Membranous lupus nephritis secondary to secukinumab therapy: A case report and literature review.

The interleukin (IL)-17 axis is involved in many inflammatory and autoimmune diseases. Secukinumab, an IL-17 inhibitor, has been approved for psoriasis treatment. There are accumulating cases of lupus erythematosus induced by IL-17 inhibition. Lupus nephritis after IL-17 inhibition has not been reported. We report the case of a 57-year-old man who developed membranous lupus nephritis after secukinumab treatment for psoriasis. Anti-SSA and PM-Scl antibodies were positive. dsDNA, anti-Smith, and anti-histone antibodies were negative, and serum complement was low. Secukinumab was discontinued, while tacrolimus was initiated, subsequently switched to cyclosporin, belimumab, glucocorticosteroid, and hydroxychloroquine with a good response. The relationship between lupus erythematosus and IL-17 inhibition requires further research.

Drug-induced lupus erythematosus in childhood: Case-based review.

BACKGROUND: Drug-induced lupus erythematosus (DILE) is the development of lupus-like syndrome following a drug exposure. DILE has been reported less frequently among children than adults. METHODS: In this study, we present four children with DILE and similar published cases through a systematic literature review. RESULTS: We report four children (three girls and one boy) who developed DILE associated with the use of topiramate, doxycycline, etanercept, and ethosuximide. Three of them were positive for anti-histone antibodies. In all patients, the drug was discontinued and symptoms resolved completely. The literature review revealed 48 articles describing 61 children with DILE. In the evaluation of 65 patients (our 4 patients and 61 patients from the literature), the most frequently reported drugs associated with DILE were ethosuximide (n = 13) and minocycline (n = 12). Fever (n = 33), arthralgia (n = 31), rash (n = 30), and arthritis (n = 29) were the most common clinical manifestations. Antinuclear antibody (ANA) was positive in 93.5% of patients and anti-histone antibodies were detected in 72.2% of the patients. As for treatment, the responsible drug was discontinued in all patients, and corticosteroids were initiated in 53.3%. Improvement was achieved in 92.0% of patients. CONCLUSION: For children presenting with SLE features, proper drug history is crucial since DILE may be more frequent than anticipated. An association of the relevant drug with the symptoms, and resolution of symptoms on drug withdrawal provides evidence for the diagnosis of DILE.

Pearls for the diagnosis and possible pathophysiological mechanisms of valproic acid-induced lupus erythematosus: A literature review.

Background: Drug-induced lupus erythematosus (DILE) accounts for 10-15% of systemic lupus erythematosus (SLE) cases, with more than 100 pharmaceutical agents implicated in its development. Depending on the offending drug, clinical and serological manifestations present great variability and, thus, DILE may be overlooked in clinical practice. Valproic acid (VPA) - induced lupus erythematosus has not been analytically reported in the literature, rendering the recognition of such cases even more difficult.Objective: The aim of this study was to analyze VPA - induced lupus features and to discuss possible pathophysiological mechanisms.Materials and Methods: This literature review was conducted in PubMed and Embase databases in June 2021, in search of DILE cases induced by VPA. We found 164 manuscripts, out of which 140 articles regarding other adverse effects or drugs were discarded. Finally, 15 cases fulfilled the eligibility criteria to be included in this review.Results: Although SLE is more common in females, VPA-induced lupus presented a male predilection. Patients developed DILE within the first three months of treatment with VPA at a percentage of 50%, whereas four patients from one to five years after VPA initiation. DILE frequently presented with mild symptoms. In most patients, serositis manifested with polyarthritis, pleural effusion or pericarditis. Notably, one patient presented with Rowell's syndrome, a rare subtype of lupus erythematosus with erythema multiforme and speckled pattern of antinuclear antibodies (ANAs). Central nervous system, renal and skin involvement was scarcely observed. Cytopenia was noted in 7 patients. Immunological findings included positive ANAs in the vast majority of the patients (86.7%), positive anti-histone antibodies in five, positive anti-dsDNA antibodies in three and hypocomplementemia in two patients. Despite the prompt resolution of clinical symptoms after VPA discontinuation, serological abnormalities persisted up to 18 months. Apart from the discontinuation of VPA administration for the resolution of DILE, treatment included corticosteroids in 8 cases.Conclusion: Valproic acid has been implicated in several cases of DILE. Clinicians should be aware of this entity and recognize it promptly to ensure a favorable outcome. Possible pathophysiologic associations may be extrapolated, but a clearer understanding of this syndrome is to be gained by further studies.

