A rare case of autoimmune dysglycemia syndrome associated with systemic lupus erythematosus and dermatomyositis

A rare case of autoimmune dysglycemia syndrome associated with systemic lupus erythematosus and dermatomyositis


INTRODUCTION
Autoimmune dysglycemia syndrome (ADS) is characterized by a high serum insulin concentration due to insulin autoantibodies or insulin receptor autoantibodies, resulting in dysglycemia [1]. ADS includes insulin autoimmune syndrome (IAS) and type B insulin resistance syndrome (TBIR), caused by insulin autoantibodies and insulin receptor autoantibodies, respectively [1,2]. Several conditions have been linked to IAS, including the use of drugs containing a sulfhydryl group (metamizole, alpha-lipoic acid, penicillamine, glutathione, captopril, isoniazid, and thiamazole, among others), some viral infections, blood dyscrasias and autoimmune diseases, while TBIR is commonly associated with autoimmune diseases [2][3][4].
Autoimmune diseases that most commonly coexist with ADS include systemic lupus erythematosus (SLE), rheumatoid arthritis, scleroderma, and myositis. Patients with ADS may even have overlapping clinical manifestations of multiple distinct immune disorders, such as SLE and dermatomyositis [5,6]. This case report aims to present a female patient with initial manifestations compatible with the two known forms of ADS (IAS and TBIR) in association with SLE, followed by the development of dermatomyositis. This triple association has not been previously reported.

