Rheumatic Disorders and Autoimmune Thyroid Disease. A Common Co-occurrence With an Unusual Presentation- A Case Report

doi:10.21203/rs.3.rs-5183368/v1

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Case Report

Rheumatic Disorders and Autoimmune Thyroid Disease. A Common Co-occurrence With an Unusual Presentation- A Case Report

https://doi.org/10.21203/rs.3.rs-5183368/v1

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Introduction

Graves’ disease (GD) and systemic lupus erythematosus (SLE) are two autoimmune disorders well known for their co-existence. Shared genetic susceptibility loci are being increasingly identified, confirming the causal bidirectional association between the two.

Case Presentation

Our case involves a young woman who presented with chronic symptoms of hyperthyroidism along with anemia, goitre, respiratory distress, and a recent onset of rheumatism. Diagnostic investigations fulfilled the criteria of GD along with SLE and Sjogren’s overlap. Pulmonary arterial hypertension (PAH) was detected via echocardiography, likely indicating the complex interplay between SLE and GD. Significant fetal and embryonic mortality raised the suspicion of anti-phospholipid syndrome, leading to the detection of anti-phospholipid antibodies. The likelihood of adrenal insufficiency and Autoimmune Polyglandular syndrome type 2 was also addressed. The patient was managed with anti-thyroid medications, steroids, and PAH-specific therapy. Our case is unique, as it involves multiple autoimmune disorders of rheumatic and endocrine origin in the same patient. The uniqueness also lies in the temporal sequence of the disorders, with GD being antecedent to SLE, contrary to what the literature suggests.

Conclusion

Although the patient tragically died, the goal here was to reinforce the idea that autoimmune disorders are complex, revealing themselves in various forms. Scouting for comorbidities and adapting a holistic treatment approach is prudent when dealing with these ailments. The social and financial dilemmas leading to noncompliance with treatment and its detrimental effects are also highlighted.

case report

goitre

Graves’ disease

sle

Addison’s disease

antiphospholipid antibody syndrome (aps)

pulmonary hypertension

Autoimmune thyroid disease (AITD) is a spectrum of disorders ranging from the most common form of Hashimoto’s thyroiditis (HT) to the less common Graves’ disease. Of interest, GD and SLE are two different entities; the former is organ-specific, whereas the latter is a multisystem inflammatory disorder. GD is characterized by agonistic antibodies against the Thyroid stimulating hormone (TSH) receptor on the thyroid gland, causing thyrotoxicosis. SLE involves autoantibody formation against various nuclear antigens and subsequent immune complex deposition, causing organ dysfunction and failure [1]. The coexistence of AITD and SLE is a well-known phenomenon. A meta-analysis from 1946–2018 revealed an increased prevalence of primary hypothyroidism in SLE patients (15–19% vs. 4.6% in the general population). Although less prevalent, the same study reported that hyperthyroidism was also more common in the lupus group (3–9% vs. 1.5%) [2]. Researchers are now inclined toward identifying single nuclear polymorphisms (SNPs) in various HLA and non-HLA genes, which serve as common genetic susceptibility loci for both SLE and GD [1][3][4]. This novel discovery can potentially revolutionize our approach toward such complex autoimmune entities. Anti-phospholipid syndrome (APS) is an acquired disorder causing recurrent venous and, notably, arterial thrombosis in young individuals and/or obstetric adversities, with persistent anti-phospholipid antibodies (APLs) [5]. Secondary APS is its co-existence with other disorders, mostly SLE. Although less acclaim, the association between AITD and APS and/or their antibodies is important, particularly in young women, since both are notoriously known for poor fetal outcomes and recurrent miscarriages (RMs) [5][6]. This case report confirms the association between GD and SLE as parent diseases in our patient, along with an interesting linkage with APS and Addison’s disease as probable co-occurrences, which, to our knowledge, is the first reported case involving multiple intricate autoimmune entities in the same patient.

A 35-year-old female, with no comorbidities or family history, presented at our clinic with a one-year history of generalized weakness, postural dizziness, dyspnea (mMRC grade two) and dry cough, which had worsened for the past week. Another chief complaint was the gradual increase in neck swelling for approximately three years, which caused pressure and discomfort. She had experienced palpitations, heat intolerance, diaphoresis, polyphagia, subfertility and proximal muscle weakness, along with substantial weight loss of approximately 10 kg. She also agreed to have polyarthralgia and myalgia with brief morning stiffness, oral ulcers, hair loss, dry mouth and gritty eyes for six months. Menses were heavy since menarche, but she had amenorrhea for three months. The obstetric history was complicated by three miscarriages and five still births, with only one surviving child. She had received several red blood cell transfusions and iron prescriptions in the past, but no formal diagnosis was given.

