21 May 2022: Articles
Cyclosporine A-Induced Conchal Hyperplasia with Nasal Obstruction in a Patient with Membranous Nephropathy
Unusual clinical course, Challenging differential diagnosis, Unusual or unexpected effect of treatment, Patient complains / malpractice, Adverse events of drug therapy , Clinical situation which can not be reproduced for ethical reasonsFrank-Peter Tillmann1ABCDEF*, Ana Harth1DEF, Fedai Özcan2DEF, Achim Jörres1DEF
Am J Case Rep 2022; 23:e935362
BACKGROUND: The immunomodulatory and pharmacokinetic effects of cyclosporine A are used to treat diverse disease entities in different medical fields, including organ transplantation and/or autoimmune diseases. It is also applied in patients with nephrotic range proteinuria as an adjunct to steroids and supportive antihypertensive/antiproteinuric medications. Cyclosporine has a small therapeutic window and is dosed with respect to the underlying disease entity and severity via trough level adaptations. Among its most frequent adverse effects are hypertension, nephrotoxicity, neurotoxicity, and electrolyte disturbances. Hypertrichosis and gingival hyperplasia are obvious and widely recognized adverse effects.
CASE REPORT: We report on a 66-year-old woman who was treated with cyclosporine A for primary membranous nephropathy. During treatment with cyclosporine, she developed hirsutism and gingival hyperplasia. Later, she reported having impaired nasal breathing and dyspnea on mild physical exercise. Clinical, rhinoscopic, and radiological evaluations showed marked conchal hyperplasia as a potential cause of her symptoms. An extensive medical work-up did not show evidence of allergic, immunologic, or other drug adverse effects, suggesting cyclosporine-induced hyperplasia of the turbinates as a hypothetical causative factor. Dose reductions did not lead to resolution of symptoms but resulted in increasing proteinuria. Therefore, cyclosporine was stopped, and the patient was treated with rituximab. Thereafter, hirsutism and gingival and conchal hyperplasia gradually regressed over 2-4 months, showing complete resolution of conchal hyperplasia on computed-tomography follow-up after 6 months.
CONCLUSIONS: Cyclosporine can not only result in gingival hyperplasia but also in hyperplasia of the turbinates leading to impaired nasal breathing and shortness of breath on exertion. An extensive search for many other known causes of conchal swelling is warranted to finally suggest an adverse effect of cyclosporine. Discontinuation of cyclosporine resulted in complete remission of conchal hyperplasia as well as other adverse effects.
Keywords: Cyclosporine, Drug-Related Side Effects and Adverse Reactions, Gingival Hyperplasia, Rhinitis, Allergic, Turbinates, Aged, Female, Glomerulonephritis, Membranous, Hirsutism, Humans, Hyperplasia, Immunosuppressive Agents, Nasal Obstruction, Proteinuria
Cyclosporine A is a cyclic peptide that is used in many diverse medical fields. It is used as an immunosuppressant in transplantation medicine, but also in chronic inflammatory bowel diseases, atopic dermatitis, psoriasis, autoimmune mediated uveitis, autoimmune chronic polyarthritis, and glomerular diseases with nephrotic range proteinuria. Cyclosporine has a narrow therapeutic window. As a result, drug dosing is dependent on the underlying clinical disease entity and individualized according to morning trough levels. Possible adverse effects, among many others, are hypertension, hirsutism, oedema, or gingival hyperplasia. Although the adverse effects described above have been known for many years, no predis-posing risk factors have been described so far in drug-naïve patients. When corresponding adverse effects occur, various therapeutic procedures have been applied besides adaptations of trough levels as first action, such as an extension of antihypertensive therapy in case of worsening of hypertension, laser surgical procedures in case of hirsutism or gingival hyper-plasia, a switch to tacrolimus, or a complete discontinuation of cyclosporine medication. Whereas cyclosporine A-induced gingival hyperplasia presents with a pathognomonic clinical picture and is generally well known as an adverse effect of cyclosporine A, most of the other adverse effects are usually diagnoses of exclusion in routine clinical practice .