Review of secukinumab-induced adverse events of special interest and its potential pathogenesis.

Although secukinumab has demonstrated high efficacy and favorable safety in moderate-to-severe psoriasis and psoriatic arthritis, patients developing adverse events of special interest (AESI) were reported increasingly in real-world practice. A systematic literature search of the PubMed database was conducted to identify clinical studies or case reports on secukinumab-induced AESI. More than 1077 patients (aged 18-74 years) from 55 studies were reported to have 24 AESI 3 days to 96 weeks after secukinumab treatment. The four most common AESI was inflammatory bowel disease (n > 1000), eczematous drug eruption (n > 30), drug-associated vasculitis (n = 8), and drug-induced lupus erythematosus (n = 4). Most of these AESI were only mild to moderately severe and resolved after secukinumab discontinuation without or with symptomatic treatment. Secukinumab has the potential to develop a number of AESI by probably dysregulating the different expression of polar T-cell axes (Th1, Th2, Th17, Th22, and/or Treg) and driving various cytokines in some patients. Physicians should be aware of these AESI for timely diagnosis and proper treatment.

[A CASE OF PROBABLE LATE-ONSET SYSTEMIC LUPUS ERYTHEMATOSUS WHERE THE INITIAL MANIFESTATION WAS A UNILATERAL PLEURAL EFFUSION].

A 74-year-old man developed with left pleural effusion and was suspected of benign asbestos pleural effusion and tuberculous pleurisy. Because of elevation of ADA level in the pleural effusion, diagnostic treatment for tuberculous pleurisy by anti-tuberculosis drugs was performed. However, right pleural effusion, cutaneous/mucosal lesions, leukocytopenia, and fever elevation occurred. The pathology of skin biopsy was consistent with systemic lupus erythematosus (SLE). Since clinical findings did not improve even after discontinuation of all drugs, he received steroid therapy was started and clinical findings improved. He was suspected of late-onset SLE. In conclusion, lupus pleurisy should also be differentiated when pleural effusion is seen in older. Late-onset SLE and drug-induced lupus should be carefully differentiated based on the clinical course.

Anti-TNF-α-induced lupus syndrome : Two case reports and review of current literature.

Anti-tumor necrosis factor­α (TNF-α)-induced lupus (ATIL) represents a diagnostic and treatment challenge. Most cases are caused by infliximab and in some cases by etanercept and adalimumab. Symptoms can range from cutaneous manifestations to more rare and serious conditions. Diagnosis requires a temporal relationship between symptoms and positive autoantibody determination. Arthritis and cutaneous symptoms are the most common manifestations accompanied by positive antinuclear antibody (ANA) and anti-double strand DNA (dsDNA) determinations. The etiology of ATILS remains to be definitively established. Several mechanisms have been proposed for anti-TNF-α-induced lupus, including apoptosis, immunosuppression and humoral autoimmunity. Treatment includes discontinuation of anti-TNF­α agents and in some cases corticosteroids and immunosuppressors. Questions to be answered: (1) Are soluble TNF receptor fusion proteins such as etanercept and anti-TNF chimeric antibodies equally likely to cause ATIL? (2) Can patients with ATIL switch from one anti-TNF­α antagonist to another? (3) Can the concurrent use of a conventional synthetic disease-modifying antirheumatic drug (csDMARD) like methotrexate or hydroxychloroquine reduce the probability of ATIL?

Cutaneous drug-induced lupus erythematosus: Clinical and immunological characteristics and update on new associated drugs.

Cutaneous drug-induced lupus erythematosus (CDILE) is a lupus-like syndrome related to drug exposure which typically resolves after drug discontinuation. It can present as a systemic or a sole cutaneous form and different drugs may be associated with each form. CDILE pharmacoepidemiology is constantly changing. Indeed, older drugs primarily associated with systemic CDILE are no longer prescribed and new drugs associated with either cutaneous or systemic CDILE have emerged. The present study discusses the clinical and laboratory aspects of CDILE and the postulated pathogenesis, and it provides an update on implicated drugs. We performed a literature review to single out the new drugs associated with CDILE in the past decade (January 2010-June 2020). Among 109 drugs reported to induce CDILE in 472 patients, we identified anti-TNFα, proton-pump inhibitors, antineoplastic drugs, and, in particular, checkpoint inhibitors, as emerging drugs in CDILE. Most of the published studies are cases reports or small case series, and further larger studies as well as the development of validated classification criteria are needed to better understand and characterize their implication in CDILE.

Severe hydralazine-induced lupus presenting as systemic lupus erythematosus.