At first glance, our patient was an anxious and fidgety young woman with a staring gaze and a BP of 100/60 with no orthostasis. Vital examination revealed tachycardia at 128 bpm (regular), tachypnea, oxygenation of 94% on room air, and normothermia. The most striking finding was a large, warm and non-tender goiter with a uniform texture and audible bruit. Lymphadenopathy, the Pamberton sign, and increased JVP were absent, as was Thyroid Ophthalmopathy. Physical examination revealed cachexia, clubbing grade two, pallor, dehydration, fine tremors, palmar sweating, receding hairlines, blepharitis, a butterfly rash sparing the nasolabial folds, a fissured beefy tongue, and dental caries. Hyperpigmentation was observed around the palmar creases, knuckles, and oral cavity. She had a hyperdynamic precordium with a loud P2 sound on auscultation.

She was admitted for severe systemic illness, and serial investigations were carried out. She had severe anemia and thrombocytopenia and a microcytic peripheral film. The corrected retic count was 0.6%. The serum thyroid profile was dramatic, with a very low TSH, high T3 and T4. Other abnormalities included hyponatremia, hypoalbuminemia, and a high ESR. The serum Iron profile suggested iron deficiency. Pregnancy was ruled out by serum β-HCG and sonography. Urinalysis revealed only trace proteinuria (Table 1). Chest imaging was normal, but an echocardiogram revealed an isolated high mean pulmonary artery pressure of 55 mmHg. Thyroid sonography confirmed a uniformly enlarged and hypervascular gland. Immunological testing demonstrated convincing results, including strongly positive antinuclear antibodies along with, positive anti-DsDNA, anti-SS-A/Ro and anti-cardiolipin IgM. Other antibodies, including Smith, Scl-70, U1-RNP, CCP, RA factor, β2GPI and LA, were negative. Serum complement levels were very low. Thyroid receptor antibodies (TRAbs) were also positive. Morning cortisol was substantially low, and anti-TTG (tissue transglutaminase) IgA was negative (Table 2). Upon constellating the above description with the ACR/EULAR criteria, SLE and Sjogren’s (SS) overlap were diagnosed along with Graves’ disease. APS and Addison’s Disease were among the likely possibilities.

Table 1

Baseline laboratory investigations over the course of hospital stay¹
Laboratory Investigations	Normal Values	Day 1	Day 5	Day 7
Hb	11.9–15.0 (g/dL)	5.5	8.3	9.1
TLC	4–11 (103/uL)	5.6	7.5	8.9
PLT	150–400 (109/L)	74	89	90
PT	10–12 (seconds)	20.4		19.4
APTT	22–41 (seconds)	25.2		30.9
INR	< 1.1	1.9		1.8
CRP	< 5 (mg/dL)	1.1		5
ESR	< 20 (mm/hr)	75		50
BUN	7–20 (mg/dL)	4	12	10
Cr	< 1.0	0.3	0.3	0.4
Na	135–146 (mEq/L)	130	135	132
K	3.5-5.0 (mEq/L)	3.4	3.0	3.9
Cl	95–106 (mEq/L)	103	104	97
Ca	8.8–10.6 (mg/dL)	7.9		7.8
Mg	1.4–1.7 (mg/dL)	1.5		1.7
Po4	3.2–6.3 (mg/dL)	3.2		3.1
T Bili	0.2–1.3 (mg/dL)	1.6	1.4	1.2
SGPT	7–55 (U/L)	36	32	31
SGOT	8–45 (U/L)	39	39	40
ALP	44–147 (IU/L)	171		120
T pro	6-8.3 (g/dL)	7.3		7.1
Alb	3.5–5.5 (g/dL)	2.3		2.2
Spot urine PCR	< 0.2	0.4

1. Hb, hemoglobin; Hct, hematocrit; TLC, total leukocyte count; PLT, platelets; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; PT, prothrombin time; APTT, activated partial thromboplastin time; INR, international normalized ratio BUN, blood urea nitrogen; Cr, creatinine; Na, sodium; K, potassium; Cl, chloride; Ca, calcium; Mg, magnesium; PO4, phosphorus; T Bili, total bilirubin; SGPT, serum glutamic pyruvic transaminase; SGOT, serum glutamic oxaloacetic transaminase ;ALP, alkaline phosphatase; T pro, total protein; Alb, albumin