CASE REPORT
This case describes a previously healthy 31-year-old Peruvian woman who was admitted to the Emergency Department with altered mental status, seizures, and a capillary glucose of 36 mg/dl, which prompted the administration of four ampoules of intravenous 33% dextrose, resulting in the complete resolution of her symptoms, meeting the criteria for Whipple's triad.
Once the hypoglycemia was corrected, she was hospitalized to complete diagnostic studies. In terms of her past medical history, she had tuberculosis at the age of 14, does not take any medications at home, and has no history of substance abuse. Regarding family history, her mother has type 2 diabetes mellitus, and her father has been diagnosed with thyroid cancer. She reported being asymptomatic until 6 months before admission when she started to present polyarthralgia, weight loss, hair loss, oral ulcers, and amenorrhea. Physical examination revealed normal vital signs, thin appearance (weight: 46 kg, body mass index: 19.2 kg/m 2 ), acanthosis nigricans in the neck and armpits, mild hirsutism (modified Ferriman-Gallwey score: 14 points), palatal erythema, malar rash, polyarthritis, and mild pretibial edema. Her hospital course was complicated by persistent fasting hypoglycemia and some episodes of postprandial hyperglycemia between 200 mg/dl and 400 mg/dl. Laboratory studies revealed fasting hypoglycemia ranging from 32 to 52 mg/dL, elevated fasting insulin ranging from 69 up to more than 300 UI/mL, C-peptide of 3 ng/ml (reference range: 0.5-2 ng/ml), and positive anti-insulin antibodies with a value of 4.7 U/mL (reference value: <0.5 U/mL), which were consistent with hyperinsulinemic hypoglycemia. The complete blood count showed normocytic normochromic anemia. Thyrotropin and free thyroxine levels were normal, and antithyroid peroxidase and anti-thyroglobulin antibodies were negative. beta-human chorionic gonadotropin subunit was negative, androgens (free testosterone, androstenedione, and dehydroepiandrosterone sulfate) were normal, liver function tests were normal, and the lipid panel showed hypercholesterolemia with normotriglyceridemia. Anti-insulin receptor antibodies were not available at that time. Positive results were found for antinuclear antibodies (ANA) with a dense fine speckled pattern, anti-smith, and anti-doublestranded DNA (anti-dsDNA) antibodies, while anticardiolipin, anti-RNP (anti-ribonucleoprotein), anti-Ro, and anti-La antibodies were negative. Further laboratory workup revealed marked proteinuria (4.2 g/24 h), and hyperprolactinemia of 55 ng/ml (reference range: 5-25 ng/ml) ( Table 1). Hypocomplementemia was also found. A kidney biopsy showed findings consistent with membranous glomerulonephritis.
Computed tomography (CT) of the chest, abdomen, and pelvis did not show significant abnormalities. As part of testing to determine the cause of elevated prolactin, magnetic resonance imaging (MRI) of the pituitary gland was ordered, but no changes were found in the pituitary gland. A triphasic dynamic contrast-enhanced CT scan of the pancreas was performed to rule out insulinoma as the cause of hypoglycemia.
Finally, the diagnosis made was ADS associated with SLE with renal, hematologic, and articular involvement. Initial treatment consisted of prednisone 30 mg/day, azathioprine 125 mg/day, and hydroxychloroquine 400 mg/day, resulting in the improvement of the proteinuria and arthritis symptoms. Glucose levels were initially stabilized with insulin (NPH 40 units/day and regular insulin 24 units/day) and subsequently, with metformin and diet.
The patient was followed up in the outpatient clinic, remaining asymptomatic and maintaining adequate glycemic control with metformin 500 mg BID, which was later suspended due to persistent euglycemia. Her menstrual cycle normalized, and acanthosis nigricans decreased significantly. According to Rheumatology follow-up visits, the proteinuria resolved, and SLE remained in remission without the use of additional corticosteroids.
At the age of 34, she presented with recurrent episodes of Raynaud's syndrome and proximal weakness of the lower extremities with difficulty going up and down the stairs. During hospitalization, we noticed crusty ulcers on the finger pads of both hands, Gottron's papules, butterfly rash, and heliotrope rash. Moreover, laboratory results showed a positive ANA (1/80) and elevated transaminases (AST: 377 UI/L, ALT: 263 UI/L) and creatine phosphokinase (CPK: 8347 UI/L). Glucose levels were normal and anti-insulin antibodies were negative. Electromyography revealed a mixed pattern that consisted of spontaneous activity with small, short, and polyphasic motor unit potentials and early recruitment. Muscle biopsy showed perifascicular atrophy as well as perivascular and perimysial inflammatory infiltrates containing CD4+ T lymphocytes and B lymphocytes. Dermatomyositis was diagnosed, and the patient was started on prednisone 60 mg/day, hydroxychloroquine 400mg/day, methotrexate 10 mg/day, and nifedipine 30 mg/day, achieving an adequate clinical and laboratory response. At the age of 39, the patient returned complaining of worsening proximal myopathy that did not improve despite an increase in prednisone dose from 15 to 60 mg daily. She also developed acanthosis nigricans on her neck and skin folds as well as a characteristic moon face. At the time, CPK level was elevated at 14 800 U/L and glucose levels were normal. As a result of these new findings, she was hospitalized and received a high dose of methylprednisolone, with subsequent favorable clinical and laboratory response. At the age of 41, during her follow-up via telemedicine throughout the pandemic, she reported feeling well without limitation of her daily activities. Her glucose levels (86 mg/dl) and insulin levels (12 UI/mL) remained normal and anti-insulin antibodies remained negative. Also, she had a decrease in CPK levels (136 UI/L) and proteinuria was absent. As of now, her episodes of dysglycemia have not recurred and she continues to have outpatient followup in rheumatology and endocrinology departments.

