Systemic lupus erythematosus and pulmonary tuberculosis in a patient developing acute-onset type 1 diabetes

Abstract

A 73-year-old Japanese woman was admitted to our hospital with anorexia, weight loss, and fever. A few weeks prior to admission, she became aware of anorexia. She was leukopenic, complement-depleted, and positive for antinuclear antibodies and anti-double stranded DNA antibodies. She was also found to have chronic airway inflammation on computed tomography. At the time of admission, she had multiple erythematous plaques on face and neck. She had blood glucose 343 mg/dL, HbA1c 12.7%, serum C-peptide 0.74 ng/mL, urinary C-peptide 17 μg/day, and urinary ketone 3+; and was positive for anti-glutamic acid decarboxylase antibodies and anti-zinc transporter 8 antibodies. Her human leukocyte antigen type was DRB1* 09:01-DQB1* 03:03, which is a susceptibility haplotype for acute-onset type 1 diabetes (T1D). Therefore, she was diagnosed as having concomitant T1D and SLE. Initial treatment with insulin and prednisolone alleviated her symptoms. However, sputum culture revealed Mycobacterium tuberculosis 23 days later, and she was treated with a multidrug regimen. The timing of onset of the SLE and T1D was estimated to be 4–7 weeks prior to admission. No imaging findings were available prior to 3 weeks of admission, making it difficult to determine the timing of onset of pulmonary tuberculosis (TB). In summary, SLE and T1D are both autoimmune diseases, but rarely occur together. Environmental and genetic factors are involved in the development of T1D and SLE, but TB is rarely thought of as a causative environmental factor. In the present case, SLE, T1D, and TB may have interacted during their respective onsets.

Introduction

Acute-onset type 1 diabetes (T1D) is an autoimmune disease that presents with absolute insulin deficiency, owing to the destruction of pancreatic beta cells over the course of several months [1, 2]. Systemic lupus erythematosus (SLE) is also an autoimmune disease, and is characterized by inflammation and immune-mediated dysfunction of multiple organ systems, including the mucocutaneous, musculoskeletal, neuropsychiatric, hematologic, and renal systems [3]. Both T1D and SLE are caused by a combination of genetic and environmental factors, including infection [1, 3], but there have been few reports of patients with both conditions. In addition, tuberculosis is rarely discussed as a potential environmental factor in the development of both SLE and T1DM. Here, we report a patient with tuberculosis and SLE that were diagnosed during the development of acute-onset T1D.

Case report

A 73-year-old Japanese woman was admitted to our hospital with anorexia and weight loss. She had a history of pulmonary tuberculosis when she was in elementary school that was successfully treated with an anti-tuberculosis drug. At the age of 53, she was diagnosed with diabetes mellitus, which was managed using diet and exercise through her local clinic. Her glycosylated hemoglobin (HbA1c) remained at approximately 6% until 5 months prior to admission. Seven weeks prior to admission, she visited another hospital because of anorexia, stiffness of the hands, and edema of the lower legs. Her HbA1c was 7.1% and her casual blood glucose concentration was 197 mg/dL. A blood count revealed a low white blood cell count of 3310/µL. Her serum C3 and C4 concentrations were also low, at 27 mg/dL and 6 mg/dL, respectively. Furthermore, her anti-nuclear antibody (ANA) titer was 1/640. Four weeks prior to admission, her anti-double stranded deoxyribonucleic acid (ds-DNA) immunoglobulin G (IgG) antibody titer was ≥ 400 IU/mL. Two weeks prior to admission, computed tomography (CT) performed at the same hospital revealed chronic inflammation in both lungs, with bronchiectasis, mucus plugs, and granular shadows, but no sputum culture or smear was analyzed. At the same time, urinalysis revealed glucose 4+, but no urinary ketones or protein. However, her blood glucose concentration was not measured at this time, and the patient was only examined and not treated at the hospital.

