (with two subtypes alpha and beta) and a 60 kDa Ro. There is only one SSB/La protein of 48 kDa. In some circumstances, other proteins such as calreticuline (MW 57 kDa) join Ro/SSA proteins on some YRNAs. Anti-SSA/Ro antibodies are detected in the sera of 30% of patients with SLE, even during preclinical setting; anti-Ro/SSA are strongly associated (90%) with some subtypes of SLE such as old-onset (>50 y) SLE, subacute lupus erythematosus, drug-induced subacute lupus erythematosus and in patients with hereditary C2 or C4 or C1q deficiency with lupus or lupus-like disease. Anti-SSA/Ro are also associated with primary Sj?gren syndrome (50% to 60%) and with undifferenciated connective tissue disease (UCTD). Anti-SSA/Ro antibodies are almost always present in sera of mothers with babies with neonatal lupus syndrome (NNL) and with complete congenital heart block (CCHB). This last event is very unusual in pregnant patients with anti-Ro/SSA antibodies (1% to 2% of primigeste women). Some good evidences such as experimental models in vitro or ex-vivo, argue for the responsibility of maternal anti-Ro/SSA 52 kDa and/or anti-La/SSB antibodies (or associated IgG antibodies) as major etiologic factor of CCHB and NNL. IgG anti-Ro 52 beta kDa has been shown able to interrupt the atrioventricular conduction as well as the L calcium channel influx of fetal cardiocytes. Other factors must be taken into account to explain discordant twins (with and without CCHB). More recently anti-Ro/SSA antibodies were associated with QT interval prolongation in newborns without CCHB.     

Challenge of liver disease in systemic lupus erythematosus:Clues for diagnosis and hints for pathogenesis

Systemic lupus erythematosus(SLE) encompass a broad spectrum of liver diseases. We propose here to classify them as follows:(1) immunological comorbilities(overlap syndromes);(2) non-immunological comorbilities associated to SLE; and(3) a putative liver damage induced by SLE itself, referred to as "lupus hepatitis". In the first group, liver injury can be ascribed to overlapping hepatopathies triggered by autoimmune mechanisms other than SLE occurring with higher incidence in the context of lupus(e.g., autoimmune hepatitis, primary biliary cirrhosis). The second group includes non-autoimmune liver diseases, such as esteatosis, hepatitis C, hypercoagulation state-related liver lesions, hyperplasic parenchymal and vascular lesions, porphyria cutanea tarda, and drug-induced hepatotoxicity. Finally, the data in the literature to support the existence of a hepatic disease produced by SLE itself, or the occurrence of a SLE-associated prone condition that increases susceptibility to acquire other liver diseases, is critically discussed. The pathological mechanisms underlying each of these liver disorders are also reviewed. Despite the high heterogeneity in the literature regarding the prevalence of SLE-associated liver diseases and, in most cases, lack of histopathological evidence or clinical studies large enough to support their existence, it is becoming increasingly apparent that liver is an important target of SLE. Consequently, biochemical liver tests should be routinely carried out in SLE patients to discard liver disorders, particularly in those patients chronically exposed to potentially hepatotoxic drugs. Diagnosing liver disease in SLE patients is always challenging, and the systematization of the current information carried out in this review is expected to be of help both to attain a better understanding of pathogenesis and to build an appropriate work-up for diagnosis.     

Drug-Induced Glomerular Disease: Immune-Mediated Injury

Drug-induced autoimmune disease was initially described decades ago, with reports of vasculitis and a lupus-like syndrome in patients taking hydralazine, procainamide, and sulfadiazine. Over the years, multiple other agents have been linked to immune-mediated glomerular disease, often with associated autoantibody formation. Certain clinical and laboratory features may distinguish these entities from their idiopathic counterparts, and making this distinction is important in the diagnosis and management of these patients. Here, drug-induced, ANCA-associated vasculitis, drug-induced lupus, and drug-associated membranous nephropathy are reviewed.     

