Drug-related Lupus Research Articles

Multidisciplinary approach to connective tissue disease (CTD) related pleural effusions: a four-year retrospective evaluation

BackgroundCTD-related pleural effusions are rare and challenging to diagnose. Our lung inflammation service (with expertise in rheumatology, interstitial lung disease and respiratory failure) works closely with the pleural team. This study aims to review the multidisciplinary approach to CTD-related pleural effusions at a tertiary centre.MethodsAll patients with CTD-related pleural effusions at St Thomas’ Hospital, London were included. Retrospective data were collected from Dec 2013 to 2016.ResultsThe lung inflammation service performed an expert clinical assessment and targeted investigations. 11 patients (ages 23–77) were identified with CTD related pleural disease. 9 (82%) patients were given a new CTD diagnosis, with pleural disease as the first manifestation. The range of conditions were: rheumatoid arthritis [3] ,IgG4-related disease [2] ,adult Still’s disease [2] ,vasculitis [1] ,SLE [1] ,drug-induced lupus [1] ,and Behcet’s [1].The pleural team review took place 1 day (median) after referral. 73% of diagnoses (8 patients) were achieved with local anaesthetic pleural interventions (a combination of: aspiration, drain, or percutaneous biopsy). This included 1 patient who required no pleural intervention. 1 required medical thoracoscopy, and 2 underwent thoracic surgery.Diagnoses were made by integrating all available evidence such as clinical assessment, imaging, and autoimmune serology. No diagnosis was achieved by pleural cytology or histology analysis alone.8 (73%) were commenced on prednisolone acutely (vasculitis, SLE, drug-related lupus, 1 patient with rheumatoid arthritis, Behcet’s, 2 patients with Adult Still’s disease, 1 patient with IgG4-related disease). Of these 8, one patient with rheumatoid arthritis received IV methylprednisolone beforehand, one patient with IgG4-related disease was weaned off prednisolone to methothrexate, two patients with Adult Still’s disease were on colchicine as well, and one patient with Behcet’s was on cyclophosphamide as well. 7 (64%) were managed as outpatients; 4 required admission. The median time from pleural review to diagnosis was 53 days.ConclusionsDiagnosis can be challenging in patients presenting with pleural disease as the first manifestation of a CTD. We recommend a multidisciplinary approach in management.

Tegafur/gimeracil/oteracil (TS-1) induced Stevens–Johnson syndrome: Case report

TS-1 is an oral fluoropyrimidine anticancer drug that contains tegafur, gimeracil, and oteracil. A 78-year-old Japanese male who was diagnosed with carcinoma of the oral floor (rT4aN0M0) was prescribed a standard dose of TS-1 (80 mg/day). On Day 8 after administration of TS-1, an eruption developed. There was erythema, along with vesicles and erosions involving the lip, face, neck, trunk, limbs, and genitals. The drug-induced lymphocyte stimulation test (DLST) for TS-1 was negative on the 23 rd day, but positive on the 43 rd day (20 days after discontinuing prednisolone). The condition was diagnosed as Stevens–Johnson syndrome due to TS-1 because of the clinical course and laboratory results. This case and 24 cases previously reported in the literature were analyzed. The types of drug eruption were drug-related lupus (9 cases), acral erythema (7 cases), scleroderma-like skin lesion (2 cases), Stevens–Johnson syndrome (2 cases), lichenoid eruption (1 case), purpura (1 case), lichen planus (1 case), erythema multiforme (1 case), hypopigmentation (1 case) and toxic epidermal necrolysis (1 case), respectively. In view of the increasing usage of TS-1 in several common cancers, clinicians should be aware of drug eruptions due to TS-1.

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.

9070 Phase II trial of S-1 with bi-weekly docetaxel for non-small-cell lung cancer previously treated with platinum-based chemotherapy: a North Japan Lung Cancer Study Group (NJLCG0701)

TS-1 is an oral fluoropyrimidine anticancer drug that contains tegafur, gimeracil, and oteracil. A 78-year-old Japanese male who was diagnosed with carcinoma of the oral floor (rT4aN0M0) was prescribed a standard dose of TS-1 (80 mg/day). On Day 8 after administration of TS-1, an eruption developed. There was erythema, along with vesicles and erosions involving the lip, face, neck, trunk, limbs, and genitals. The drug-induced lymphocyte stimulation test (DLST) for TS-1 was negative on the 23rd day, but positive on the 43rd day (20 days after discontinuing prednisolone). The condition was diagnosed as Stevens–Johnson syndrome due to TS-1 because of the clinical course and laboratory results. This case and 24 cases previously reported in the literature were analyzed. The types of drug eruption were drug-related lupus (9 cases), acral erythema (7 cases), scleroderma-like skin lesion (2 cases), Stevens–Johnson syndrome (2 cases), lichenoid eruption (1 case), purpura (1 case), lichen planus (1 case), erythema multiforme (1 case), hypopigmentation (1 case) and toxic epidermal necrolysis (1 case), respectively. In view of the increasing usage of TS-1 in several common cancers, clinicians should be aware of drug eruptions due to TS-1.