Despite its long history of untoward side effects of a systemic autoimmune disease, drug-induced lupus can be difficult to recognize because of the disconnect between chronic drug usage and onset of symptoms. In this case, the patient was treated with hydralazine for two years when symptoms were initially reported, but a diagnosis of hydralazine-induced lupus was not considered for another half year. Despite treatment with steroidal and nonsteroidal anti-inflammatory medications during this period, rheumatologic symptoms and signs continued to deteriorate, consistent with the diagnosis of systemic lupus erythematosus. Not until the patient voluntarily discontinued hydralazine did symptoms begin to improve, fully resolving over the subsequent 6-12 months largely in the absence of anti-inflammatory medication. This patient demonstrates that failure to recognize a drug-induced disease etiology can result in substantial worsening of rheumatologic symptoms over the subsequent six months, ultimately satisfying criteria for systemic lupus erythematosus. While symptoms and signs largely normalized, some laboratory abnormalities and occasional arthralgia remained two years after discontinuing hydralazine, suggesting smoldering inflammatory disease.

Cutaneous Lupus Erythematosus: Progress and Challenges.

PURPOSE OF REVIEW: The review provides an update on the diagnosis, pathogenesis, and treatment of cutaneous lupus erythematosus (CLE). RECENT FINDINGS: Diagnostic challenges exist in better defining CLE as an independent disease distinct from systemic lupus erythematosus with cutaneous features and further classifying CLE based on clinical, histological, and laboratory features. Recent mechanistic studies revealed more genetic variations, environmental triggers, and immunologic dysfunctions that are associated with CLE. Drug induction specifically has emerged as one of the most important triggers for CLE. Treatment options include topical agents and systemic therapies, including newer biologics such as belimumab, rituximab, ustekinumab, anifrolumab, and BIIB059 that have shown good clinical efficacy in trials. CLE is a group of complex and heterogenous diseases. Future studies are warranted to better define CLE within the spectrum of lupus erythematosus. Better insight into the pathogenesis of CLE could facilitate the design of more targeted therapies.

Drug-induced systemic lupus: revisiting the ever-changing spectrum of the disease using the WHO pharmacovigilance database.

OBJECTIVE: Drug-induced lupus (DIL) is an idiosyncratic side effect of treatments in which symptoms overlap with those of systemic lupus erythematosus (SLE). The spectrum of DIL constantly evolves with that of the pharmacopoeia. Here, we used VigiBase, the WHO global individual case safety reports (ICSRs) database, to identify the main drugs associated with DIL. METHODS: We analysed all ICSRs classified as 'systemic lupus erythematosus' according to the Medical Dictionary for Drug Regulatory Activities term (preferred term level) in VigiBase. The drugs considered in the analysis were those not used to treat SLE, with a positive lower end of the 95% credibility interval for the information component (IC025) ≥0, an indicator value for disproportionate Bayesian reporting. RESULTS: A total of 12 166 DIL ICSRs were identified using VigiBase. From those, 8163 ICSRs reporting on 118 suspected drugs with IC025 ≥0 were extracted. The median age at DIL onset was 49 years and the female to male sex ratio was 4.3. The median delay between start of suspected treatment and DIL occurrence was 172 days. DIL was reported as serious adverse event in 55.4%. Among the 118 suspected drugs, 42 had not been previously reported in association with DIL. The drugs associated with the highest number of DIL cases were infliximab, adalimumab, etanercept, procainamide and hydralazine. CONCLUSION: This study enables the identification of 118 drugs associated with DIL. The list of suspected drugs may prove useful to physicians when confronted with potential DIL cases. TRIAL REGISTRATION NUMBER: NCT03480529.

A case of drug-induced lupus erythematosus secondary to trimethoprim/sulfamethoxazole presenting with pleural effusions and pericardial tamponade.

We report a case of drug-induced lupus erythematosus (DILE) secondary to trimethoprim/sulfamethoxazole (TMP/SMX) in a patient with underlying inflammatory bowel disease (IBD). The initial presentation was with febrile pleural and pericardial effusions followed by cardiac tamponade. The patient was treated with a short course of corticosteroids with complete resolution of symptoms. To our knowledge this is the first reported case of TMP/SMX-induced DILE presenting with life-threatening serositis. When confronted with sterile exudative effusions, clinicians should strongly consider non-infectious etiologies.

A case of lupus-like syndrome in a patient receiving adalimumab and a brief review of the literature on drug-induced lupus erythematosus.