Subsequently, she was admitted to our hospital with anorexia, weight loss (3 kg over 2 months), and fever. A physical examination performed on admission revealed that the patient’s height, body mass, and body mass index were 151.5 cm, 45.4 kg, and 19.8 kg/m², respectively. Her body temperature was 37.6 °C, her pulse rate was 112 beats/minute, her blood pressure was 144/80 mmHg, her peripheral oxygen saturation was 96% in room air, and her respiratory rate was 18 breaths/min. She had multiple erythematous plaques approximately of 5 mm in diameter scattered across her face, neck, and anterior chest. She also had bilateral slow pitting edema of her lower legs. She had no oral ulcers, neuropsychiatric symptoms, or arthritis. Laboratory examination revealed the following (Table 1): a blood glucose concentration of 343 mg/dL, an HbA1c of 12.7%, and a glycated albumin of 39.5%. Her endogenous insulin secretory capacity was very low, indicated by a serum C-peptide concentration of 0.74 ng/mL and a urinary C-peptide loss of 17 μg/day. Urinalysis revealed urine ketones 3+; and arterial blood gas analysis revealed pH 7.465, HCO₃⁻ 21.6 mmol/L, and anion gap 10.4 mmol/L, indicative of diabetic ketosis. The urinalysis was negative for protein and occult blood.

Table 1.

Laboratory tests on referral

Arterial blood gas (room air)		Blood chemistry		Immunology
pH	7.465	TP	5.9 g/dL	Anti-GAD Ab	63.0 U/mL
PO2	98.9 mmHg	Alb	2.8 g/dL	Anti-IA-2 Ab	< 0.6 U/mL
PCO2	30.7 mmHg	Cre	0.53 mg/dL	Anti-ZnT8 Ab	73.3 U/mL
HCO3−	21.6 mmol/L	eGFR	84 mL/min/1.73m2	ICA	-
Anion gap	10.4 mmol/L	AST	53 U/L	Anti-TPO Ab	< 28.0 IU/mL
		ALT	45 U/L	Anti-Tg Ab	< 16.0 IU/mL
Blood Count		Na	129 mmol/L	ANA (Homogeneous)	× 2,560
WBC	3900 /μL	K	3.9 mmol/L	anti-ds DNA IgG Ab	> 380 IU/mL
Neutrophils	84.6%	Cl	97 mmol/L	Anti-Sm Ab	< 7.0 U/mL
Lymphocytes	9.7%	CRP	1.47 mg/dL	Anti-U1-RNP Ab	< 3.5 U/mL
Monocytes	5.4%	NT-proBNP	256 pg/mL	Anti-SS-A Ab	< 0.4 U/mL
Eosinophils	0.0%			MPO-ANCA	< 0.2 IU/mL
Basophils	0.3%	Diabetology		PR3-ANCA	< 0.6 IU/mL
Atypical lymphocyte	0.5%	BG	343 mg/dL	C3	31 mg/dL
RBC	343 × 104/μL	HbA1c	12.7%	C4	7.7 mg/dL
Hb	10.3 g/dL	Glycated albumin	39.5%
Hct	30.5%	Serum C-peptide	0.74 ng/mL	Infection
PLT	15.3 × 104 /μL	Urinary C-peptide	17 μg/24 h	IGRA	–
	10.4 mmol/L			MAC Ab	< 0.50 U/mL
Urinalysis	10.4 mmol/L	Endocrinology		Sputum smear	–, –, –
Glucose	3+	ACTH	22.2 pg/mL	Sputum culture	Mycobacterium tuberculosis
Keton	3+	Cortisol	18.1 μg/dL
Occult blood	–	TSH	6.1 μIU/mL	HLA typing	DRB1* 09:01-DQB1* 03:03
Column	–	FreeT4	0.93 ng/dL
TP	0.29 g/gCre	FreeT3	0.95 pg/mL