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.

Drug Insight: autoimmune effects of medications—what's new?

Autoantibodies and lupus-like syndromes can develop following the use of certain medications; however, although many patients develop autoantibodies, only a minority develop clinical features. Although these autoantibodies primarily consist of antinuclear and antihistone antibodies, additional types of antibody, such as antineutrophil cytoplasmic antibodies and anti-double-stranded DNA antibodies, have been reported in association with minocycline and tumor necrosis factor inhibitor therapy. Clinical features of drug-related lupus usually consist of constitutional symptoms, arthralgias, arthritis, myalgias and serositis, although cutaneous manifestations have been reported in association with the use of tumor necrosis factor inhibitors. Typically, clinical features resolve with discontinuation of the medication, although antibodies can persist for months or years. Arthralgias and inflammatory arthritis have also been reported in association with the use of aromatase inhibitors and other biologic agents such as interleukins and interferons.

Drug-Related Lupus Rises With Anti-TNF Agent Use

Drug-Related Lupus Rises With Anti-TNF Agent Use

3553 POSTER Phase I/II study of S-1 in patients (pts) with advanced hepatocellular carcinoma (HCC): Results of phase I part – Correlation between pharmacokinetics (PK) and hepatic dysfunction

TS-1 is an oral fluoropyrimidine anticancer drug that contains tegafur, gimeracil, and oteracil. A 78-year-old Japanese male who was diagnosed with carcinoma of the oral floor (rT4aN0M0) was prescribed a standard dose of TS-1 (80 mg/day). On Day 8 after administration of TS-1, an eruption developed. There was erythema, along with vesicles and erosions involving the lip, face, neck, trunk, limbs, and genitals. The drug-induced lymphocyte stimulation test (DLST) for TS-1 was negative on the 23rd day, but positive on the 43rd day (20 days after discontinuing prednisolone). The condition was diagnosed as Stevens–Johnson syndrome due to TS-1 because of the clinical course and laboratory results. This case and 24 cases previously reported in the literature were analyzed. The types of drug eruption were drug-related lupus (9 cases), acral erythema (7 cases), scleroderma-like skin lesion (2 cases), Stevens–Johnson syndrome (2 cases), lichenoid eruption (1 case), purpura (1 case), lichen planus (1 case), erythema multiforme (1 case), hypopigmentation (1 case) and toxic epidermal necrolysis (1 case), respectively. In view of the increasing usage of TS-1 in several common cancers, clinicians should be aware of drug eruptions due to TS-1.

Drug-Related Lupus Cases Rise With Use of Anti-TNF Drugs

Drug-Related Lupus Cases Rise With Use of Anti-TNF Drugs

Are there environmental forms of systemic autoimmune diseases?

A large number of drugs and an increasing number of environmental agents reportedly result in the appearance of a number of autoantibodies and in many instances in the appearance of a range of autoimmune clinical syndromes. The major disorders so recognized have marked resemblances to the autoimmune disease systemic lupus erythematosus. The commonly used term is drug-induced lupus; a better term is drug-related lupus. There is considerable interest at the present time in an increasing number of environmental agents. There have been two epidemics in recent years--one in Spain to a contaminant of rapeseed oil and one in the United States to a contaminant of l-tryptophan that caused an eosinophilic myositis. It is important for physicians and others involved in health care to recognize the potential associations of these diseases of unknown cause or causes.

Réactions systémiques secondaires à la prise de minocycline. À propos de quatre observations et revue de la littérature

We report four cases of the side effects of minocycline seen during the last two years in our department. There was one case of drug-related lupus and three cases of hypersensitivity reactions, including one eosinophilic pneumopathy with pericarditis, one nephropathy and one severe, pseudo-infectious episode of high fever, rash, lympadenopathy, hepatitis and eosinophilia. Minocycline is a tetracycline agent widely used for acne therapy in France and all over the world. During the last few years, there has been an increasing number of reports concerning systemic adverse reactions to minocycline, with on the one hand auto-immune disorders (lupus, autoimmune hepatitis, vascularitis with ANCA), occurring after a prolonged course of therapy and reported recently in the last few years, and on the other hand, hypersensitivity reactions (eosinophilic pneumopathies, hepatitis, nephropathies, myocarditis, serum sickness or pseudo-infectious reactions), occurring precociously in the course of therapy, and potentially severe. Although these side effects are uncommon in the context of the high number of patients who have been prescribed the drug, the first-line antibiotic therapy in acne must probably be reconsidered.