WHAT IS KNOWN AND OBJECTIVE: Drug-induced lupus erythematosus occurs with some drugs and resolves with their withdrawal. Anti-TNF therapies have been found to be associated with a lupus-like syndrome, which is clinically distinct from classical drug-induced as well as idiopathic lupus erythematosus. CASE DESCRIPTION: We describe a case of a patient with severe psoriasis, who developed muscle pain with paraesthesia accompanied by ANA titres elevation with adalimumab treatment. The condition resolved after adalimumab cessation, and the patient was started on ustekinumab with good results. WHAT IS NEW AND CONCLUSION: Ustekinumab might be a useful treatment option for patients with a history of TNF-induced lupus-like syndrome.

Drug-induced systemic lupus erythematosus in a child after 3 years of treatment with carbamazepine.

Drug-induced lupus erythematosus (DILE) is a less severe variant of systemic lupus erythematosus (SLE) that generally resolves within weeks or months after the withdrawal of the implicated drug. DILE is unusual during childhood, with the most frequent age of presentation being at 50-70 years of age. Among different drugs, most commonly procainamide and hydralazine have been implicated as a cause of DILE. However carbamazepine (CBZ) is considered a low-risk drug and very few cases have been reported in children. We describe the case of CBZ-induced SLE in a 9-year-old girl following 3 years of CBZ therapy. This case report shows that drug-induced SLE is an important side-effect to be considered, even after long-term treatment with CBZ, and also during childhood.

Ultraviolet light converts propranolol, a nonselective ß-blocker and potential lupus-inducing drug, into a proinflammatory AhR ligand.

UV light and some medications are known to trigger lupus erythematosus (LE). A common mechanism underlying the immunopathologic effect, resulting from exposure to these two seemingly unrelated factors, remains unknown. The aryl hydrocarbon receptor (AhR) plays a key role in the regulation of IL-22 production in humans and can be activated by both xenobiotics and naturally occurring photoproducts. A significant expansion of Th17 and Th22 cells was observed in the peripheral blood of active systemic LE (SLE) patients, compared to inactive patients and controls. We also show that propranolol, a potential lupus-inducing drug, induced stronger AhR activation in PBMCs of SLE patients than in those of controls. AhR agonist activity of propranolol was enhanced by UV light exposure. MS analysis of irradiated propranolol revealed the generation of a proinflammatory photoproduct. This compound behaves like the prototypic AhR ligand 6-formylindolo[3,2-b]carbazole, a cutaneous UV light-induced tryptophan metabolite, both promoting IL-22, IL-8, and CCL2 secretion by T-cells and macrophages. Finally, LE patients exhibit signs of cutaneous AhR activation that correlate with lesional expression of the same proinflammatory cytokines, suggesting a role for photometabolites in the induction of skin inflammation. The AhR might therefore represent a target for therapeutic intervention in LE.

Drug-induced lupus erythematosus associated with donepezil: a case report.

The possibility that drug-induced lupus erythematosus (DILE) can be induced by donepezil is presented in this clinical case. Donepezil is an inhibitor of acetylcholinesterase used for the treatment of Alzheimer's disease. It is the first time that donepezil causes DILE.

Spondyloarthropathy in inflammatory bowel disease patients on TNF inhibitors.

BACKGROUND: Musculoskeletal symptoms are the most common extra-intestinal manifestation associated with inflammatory bowel disease (IBD). Spondyloarthritis (SpA) is an umbrella term applied to a group of rheumatic diseases with some features in common and others distinct from other inflammatory arthritides. AIM: To determine self-reported prevalence of SpA associated musculoskeletal manifestations in an IBD cohort on tumour necrosis factor (TNF) inhibitors using a questionnaire incorporating Assessment of SpondyloArthritis International Society (ASAS) criteria. METHODS: Consecutive IBD patients on TNF inhibitors attending a single IBD centre (May-September 2011) were asked to complete a SpA questionnaire. Data collected included SpA and IBD variables, demographics, concurrent medications, co-morbidities and autoimmune serology. RESULTS: The 140-patient cohort included 96 suffering from Crohn disease and 44 from ulcerative colitis. The mean age of disease onset was 29.3 years and 45% were men. Concurrent or past history of inflammatory back pain was reported by 29% subjects. Using the imaging and clinical arms of the ASAS criteria, 30% and 14% subjects respectively had axial SpA. Arthritis was reported by 34%, enthesitis 17%, dactylitis 4%, uveitis 6%, psoriasis 6% and a family history of SpA in 39%. Peripheral SpA was present in 41% by the ASAS criteria. There were no differences in these frequencies between Crohn disease and ulcerative colitis. A positive antinuclear antibodies (>1:80) was found in 19% before commencement of TNF inhibitor therapy and increased to 78% on therapy. Clinical drug-induced lupus erythematosus was uncommon (4%) and was characterised by new clinical signs and symptoms, including arthralgia, rash with elevated dsDNA titres and positive antinuclear antibodies. CONCLUSIONS: Inflammatory bowel disease patients on TNF inhibitors frequently reported musculoskeletal manifestations. Increased recognition of SpA occurred with use of an SpA self-reported questionnaire in IBD patients: this could alter management and improve patient outcomes. Clinical drug-induced lupus erythematosus was uncommon.