WBC: white blood cell, RBC: red blood cell, Hb: hemoglobin, Hct: hematocrit, TP: total protein, Alb: albumin, Cre: creatinine, eGFR: estimated glomerular filtration rate, AST: aspartate aminotransferase, ALT: alanine aminotransferase, CRP: C-reactive protein, NT-proBNP: N-terminal pro-brain natriuretic peptide, BG: blood glucose, ACTH: adrenocorticotropic hormone, TSH: thyroid stimulating hormone, ADH: antidiuretic hormone, Ab: antibodies, GAD: glutamic acid decarboxylase, IA-2: tyrosine phosphatase IA-2, ZnT8: zinc transporter 8, ICA: islet cell antibodies, TPO: thyroid peroxidase, Tg: thyrogloblin, ANA: anti-nuclear antibodies, DNA: deoxyribonucleic acid, Sm: smith, U1-RNP: U1-ribonucleoprotein, SS-A: Sjogren's syndrome A, MPO-ANCA: myeloperoxidase anti-neutrophil cytoplasmic antibodies, PR3-ANCA: proteinase 3 anti-neutrophil cytoplasmic antibodies, IGRA: interferon-gamma release assay, MAC: Mycobacterium avium complex, HLA: human leukocyte antigen

At this time, she was treated by frequent subcutaneous injection of insulin. She was negative for islet-cell antibodies (ICAs) and anti-tyrosine phosphatase IA-2 (IA-2) antibodies, but positive for anti-glutamic acid decarboxylase (GAD) and anti-zinc transporter 8 (ZnT8) antibodies. On the basis of these findings, we diagnosed acute-onset T1D. Subsequently, we performed human leukocyte antigen (HLA) typing, and found that she carried HLA-DRB1* 09:01-DQB1* 03:03 with homozygosity. Her thyroid hormone concentrations, including of thyroid stimulating hormone (TSH), freeT4, and freeT3, were consistent with subclinical hypothyroidism. However, she was negative for anti-thyroid peroxidase (TPO) and anti-thyroglobulin (Tg) antibodies, and thyroid ultrasonography did not reveal any abnormalities. As her general condition improved, her thyroid hormone concentrations also improved, and she tested negative for autoimmune thyroid disease, consistent with the course of low-T3 syndrome. Her adrenocorticotropic hormone (ACTH) concentration of 22.2 pg/mL and her cortisol concentration of 18.1 μg/dL were normal. Her transaminase activities, including of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), were slightly high, but there was no evidence of cirrhosis. She also had a slightly high NT-proBNP concentration, but no signs of heart failure. In addition, she was positive for ANA and anti-ds-DNA IgG antibodies. She had a low white blood cell count, of 3900/µL. Furthermore, her serum C3 and C4 concentrations were low, at 31 mg/dL and 7.7 mg/dL, respectively. She had no more than moderate proteinuria and no cellular casts in her urine.

Biopsy of the erythematous area of her neck revealed the infiltration of lymphocytes and neutrophils around the sweat glands in the dermal reticular layer, and vacuolar degeneration was observed at the epidermal dermal border. Alcian blue staining showed mild mucin deposition in the shallow dermis. Fluorescent antibody staining revealed IgG, IgM, and C1q on the basement membrane, slight positivity for C3, and negativity for IgA and fibrinogen. C3, C1q, and fibrinogen staining also revealed the presence of these proteins in the walls of the small dermal vessels. These findings were consistent with a positive result of lupus band testing. CT revealed granular shadows in both of her lungs, but initial screening by means of a sputum smear and an interferon-gamma release assay (IGRA) was negative. Furthermore, she was aware of a slight increase in sputum volume. On day 17, she was diagnosed with SLE and treatment with prednisolone (PSL) 20 mg/day (approximately 0.5 mg/kg/day) was commenced. The patient’s temperature during hospitalization peaked at 38.2 °C, but decreased after the introduction of PSL. On day 19, she was discharged, after her fever and anorexia improved. However, 4 days after discharge (23 days after admission), sputum culture revealed Mycobacterium tuberculosis. Therefore, she was also diagnosed with pulmonary tuberculosis, and treatment with a four-drug combination (isoniazid, rifampicin, ethambutol, and levofloxacin) was commenced. The clinical course of the patient is shown in the Fig. 1.

Fig. 1.