The effect of TNFalpha blockade on the antinuclear antibody profile in patients with chronic arthritis: biological and clinical implications

Since the first proof of efficacy of TNFalpha blockade, both the number of patients treated worldwide and the number of indications for treatment with TNFalpha blockers have grown steadily. Surprisingly, the profound immunomodulation induced by anti-TNFalpha therapy is associated with a relatively low incidence of immune-related complications such as lupus-like syndromes and demyelinating disease. This contrasts sharply with the prominent induction of autoantibodies such as antinuclear antibodies (ANA) and anti-dsDNA antibodies during TNFalpha blockade. Although this phenomenon has been recognized for several years, the clinical and biological implications are not yet fully understood. In this review, recent studies analysing the effect of TNFalpha blockade (infliximab and etanercept) on the ANA profile in autoimmune arthritis will be discussed. Taken together, these reports indicate that the prominent ANA and anti-dsDNA autoantibody response is 1) not a pure class effect of TNFalpha blockers, 2) independent of the disease background, 3) largely restricted to the induction of short-term IgM anti-dsDNA antibodies, and 4) not associated with other serological or clinically relevant signs of lupus. Nevertheless, a careful follow-up of patients treated with TNFalpha blockers remains mandatory, including monitoring for lupus-like characteristics.     

Lupus anticoagulant: correlation with magnetic resonance imaging of brain lesions.

Brain magnetic resonance imaging (MRI) was performed in 21 patients with systemic lupus erythematosus (SLE) with and without lupus anticoagulant (LAC), one lupus-like patient and 5 patients with primary antiphospholipid antibody syndrome. Thirteen patients had white matter focal brain lesions on MRI, 10 of whom had LAC (p = 0.03). We found no correlation between these lesions and neurologic manifestations, nor any clinical or serologic indices of activity of SLE. Our MRI lesions were similar to those described in multiple sclerosis and may indicate a similar pathologic process.     

The prevalence and clinical associations of the lupus anticoagulant in systemic lupus erythematosus

To determine the prevalence and clinical associations of the lupus anticoagulant (LAC) in patients with systemic lupus erythematosus (SLE), we studied 74 patients with SLE, 6 with lupus-like disease and a heterogeneous group of 45 patients with various autoimmune diseases. LAC was demonstrated in 19 SLE patients (26%), 5 patients with lupus-like disease (83%) and in none of the other patients. Statistically significant associations were found between LAC and a history of thromboembolic events (p less than 0.001), fetal loss (p less than 0.001), thrombocytopenia (p less than 0.01), biologically false-positive VDRL test (p less than 0.02) and convulsions (p less than 0.05). A negative correlation was found between LAC and a history of butterfly rash (p less than 0.01) and the presence of antibodies against extractable nuclear antigen (p less than 0.01). No significant difference was found between LAC-negative SLE patients and patients with other autoimmune diseases with respect to the prevalence of thromboembolic events or fetal loss. We conclude that LAC is a useful marker to identify a subset of patients with SLE or lupus-like disease at risk of thromboembolic events, fetal wastage, and thrombocytopenia.     

Cerebrovascular disease and antiphospholipid antibodies in systemic lupus erythematosus, lupus-like disease, and the primary antiphospholipid syndrome