Drug-Induced Lupus Erythematosus

Lupus erythematosus is an autoimmune disease of the connective tissue, whose specific causes are still unknown. In the last 40 years many drugs and other chemical agents have been reported to cause a syndrome similar to systemic lupus erythematosus (SLE). The terms used for this condition are lupus-like syndrome, drug-induced lupus erythematosus, drugrelated lupus, and lupus erythematosus medicamentosus. I prefer the term “drug-induced lupus erythematosus” (DILE), but there are no specific diagnostic criteria for DILE.1 One of the problems concerns the fact that many patients with probable DILE have the clinical picture and serologic findings typical for the primary disease. The second difficulty derives from the insufficient unified technique used to detect autoantibodies.2 Despite this, several diagnostic criteria for DILE should be made: (1) exposure to a drug suspected to induce DILE; (2) no history for SLE prior to the use of the drug therapy; (3) detection of positive antinuclear antibodies (ANA) with at least one clinical sign of SLE; (4) rapid improvement and gradual fall in the ANA and other serologic findings upon withdrawal of the drug.1 There is controversy concerning the period the implicated drug may provoke the onset of the signs of DILE. This period can range from 3 weeks to 2 years. More than 80 drugs have been associated with DILE (Fig 1). The first case of DILE was reported in 1945 and was associated with sulfadiazin.3 In 1953 it was reported that DILE was related to the use of hydralazine.4 Procainamide-related DILE—one of the typical examples of DILE—was reported in 1962.5 Because the number of drugs associated with DILE is increasing rapidly, the latter is the subject of numerous reviews, editorial notes, and reports. Drugs responsible for the development of DILE can be divided into three groups (Table 1). The first (1) includes drugs for which there are well-controlled studies and their role for inducing DILE has been documented. To this group belong such drugs as hydralazine, procainamide, isoniazid, methyldopa, chlorpromazine, and quinidine. To the second (2) group belong drugs very possibly related to DILE such as anticonvulsant agents, antithyroid drugs, penicillamine, sulfasalazine, beta-blockers, and lithium. The third (3) group comprises drugs suggested as causes for DILE but lacking well-controlled studies. The list of these drugs is a long one, with new drugs being entered annually (4).

Drug Related Lupus Misdiagnosed as Fibromyalgia:

Background: Drug-related lupus [DRL] especially with hydralazine has been known for 40 years. Signs and symptoms of DRL may be readily mistaken for other disorders such as fibromyalgia. The purpose of the case presentation is to review the pathophysiology and similarities between DRL and fibromyalgia in addition to emphasize the importance of accurate diagnosis in physiatric practice. Findings: This is a case of 57-year-old hypertensive woman on hydralazine for nine years who developed multiple complaints including bilateral chest pain, cough, shortness of breath, joint pain at knees and ankles, muscle pain in thighs and calf, swelling of hands and feet, intermittent skin lesions, depression and anxiety. She was referred to a physiatrist with the mistaken diagnosis of fibromyalgia. The patient's sings and symptoms were not diagnostic of DRL but were suspicious of something other than fibromyalgia. An immunological work-up showed suggestion of DRL and hydralazine was discontinued. Conclusion: Drug-related ...

Drugs recently associated with lupus syndromes.

A number of drugs have recently been implicated in a syndrome that resembles systemic lupus erythematosus. One of the difficulties in many of these patients is that the signs, symptoms and serological abnormalities reported in these patients may be a natural consequence of the primary diseases rather than the incriminated drug. A second problem with the studies is a lack of uniform reporting of the techniques used to detect autoantibodies. For example, a patient that has a highly positive ANA with a homogeneous pattern of staining or a positive LE cell test usually has antibodies directed against chromatin components (DNA, histones, high mobility group (HMG) proteins). The discrepancies in clinical criteria and the serological techniques in many of these reports, emphasize the importance of using guidelines for the diagnosis of drug-induced or drug-related lupus. In the future, it appears that the increased use of biological response modifiers such as interferon-alpha and other cytokines may prompt more reports of lupus syndromes associated with their use.