Clinical course of the patient. For each disease and symptom of the patient, the estimated time of onset and the course of improvement were indicated by a band with shading. The exact date of onset of tuberculosis was unknown, and the period during which no imaging findings were available was also indicated by a dotted band. The date when each laboratory finding of the patient was first noted is indicated by black stars. The date when the examination was submitted was also indicated by a white star. The course of each treatment is indicated by white boxes. SLE systemic lupus erythematosus, TB tuberculosis, T1D type 1 diabetes, CT computed tomography, HbA1c glycosylated hemoglobin, PSL prednisolone, INH isoniazid, RFP rifampicin, EB ethambutol, LVFX levofloxacin

Discussion

We have described a patient with acute-onset T1D that developed immediately after the onset of SLE, progressed to diabetic ketosis, and was complicated by pulmonary tuberculosis.

T1D is a disease that develops because of absolute insulin deficiency, owing to the destruction of pancreatic beta cells, and is predisposed to by both genetic and environmental factors [1]. The present patient met the diagnostic criteria for acute-onset T1D (2012) [2]. The genetic factor with the strongest influence on the development of T1D is HLA type [4], and the present patient’s HLA type was DRB1*09:01-DQB1*03:03, which has been reported to increase susceptibility to acute-onset T1D in Japanese people [5]. However, we were unable to obtain islet-associated autoantibodies or C-peptide levels at the time the patient was first diagnosed with diabetes. Thus, we could not completely rule out the possibility that she had slowly progressive insulin dependent diabetes mellitus.

Many environmental factors are associated with T1D, including exposure to some viruses. Many studies have shown an association between the development of T1D and infection with viruses, of which the principal types are enteroviruses, including coxsackie virus [6, 7]. Furthermore, various immunologic mechanisms have been proposed to explain the process of pancreatic beta-cell injury [8–10]. Diabetes mellitus is a common cause of immunosuppression [11], and it specifically increases the risk of contracting tuberculosis [12]. However, bacterial infections, including with M. tuberculosis, have rarely been identified as triggers for T1D. Few reports have mentioned the possibility that Microbacterium avium subspecies paratuberculosis (MAP), which is an intracellular pathogen, may be trigger of T1D [13–16]. M. tuberculosis is also an intracellular pathogen, and therefore can avoid macrophages, which differentiates this species from other bacteria [17]. There are many differences between the immune response to bacteria and that to viruses [18]. However, a common feature of the immune response to both viral and intracellular bacterial infections is that it is usually impossible to eradicate the pathogen without destroying host tissue. Therefore, apoptosis represents an important mechanism for the elimination of infected cells [18]. Paccagnini et al. proposed the hypothesis that SLC11A1 polymorphism is involved in the mechanism of disease susceptibility common to both MAP and T1D [16]. SLC11A1, which functions as a transporter for divalent cations, is crucial in the early stages of macrophage activation and has a range of diverse effects on macrophage activity [19]. Several specific polymorphisms of SLC11A1 have been reported to be involved in susceptibility and resistance to autoimmune diseases and infections, such as T1D and tuberculosis [19–22]. Some specific polymorphisms in the SLC11A1 would be risk factors for tuberculosis in Asians [22]. T1D has also been reported to involve several SLC11A1 polymorphisms in disease susceptibility depending on race [19–21]. However, polymorphisms that increase the risk of both T1D and tuberculosis in specific races are not clear. The exact timing of the onset of tuberculosis in the present patient was unknown, and T1D was developing when it was first noted on CT (Fig. 1). Therefore, it was unclear whether the tuberculosis was involved in the development of the T1D.

SLE is a chronic autoimmune disease that is characterized by inflammation and immune-mediated dysfunction of multiple organ systems, including the mucocutaneous, musculoskeletal, neuropsychiatric, hematologic, and renal systems [3]. The present patient had clinical symptoms of SLE relating to two organ systems: the skin and the blood. She also had immunologic abnormalities, including strong positivity for ANA, positivity for anti-ds-DNA antibodies, and hypocomplementemia. The total score for the 2019 EULAR/ACR classification criteria for the patient was > 10 points, which is consistent with SLE [23]. Patients with SLE sometimes develop edema of the lower legs in the absence of renal or cardiac failure [24–26].