Hereby, we report on a 66-year-old non-smoking woman who was treated with cyclosporine A as part of a drug regimen for recurrent proteinuria due to primary membranous nephropathy. The initial clinical course of the glomerulonephritis was characterized by sudden increases in proteinuria with slow reduction and finally complete resolution during 6–12 months on antihypertensive therapy alone, consisting mainly of strict blood pressure control using blockers of the renin-angiotensin-aldosterone-system as a mainstay of the drug regimen. Further medications consisted only of low-dose prednisolone and calcidiol to treat secondary hypovitaminosis. After 3 relapses, cyclosporine A was introduced to the regimen to accelerate the decline of proteinuria and to prevent or delay a further relapse. Six months after the introduction of cyclosporine A, the patient developed mild hirsutism and gingival hyperplasia (Figure 1). She also reported feeling a nasal obstruction with impaired nasal breathing associated with dyspnea, even during light physical exertion such as climbing stairs, and disturbed sleep at night. Besides gingival hyperplasia and mild hirsutism, no other remarkable signs were found on clinical examination. Especially, there were no signs of nasal discharge or infectious rhinitis, nor did the patient report having chronic rhinitis in the past. The past medical history was also unremarkable with respect to increased allergic reactions. The mean cyclosporine trough level over the whole treatment course was 86 ng/ml (min 52; max 148 ng/ml, 92 ng/ml at presentation) and the estimated glomerular filtration rate at first CT-evaluation was 65 ml/min/1.73 m2 body surface area (BSA). There were no laboratory signs of infections, disturbed thyroid function, peripheral blood eosinophilia, or local or systemic vasculitis such as ANCA-associated disease entities. An ear-nose-throat (ENT) examination did not reveal any indicative cause, but rhinoscopic and computed-tomography (CT) of the head showed evidence of a pronounced nasal conchal hyperplasia (Figures 2, 3). Although there were no indications of an allergic cause clinically and anamnestically, alongside with a normal IgE antibody titer, topical therapy with cortisone was carried out without any effect on the conchal hyperplasia. As an extensive search for other causes of the hyperplastic turbinates (pharmacological, allergic, and autoimmune) was unremarkable, biopsy of the nasal mucosa was discussed but discarded because of potential risks. In addition, the benefit of bioptically evaluating the hyperplastic conchae was seen as controversial, as progressive gingival hyperplasia also suggested a therapeutic omission of cyclosporine medication from a dental and dermatological perspective. As the patient remained proteinuric and dyspneic, medication with cyclosporine A was discontinued and rituximab was introduced (4 times 375 mg/m2 BSA) to treat membranous nephropathy, inducing a lasting remission of proteinuria and anti-phospholipase-2-receptor autoantibodies. Thereafter, the hirsutism and gingival hyperplasia slowly resolved over several months and a CT-radiologic control showed complete resolution of turbinate hyperplasia (Figures 4, 5). On last follow-up visit, the patient was free of immunomodulatory medications and had normal renal function without signs of proteinuria and/or albumin-uria on urine analysis. After the cyclosporine medication was discontinued, no signs of nasal obstruction or mucosal swelling have reoccurred so far.
Cyclosporine A is a cyclic peptide isolated in 1971 from the Norwegian tubular fungi
A major limitation of this case report is the lack of strong evidence of an actual cyclosporine A-induced cause of the conchal hyperplasia. Nevertheless, in our opinion there are so far no other means to definitively prove this hypothesis. Instead, we relied on a diagnosis of exclusion in this hypothesis-generating case report.
Cyclosporin A is often used as part of an immunomodulatory therapy in diverse medical fields. In the case of corresponding symptoms, this case raises the hypothetical, unproven possibility of cyclosporin A-induced turbinate hyperplasia, and we suggest considering this as an extremely rare potential cause in the differential work-up of respective cases. Nevertheless, this entity, if supported in further investigations, will remain a diagnosis of exclusion warranting thorough prior diagnostic work-up.
FiguresFigure 1.. A 66-year-old female patient with gingival hyperplasia due to cyclosporine A medication as part of a multi-drug regimen for membranous nephropathy. Figure 2.. CT scan under cyclosporine A medication showing hyperplastic turbinates of 3.7 mm. Figure 3.. CT scan under cyclosporine A medication showing hyperplastic turbinates of 4.2 mm. Figure 4.. CT scan showing regression of hyperplasia 6 months after discontinuation of cyclosporine A. The diameter at a corresponding anatomical location as compared to the baseline scan was 2.6 mm. Figure 5.. CT scan showing regression of hyperplasia 6 months after discontinuation of cyclosporin A. The diameter at a corresponding anatomical location as compared to the baseline scan was 2.8 mm.
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