Table 2

Diagnostic Investigations²
Laboratory Investigations	Normal Range	Patient Results
TSH	0.5–4.5 (mIU/L)	0.005
T3	1.08–3.14 (nmol/L)	4.65
T4	5.5–11 (5.5–11 mcg/dL)	14
TRAb	0-0.9 (IU/L)	3.9
ANA	< 1:80	1:2560 (homogenous pattern)
Anti Ds DNA	0–25 (IU/L)	34.9
Anti SSA Ab	< 3.2 (IU/mL)	30.8
Anti SSB Ab	< 7 (IU/mL)	9.22
C3 levels	> 0.8 (g/dL)	0.43
C4 levels	> 0.129 (g/dL)	0.072
ACLA (IgM)	< 20 (U/mL)	57.4
Anti-β2GPI (IgM)	< 20 (U/mL)	12
LAA	20–40 (g/L)	35
8am serum cortisol	5.0–23 (mcg/dl)	0.3

2. TSH, thyroid stimulating hormone; T3, total triiodothyronine; T4, total thyroxine; ANA, anti-nuclear antigen; Anti Ds DNA, anti-double stranded deoxyribonucleic acid; Anti SSA Ab, anti–Sjogren's-syndrome-related antigen A autoantibodies; Anti SSB Ab, anti–Sjogren's-syndrome-related antigen B autoantibodies; C3, compliment component 3; C4, compliment component 4; ACLA, Anti cardiolipin autoantibodies; Anti-β2GPI, Anti beta 2 glycoprotein 1 autoantibodies; LAA, lupus anticoagulant antibodies

Initial management included blood transfusions, propranolol, omeprazole, and nutritional support. Upon confirmation of the diagnosis, 30 mg of oral Carbimazole and 400 mg of Hydroxychloroquine were started in divided doses. Dyspnea and PAH were curbed with Furosemide and the Endothelin receptor antagonist Bosentan. Given the high inflammatory activity of SLE, intravenous Dexamethasone was started at a dosage of 4 mg eight hourly to supplement hypoadrenalism. Mineralocorticoids were not used. In the absence of pregnancy and thrombosis, anticoagulation was not given. The patient and her family were counseled in detail about the importance of the frequency and timing of the medications to be taken, explaining the severity of her disease(s).

With the given treatment, the patient experienced remarkable improvement within one week and was discharged on oral medications, including equivalent doses of Prednisolone. Our further plan included testing for APL after 12 weeks, serum Adrenocorticotropic hormone (ACTH) levels along with adrenal imaging and a CT pulmonary angiogram, which were delayed due to financial limitations. Unfortunately, owing to noncompliance, she returned after two weeks with altered sensorium. Examination revealed hypotension, cold peripheries, tachycardia, and clear chest with respiratory distress. Blood gases revealed metabolic acidosis and hypoxemia. Her blood glucose level was 80 mg/dL. Admission to ICU was made. A whole panel of laboratories, including electrolytes, CBC, D-dimers and cortisol, was sent. The initial CT brain was unremarkable. Oxygen, vasopressors, antibiotics and IV hydrocortisone were initiated. While being prepared for intubation, she experienced intractable seizures and died shortly afterwards.

The coexistence of GD and SLE has been widely reported for more than a decade [1–4][7–8]. Anti-thyroid drugs have also been implicated as an independent cause of lupus [1]. Various East Asian studies have emerged recently, establishing a bidirectional causal association between the two, concluding that having one disease increases the risk of the other [1][3][4][9]. This is important, as it eliminates confounding bias, since both SLE and GD predominantly victimize young women. One retrospective cohort of 2796 new SLE patients concluded that patients with lupus with overlap had a greater relative risk of thyreopathy than did those with lupus alone. Additionally, it concluded that SLE patients with thyroid diseases more frequently have renal and CNS involvement [7]. This is reflected in our patient who had SLE overlapping with severe GD and later presented with intractable seizures. With respect to temporal associations, the majority of studies report that thyroid disorders are diagnosed months to years later in known SLE patients, mainly because of persistent nonspecific symptoms despite immunosuppression and low disease activity [2][7][8]. In contrast, our patient presented with chronic hyperthyroidism and goiter with acute decompensated thyrotoxicosis. The onset of rheumatism was recent and subtle, submerged in the chronicity and non-specificity of hyperthyroidism.