As for T1D, the pathogenesis of SLE is still largely uncharacterized, but it is thought that both genetic and environmental factors are involved in its etiology [27]. Shimane et al. reported that HLA DRB1^* 09:01 was associated with SLE susceptibility in a large-scale cohort study of Japanese people [28], and the present patient had the same HLA type, further suggesting that this genetic variant predisposes toward SLE.

Environmental factors, such as viral and bacterial infections, are thought to be associated with the onset and exacerbation of SLE [3], and SLE predisposes toward tuberculosis [29]. One possible mechanism is the influence of immunosuppressive drugs, including steroids. Another possible factor is that the frequency of proinflammatory cytokine-producing natural killer (NK) cells and NKT cells, which are involved in suppressing the growth of mycobacterium, is decreased in patients with active SLE [30]. However, there has been little discussion regarding the potential for TB to trigger SLE.

T1D is often associated with other autoimmune diseases [31], of which autoimmune thyroid diseases are the most commonly linked [31, 32]. However, concomitant T1D and SLE is not common [32–35]. Kota et al. reported that the prevalence of SLE in patients with T1D is 1.2% [32], and Cortes et al. reported that the prevalence of T1D in patients with SLE is 0.62% [36]. Reports of the simultaneous onset of T1D and SLE are even rarer, and of the 12 reported cases of concomitant T1D and SLE, only three involved a difference of < 1 year between the timing of onset of the two diseases [36–38]. We were unable to find any similarities between these three patients and the present patient, including with respect to HLA type. However, several genetic factors other than HLA type have been reported to increase the risk of developing T1D and SLE [39–41]. The microRNA miR-155 plays an important role in both innate and adaptive immunity, has been reported to be aberrantly expressed in patients with autoimmune diseases such as SLE andT1D, and has also been reported to affect their pathogenesis [39]. The 1858 T allele of the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene affects the development of 12 autoimmune diseases, including T1D and SLE [40]. Furthermore, multiple single nucleotide polymorphisms of the TYK2 gene have been shown to be associated with autoimmune diseases, with rs34536443 being protective against both T1D and SLE [41]. These genetic variants have not been looked for during previous case studies of patients with T1D and SLE, including in the present patient, but may be involved in the etiology.

As a supplementary note, autoimmune polyendocrine syndrome (APS) has been proposed to involve multiple autoimmune diseases, and can be classified as types 1–4 [42]. T1D and systemic autoimmune diseases are both present in APS3, but a diagnosis of autoimmune thyroid disease is essential for this diagnosis to be made, and in the present patient, the diagnostic criteria were not met.

In conclusion, we have described a patient who had concomitant SLE and tuberculosis during the development of acute-onset T1D. Both T1D and SLE are autoimmune diseases, but they rarely occur together. The patient had an HLA type that is a common disease susceptibility factor for both T1D and SLE, and this may have contributed to the presence of both diseases. In addition, although it was not possible to prove that tuberculosis was the direct trigger for the onset of each autoimmune disease, it is likely that the T1D, SLE, and tuberculosis may each have affected the course of the others.

Author contributions

Conceptualization: Takanobu Jinnouchi; Methodology: Takanobu Jinnouchi; Formal analysis and investigation: Riko Henmi, Takanobu Jinnouchi; Writing – original draft preparation: Takanobu Jinnouchi; Writing – review and editing: Kaoru Watanabe, Yasuhiro Suyama, Reiko Sakama, Takeo Idezuki, Supervision: Michio Hayashi.

Data availability

The data that support the findings of this study are available from the corresponding author, Michio Hayashi, upon reasonable request.

Declarations

Conflict of interest

None of the authors have any potential conflicts of interest associated with this research.

Ethical approval

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and/or with the Helsinki Declaration of 1964 and later versions. Informed consent or substitute for it was obtained from all patients for being included in the study.