DISCUSSION
In this case, ADS was suspected due to episodes of recurrent hypoglycemia alternating with postprandial hyperglycemia associated with inappropriately elevated fasting insulin and was confirmed by the presence of antiinsulin antibodies, compatible with IAS. Remarkably, she also exhibited clinical features consistent with TBIR. Our patient had not received insulin prior to her hospitalization at age 31.
IAS affects white men and women with an average age between 40 and 80 years old and is characterized by hyperinsulinemic hypoglycemia associated with a high titer of anti-insulin antibodies, in the absence of pathologic abnormalities of the β islets and prior exposure to exogenous insulin [1,7]. While 50% of reported cases of IAS are related to medications, such as methimazole, alpha-lipoic acid, clopidogrel, esomeprazole, and captopril, less than 5% of cases are associated with rheumatologic autoimmune diseases [7]. Acanthosis nigricans is rare in IAS and there is usually no hyperandrogenism. In IAS, hypoglycemia is usually described as fasting, reactive, or both, and there is also postprandial hyperglycemia [7]. IAS treatment usually involve withdrawing suspected medication, dietary adjustments, and α-glucosidase inhibitors [7]. Patients who do not respond to initial therapy are treated with immunosuppression. It was shown that 41.7% of IAS cases required immunosuppressant treatment; while 54.4% recovered with changes in diet, discontinuation of triggering factor, and α-glucosidase inhibitors [8].
Furthermore, our patient presented acanthosis nigricans, hyperandrogenism, and episodes of hyperglycemia; features found in TBIR [3]. This entity mainly affects black women between 40 and 50 years old, and is not typically drug-induced, but is associated with other autoimmune disorders, particularly SLE, which is present in 35% of cases [9]. Acanthosis nigricans and hyperandrogenism are common features of TBIR. There is mainly hyperglycemia, and less commonly, fasting, or reactive hypoglycemia. There are also normal or low levels of blood triglycerides [9]. Considering that the levels of antibodies against insulin were markedly elevated in association with the clinical manifestations described above, we concluded that the diagnosis of our patient was IAS and TBIR. Moreover, the coexistence of anti-insulin and antiinsulin receptor antibodies has been reported [10,11]. TBIR is usually managed with dietary fragmentation, high doses of insulin, and immunosuppressants such as prednisone and cyclophosphamide [9].
The pathophysiology of IAS is not fully understood, however, after a meal or glucose load, anti-insulin antibodies bind the insulin secreted in response to rising blood glucose levels, leading to reduced insulin availability at the receptors in the liver and peripheral tissues, causing hyperglycemia and further insulin secretion [3,7,12]. When blood glucose levels start to decrease and insulin secretion declines, the insulin bound to the antibodies is released, leading to inappropriately high free insulin concentrations for the blood glucose, causing hypoglycemia (part A in Figure 1) [3,12].
About TBIR, anti-insulin receptor autoantibodies can initially act like insulin and prevent insulin degradation, leading to hyperinsulinemia and subsequent hypoglycemia [3,13]. However, chronic exposure to these autoantibodies can lead to persistent hyperglycemia and insulin resistance [3,9,13]. The effect of these antibodies varies based on their concentration: high titers result in an antagonistic effect causing hyperglycemia, while low titers result in an agonistic effect causing hypoglycemia (part B in Figure 1) [3,12,13]. SLE is the most common autoimmune disease associated with ADS, specifically with TBIR [10,11]. Dermatomyositis is also considered among the triggering autoimmune disorders for ADS [14]. Our patient had dermatomyositis, which was evidenced by proximal muscle weakness as well as elevation in CPK and confirmed by electromyography and muscle biopsy. Over the course of a 10-year follow-up, our patient presented ADS, SLE and dermatomyositis, making it a unique case that has not been reported in the literature so far (Figure 2). Furthermore, our patient presented hyperprolactinemia, but no abnormalities were found on MRI of the pituitary gland. A possible association between hyperprolactinemia and SLE has been proposed. According to [15], elevated levels of prolactin are seen more frequently in patients with SLE than in the general population. The suggested mechanisms for this association include increased production of prolactin by lymphocytes, stimulation of pituitary prolactin secretion by proinflammatory cytokines and genetic factors [15].
Regarding treatment of IAS and TBIR, there are two approaches: glycemic control and immunosuppressive therapy. In our patient, glycemic control was achieved by insulin administration and subsequently metformin, which is usually used in TBIR [11]. Corticosteroids, azathioprine, plasmapheresis, and rituximab, among others, are usually used as immuno-modulating therapy for IAS and TBIR [16]. In this case, prednisone, hydroxychloroquine, and azathioprine were required for SLE treatment. The remission of SLE led to the stabilization of her blood sugars and resolution of the ADS. Cyclophosphamide and rituximab are reserved for severe cases of SLE [10,17,18].
In relation to the management of dermatomyositis [19], although the disease seemed controlled after its diagnosis, it progressed with an exacerbation that did not respond to an increase in the dose of prednisone (1 mg/kg/day), requiring high doses of methylprednisolone and cyclophosphamide; combination previously used in four out of six cases of SLE and dermatomyositis [4].

CONCLUSIONS
In conclusion, ADS (IAS and TBIR) is a rare but important cause of hypoglycemia. Although both have an autoimmune basis and both can cause hyperinsulinemic hypoglycemia, their pathophysiology, treatment, and prognosis are different. This case demonstrates the coexistence of both in a patient with SLE who subsequently developed DM, highlighting the importance of addressing the underlying autoimmune disorders in patients with ADS to achieve optimal glycemic control.