Recurrent miscarriage (RM) and pregnancy loss are some of the highlights of our case. Although a diseased thyroid status and SLE itself are well-known causes of subfertility and recurrent pregnancy loss, the high likelihood of Anti-Phospholipid syndrome (APS) in our patient is worth mentioning. Interestingly, the presence of isolated anti-thyroid antibodies and anti-phospholipid antibodies has been linked to an increased risk of RM and worse pregnancy outcomes, even in the absence of proven disease [5][6]. This is of paramount importance, as this association signifies the need for screening women with unexplained RM and poor fetal well-being for the presence of both anti-thyroid antibodies and anti-phospholipid antibodies.

On careful analysis, the compelling cause of this patient’s visit alongside thyrotoxicosis was respiratory limitation. The likely cause of this was found to be pulmonary arterial hypertension (PAH), in addition to anemia. The probable confounders of this were SLE and GD since both are recognized causes of pulmonary hypertension (PH) and/or PAH according to the WHO [10][11]. APS is also a notable culprit of thromboembolic (CTEPH)[12] and non-thromboembolic PH [13][14]. Recently, a study proposed that the prevalence of PH in GD patients did not differ significantly between the hyperthyroid and euthyroid groups,while 30% of patients sustained PH despite long-term thyrotoxic control, necessitating PAH-specific therapy [15]. This serves as a potential area of research to establish whether employing cardiorespiratory assessment routinely in evaluating patients with thyrotoxicosis and connective tissue disorder provides any long-term benefit.

Finally, shedding light on the gray area, underlying Addison’s disease (AD) in our patient was suggested by a low normal BP despite thyrotoxicosis, hyponatremia, and hyperpigmentation alongside postural dizziness [16][17]. Constellation of AITD and AD constitutes a polygenic disorder termed AUTOIMMUNE POLYGLANDULAR SYNDROME TYPE 2 [18]. Autoimmune polyendocrine syndromes have been reported to accompany rheumatic diseases, altering their natural history and rendering them resistant to rheumatological treatment. Moreover, overlooked endocrinopathies may accentuate the metabolic, musculoskeletal, and cardiovascular disorders encountered in the course of rheumatic disorders [19]. Although not conclusively diagnosed, identifying the adrenal status of our patient was crucial because the coexistence of AD necessitated the use of steroids, which are not otherwise used in the management of GD. Although highly active SLE also prompted their use in our patient, the indication was momentary.

Our report also highlights the dilemma of nonadherence of our community to the treatment advised, stemming from various reasons, notably poverty, illiteracy, relying solely on spiritual treatment and embarrassment. The burden imposed on healthcare in underdeveloped countries such as Pakistan involves not only the disease itself but also the reasons stated above.

We present an interesting and unusual case of Graves’ disease and SLE alongside Sjogren’s syndrome. The simultaneous existence of APS and AD was also highlighted. The clinical domains here, including chronic fatigue, anemia, PH, hypoadrenalism, and obstetric morbidity, can be partly explained by each of these diseases alone. However, it is prudent to realize that the overlap among these disorders is real and challenging, while focusing solely on a single diagnosis is detrimental, leading to treatment failure.Our aim is to therefore remind clinicians of the necessity of vigilant consideration and regular screening of concurrent autoimmune diseases and/or endocrinopathies while treating patients with these diseases. This ensures timely diagnosis and a holistic management approach, thereby reducing all-cause morbidity and mortality and improving the quality of life of patients.

All the abbreviations used in this manuscript are appropriately explained where necessary.

Funding Statement: Not Applicable

Conflict Of Interest: The author(s) of this work have nothing to disclose.

Ethics Approval: Not applicable as no human or animal objects were used, patients’ identity anonymized.

Consent to participate: Not Applicable

Consent for publication: Given that the patient died before the initiation of report writing, written consent was signed by the patients’ mothers. The translated details were explained in the native language because English was not understood. Patients’ images were not included for social and religious reasons.

Availability of data: Not Applicable

Code Availability: Not Applicable

Authors’ Contribution:

Tehreem Manzoor: Concept and design, Acquisition, analysis and interpretation of data, Drafting of the manuscript, Critical review of the manuscript, approved final version

Aiman Ali: Concept and design, Drafting of the manuscript, Critical review of the manuscript ,approved final version

Rida Masood: Concept and design, Acquisition, analysis and interpretation of data, Critical review of the manuscript ,approved final version

Syed Muhammad Kashif : Acquisition, analysis and interpretation of data, Critical review of the manuscript , approved final version

Muhammad Tanveer Alam: Acquisition, analysis and interpretation of data, Critical review of the manuscript , approved final version

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No competing interests reported.

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Rheumatic Disorders and Autoimmune Thyroid Disease. A Common Co-occurrence With an Unusual Presentation- A Case Report

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INTRODUCTION

CASE PRESENTATION

DISCUSSION

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References

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