Ethosuximide-associated systemic lupus erythematosis in childhood

Systemic lupus erythematosis (SLE) is an autoimmune disorder that may be associated with antiepileptic drugs (AEDs). The postulated mechanisms of drug-related lupus (DRL) include either an unmasking of idiopathic SLE or the actual induction of autoantibodies. Although ethosuximide (ETH) is one of the drugs most implicated in childhood DRL, our treatment of a 13-year-old girl with ETH-associated DRL prompted a literature search that revealed only 15 other cases. Many of these were on multiple AEDs. We subsequently became aware of two other cases. The relationship of ETH to SLE in these three children is discussed, and clinical and laboratory features useful in the differentiation of various types of SLE are reviewed.

Study of procainamide hapten-specific antibodies in rabbits and humans

Procainamide (PA) is the drug most commonly associated with the induction of autoantibodies and drug-related lupus (DRL). While the majority of these patients express autoantibodies, antibodies to the parent drug and metabolites, PA-hydroxylamine (PAHA) or nitroso-PA (NOPA), have not been reported in humans. Hapten-carrier conjugates were prepared using human hemoglobin (HgB) or autologous rabbit erythrocytes with PAHA or NOPA. PA was conjugated to rabbit serum albumin (RSA) or egg albumin (OVA) via diazotization and condensation methods. Rabbits were immunized with hapten conjugates in Freund's adjuvant. These hapten-carrier compounds (5 – 10 μg/ml) were used as test antigens for antibodies in sera from the rabbits and 40 patients on chronic PA treatment, 10 SLE patients, 33 elderly and 20 young normal controls by ELISA. Type I and II collagens were also used as test antigens for human sera. Sera from rabbits immunized with the PA compounds had elevated IgG antibody values to PA, PAHA and NOPA, but no autoantibodies. Absorption of the rabbit sera with the PA compounds reduced the antibody levels; ssDNA and histones failed to inhibit the total binding values. Mean binding to PA - OVA was 0.95 ± 0.41 for PA patients and 1.37 ± 0.26 standard error of means (S.E.M.) in the SLE patients compared to 0.37 ± 0.14 S.E.M. in the normal sera ( P⩽0.05); similar binding values to PAHA - HgB and NOPA - HgB were also observed. Sixty-eight percent of the PA patients had antibodies to type II collagen. Elevated binding values to PA compounds were inhibited by absorption of human sera with ssDNA or total histones; absorption with PA or PAHA had no significant effect. These findings suggest that sera from PA patients containing high titers of autoantibodies cross-react in vitro with unrelated antigens.

Hydralazine induces Z-DNA conformation in a polynucleotide and elicits anti(Z-DNA) antibodies in treated patients

We studied the effect of hydralazine, an antihypertensive drug with lupus-inducing side effects, on the conformation of poly(dG-m5dC).poly(dG-m5dC) and a plasmid with a 23 bp insert of (dG-dC)n.(dG-dC)n sequences. Using an e.l.i.s.a. with a monoclonal anti-(Z-DNA) antibody Z22, we found that hydralazine provoked the Z-DNA conformation in poly(dG-m5dC).poly(dG-m5dC) at 250-500 microM concentration. The supercoiled form of hydralazine-treated plasmid bound to Z22 in a gel-retardation assay. To examine further whether Z-DNA could act as an inciting agent in anti-nuclear antibody production in patients, we analysed 65 sera from 25 hypertensive patients taking hydralazine and found anti-(Z-DNA) antibodies in 82% of these sera. Sera from age-matched normal controls showed no binding to Z-DNA. Data on sera drawn sequentially from four hypertensive patients showed that antibodies were present after the drug treatment. These data demonstrate the presence of a high incidence of anti-(Z-DNA) antibodies in patients treated with hydralazine and suggest that a possible mechanism for the production of autoantibodies in drug-related lupus might involve the induction and stabilization of Z-DNA by drugs.

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.

Drug related lupus (procainamide), antibodies to histones, histone subfractions and class II antigens

Drug related lupus (procainamide), antibodies to histones, histone subfractions and class II antigens

Drug-related lupus

All physicians should be alerted to the many drugs and other agents that are associated with drug-related lupus, as there is an increasing number of such drugs. A wide range of immune responses and antibodies are being reported with this syndrome. A new concern is the perceived ability of new biologic treatments to induce these autoimmune phenomena. More in-depth studies of various environmental factors are providing new insights into possible mechanisms. These include the immune responses to the drugs, their metabolites, and drug-altered conjugates; bioactivation mechanisms of drug protein conjugation; the role of macrophages in antigen recognition and processing; and lastly, the important role of the acetylation of various drugs and the relationship to immunogenetic factors. Continued study of this human experimental model of lupus will help to clarify the etiology and mechanisms of systemic lupus erythematosus itself.