PURPOSE AND PATIENTS AND METHODS: Antiphospholipid antibodies, lupus anticoagulant antibodies to cardiolipin, and a false-positive result on testing for syphilis have been linked to thrombotic vascular occlusions, particularly in patients with systemic lupus erythematosus (SLE) or lupus-like disease, i.e., patients not fulfilling four American Rheumatism Association criteria for the classification of SLE. The clinical and serologic features of 35 patients with cerebrovascular disease (strokes/transient ischemic attacks) who demonstrated antibodies to phospholipids are presented. Complete histories were obtained from all 35 patients, and all underwent routine physical examinations, radiography, electrocardiography, computed tomographic brain scanning, and immunologic studies. Psychometric tests were performed in nine patients. RESULTS: The strokes were often multiple and were followed by multi-infarct dementia in nine patients. Of particular interest were 10 patients in whom the presence of antiphospholipid antibodies was the major and often the sole immunologic disturbance present. Several of these patients were antinuclear antibody-negative, and the antinuclear antibodies, when present, were usually of a low titer (1:40 to 1:160). These patients conform to a group classified as having a primary antiphospholipid syndrome. CONCLUSION: Antiphospholipid antibodies are strongly associated with cerebrovascular occlusions in patients with SLE as well as in those with lupus-like disease and the primary antiphospholipid syndrome. All patients with any of these conditions who present with vascular events should be screened for these antibodies, as their occurrence may have a bearing on future therapy.     

Lymphocyte apoptosis in systemic lupus erythematosus: relationships with Fas expression, serum soluble Fas and disease activity.

Lupus specific autoantigens are exposed on apoptotic cells. The increased number of apoptotic lymphocytes reported in systemic lupus erythematosus (SLE) may be attributable to abnormalities of lymphocyte Fas expression or serum soluble Fas. In the present study we analysed the count of circulating apoptotic lymphocytes in SLE patients (n=50), by flow cytometry using Annexin V, compared to rheumatoid arthritis patients (RA, n=20), inflammatory bowel disease patients (IBD, n=20) and normal controls (n=20). Lymphocyte Fas expression and serum soluble Fas were measured and related to numbers of apoptotic lymphocytes. The percentage of apoptotic lymphocytes, determined by Annexin V binding, was significantly increased in peripheral blood of SLE patients (median=4.2%) compared with normal healthy donors (median=1.1%) and IBD patients (median=2. 0%) but not RA (median=3.9%). SLE lymphocyte Fas expression was not significantly different from RA or IBD patients. Serum soluble Fas in SLE patients correlated positively with apoptotic lymphocytes and antibodies to double stranded DNA. This study suggests that increased apoptotic lymphocytes and increased lymphocyte Fas expression may not be specific to SLE. Serum soluble Fas may have a role in the regulation of lymphocyte apoptosis in SLE.     

Standardised assessment of membrane proteinase 3 expression. Analysis in ANCA-associated vasculitis and controls

OBJECTIVES: Increased numbers of neutrophils expressing proteinase 3 on their membrane (mPR3) have been reported in anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) and are suggested to be involved in AAV immunopathogenesis. In most studies, neutrophils were analysed for mPR3 expression without priming with TNFalpha, suggesting that mPR3 expression on neutrophils is dependent on other priming events, such as isolation procedures . These priming events can be variable. Therefore, we analysed mPR3 expression on neutrophils before and after priming with TNFalpha to assess whether standardised assessment of mPR3 expression requires priming. Using neutrophils before and after priming with TNFalpha, we assessed percentages of mPR3(+) neutrophils in patients with AAV and in disease and healthy controls. METHODS: Neutrophils from patients with PR3-AAV and MPO-AAV, systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), and from healthy controls were analysed before and after priming with TNFalpha for mPR3 expression. RESULTS: 42% of all individuals analysed showed minimal expression for mPR3 on all neutrophils before priming with TNFalpha, whereas after priming a clear mPR3(+) subset was observed next to mPR3(-) neutrophils, corresponding to bimodal mPR3 expression. In patients with PR3-AAV or MPO-AAV, the percentage of mPR3(+) neutrophils after priming with TNFalpha was significantly increased (p<0.01 and p<0.05, respectively) compared with healthy controls. Percentages of mPR3(+) PMN were also increased in patients with SLE (p<0.01) but not in RA. CONCLUSION: Standardised assessment of proteinase 3 on the membrane of neutrophils requires priming with TNFalpha. Percentages of mPR3(+) PMN are increased in AAV and SLE, but not in RA.