Propylthiouracil-induced autoimmune disease.

Hyperthyroidism is a condition characterized by excessive production of thyroid hormones. Propylthiouracil (PTU) is commonly used as first line drug in the management of hyperthyroidism. This is a case report of 24-year-old female, a known case of hyperthyroidism since 4 years, who came with a history of fever and myalgia since 3 days and dyspnea with coughing out of blood since 1 day. Patient was taking PTU (100 mg per day) since 4 years for hyperthyroidism. Patient was immediately intubated for type-II respiratory failure. Diagnosed to be having PTU-induced autoimmune disease. PTU was stopped and treated with methylprednisolone and cyclophosphamide. Clinical features improved over a period of 8 days and discharged home successfully. Having a high suspicion for the onset of autoimmune disease in hyperthyroidism patients who are on PTU therapy and timely treatment with immunosuppressants and supportive care along with the withdrawal of the drug can make a difference in morbidity and mortality.

Autoimmunogenicity during anti-TNF therapy in patients with psoriasis and psoriatic arthritis.

INTRODUCTION: The tumor necrosis factor (TNF-α) was initially described as lymphotoxin or cachectin. The discovery of therapies blocking the action of TNF-α, in 1988, started a new era in the therapy. One of often reported adverse effects related to the use of TNF-α antagonists is induction of the formation of autologous antibodies and antibodies neutralizing anti-TNF drugs. The development of anti-TNF-induced lupus or classical drug-induced lupus is more rarely reported. AIM: To evaluate the presence and the level of anti-nuclear antibodies in patients with psoriasis and psoriatic arthritis and the influence of anti-TNF therapy used on the concentration of antinuclear antibody (ANA). MATERIAL AND METHODS: A total of 28 subjects were included in the study. 71.4% of subjects were diagnosed with psoriatic arthritis and 28.6% with plaque psoriasis. RESULTS: Among the patients with plaque psoriasis, the antinuclear antibodies were found in 25% of subjects and in 80% of patients with psoriatic arthritis. After the treatment an increase in the titer or appearance of antibodies was found in 66.7% in the infliximab group, 18.2% in the etanercept group and 54.7% in the adalimumab group. No subjects developed symptoms of drug-induced systemic lupus. CONCLUSIONS: Our findings have shown that all anti-TNF therapies induced ANA in psoriatic arthritis and psoriatic patients. Considering a mild course of lupus induced by anti-TNF treatment and, usually intrinsic, resolution of symptoms, the biological therapy still appears as a safe treatment for patients.

Diagnosis and classification of drug-induced autoimmunity (DIA).

Since sulfadiazine associated lupus-like symptoms were first described in 1945, certain drugs have been reported to interfere with the immune system and induce a series of autoimmune diseases (named drug-induced autoimmunity, DIA), exemplified by systemic lupus erythematosus (SLE). Among the drugs, procainamide and hydralazine are considered to be associated with the highest risk for developing lupus, while quinidine has a moderate risk, and all other drugs have low or very low risk. More recently, drug-induced lupus has been associated with the use of newer biological modulators, such as tumor necrosis factor (TNF)-alpha inhibitors and cytokines. In addition to lupus, other major autoimmune diseases, including vasculitis and arthritis, have also been associated with drugs. Because resolution of symptoms generally occurs after cessation of the offending drugs, early diagnosis is crucial for treatment strategy and improvement of prognosis. Unfortunately, it is difficult to establish standardized criteria for DIA diagnosis. Diagnosis of DIA requires identification of a temporal relationship between drug administration and the onset of symptoms, but the relative risk with respect to dose and duration for each drug has rarely been determined. DIA is affected by multiple genetic and environmental factors, leading to difficulties in establishing a list of global clinical features that are characteristic of most or all DIA patients. Moreover, the distinction between authentic DIA and unmasking of a latent autoimmune disease also poses challenges. In this review, we summarize the highly variable clinical features and laboratory findings of DIA, with an emphasis on the diagnostic criteria.