1 Introduction

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory condition that primarily impacts the joints, leading to cartilage degradation, bone deterioration, and systemic health complications. It ranks among the most common autoimmune disorders globally, with a prevalence of 0.5%–1% [1]. Females exhibit a two- to threefold higher prevalence of RA compared to males. Both genetic and environmental factors play an important role in the disease's pathogenesis [2]. While primarily affecting joints, RA is a systemic disease, with nearly 40.6% of patients experiencing extra-articular manifestations [2].

Graves' disease (GD) is an autoimmune disorder characterized by the excessive production of thyroid hormones from an enlarged and hyperactive thyroid gland. This condition is the primary cause of thyrotoxicosis and impacts around 0.5% of men and 3% of women [3]. The pathogenesis of GD is complex, with a wide range of predisposing environmental, endogenous, genetic, and epigenetic factors [4].

Several studies determined various ranges of frequency of thyroid disorders, autoimmune thyroid dysfunction, and anti-thyroid autoantibody-like anti-thyroid peroxidase (anti-TPO) in RA patients [5]. Moreover, a bidirectional association has been revealed by other studies, suggesting an increased risk of developing thyroid dysfunction in patients with RA and vice versa [6, 7].

We present a case report that may represent complex immunological challenges when these two disorders overlap in the same young male patient, and we aim to shed light on the nuances of managing GD and RA when they intersect, offering insights for improved patient care and enhanced therapeutic interventions.

2 Case Presentation

2.2 Investigations and Treatment

The thyroid ultrasound showed an enlarged thyroid (Figure 1). He was diagnosed with GD and initiated on anti-thyroid medication Methimazole 5 mg TID. He had been undergoing treatment for GD for 5 years. Although his thyroid function had normalized for a period, the inflammatory pain worsened over time.

The patient was then referred to a rheumatologist. Upon physical examination, he appeared anxious and fatigued. No pallor, cyanosis, or lymphadenopathy were noted. His vital signs were (pulse: 110 bpm, blood pressure: 130/80 mmHg, and temperature: 37.5°C).

Locomotor examination showed synovitis in the 2nd and 3rd proximal interphalangeal (PIP) joints bilaterally, along with morning stiffness that lasted around 30 min. Limited range of motion in the affected joints was also present. Palmer erythema was also present. Rheumatoid nodules were seen on the extensor surfaces of both feet. There were no signs of psoriatic rash or dactylitis. The laboratory analysis included assessments presented in (Table 1).

TABLE 1. Laboratory tests results.

Laboratory test	Result	Reference range
WBC (white blood cells)	10,700	4.0–11.0 × 109/L
L/N (Lymphocytes/neutrophils ratio)	67/30	___
HB (hemoglobin)	11	Men: 13.8–17.2 g/dL Women: 12.1–15.1 g/dL
MCV (mean corpuscular volume)	85	80–96 fL
MCH (mean corpuscular hemoglobin)	27	27–33 pg/cell
PLT (platelets)	240	150–400 × 109/L
ESR (erythrocyte sedimentation rate)	65	Men: 0–15 mm/h Women: 0–20 mm/h
CRP (C-Reactive protein)	14.3	< 10 mg/L
RF (rheumatoid factor)	59.9	< 14 IU/mL
Anti CCP (anti-cyclic citrullinated peptide)	392	< 20 units/mL
TSH (thyroid stimulating hormone)	< 0.001	0.4–4.0 mIU/L
FT4 (Free T4)	2.72	0.9–1.7 ng/dL
ANTI TSH Receptor Abs (TRAb)	0.7	Negative: up to 1.25 IU/L Gray zone: 1.25–1.75 IU/L Positive: more than 1.75 IU/L
ALT (alanine aminotransferase)	13	Men: 7–55 units/L Women: 7–45 units/L
AST (aspartate aminotransferase)	25	Men: 8–48 units/L Women: 7–43 units/L
Cr (creatinine)	1.16	Men: 0.74–1.35 mg/dL Women: 0.59–1.04 mg/dL
Urea	29	10–50 mg/dL
Glucose (fasting)	80	70–99 mg/dL
Mg (magnesium)	1.9	1.7–2.2 mg/dL
Calcium	9.8	8.5–10.2 mg/dL
ALP (alkaline phosphatase)	172	40–129 U/L
Iron	71	50–170 μg/dL
Vit b12	758	200–900 pg/mL
Thyroid peroxidase antibodies (TPO)	687.80	< 9 IU/mL
ANA (anti-nuclear antibodies)	Negative (normal)	Titers below 1:160
Uric acid	3.2	Men: 3.4–7.0 mg/dL Women: 2.4–6.0 mg/dL
Triglycerid	121	< 150 mg/dL
Cholesterol	217	< 200 mg/dL
Widal test	Negative	___
Wright test	Negative	___
Tuberculin	Negative	___

Based on the previous findings, the patient was diagnosed with RA. He was discharged with a prescription for Methotrexate (He was instructed to take five oral pills of 2.5 mg Methotrexate on the same day each week, accumulating to a total dosage of 12.5 mg), Folic acid 5 mg (1 pill per week) and Prednisolone 5 mg (1.5 pills per day).

3 Discussion

The complicated link between RA and thyroid dysfunction often exists in the form of Autoimmune Thyroid Diseases (AITD) such as Hashimoto's thyroiditis (HT) and Graves' disease (GD) [7, 8].

The estimated occurrence of thyroid dysfunction in patients with RA varies from 6% to 33.8%, regardless of its classification as AITD, with the percentage potentially fluctuating based on geographical location [2].

In certain instances, simultaneous onset of both GD and RA has been observed after a significant serious event in the patient's life [9]. However, it remains unclear what precisely triggered both conditions at the same time in this scenario.

These two prevalent autoimmune conditions could possess similar initial mechanisms, as both of them are significantly more common in females than in males, a pattern observed across all ages [6, 9]. This phenomenon is intricately linked to DNA methylation, a crucial epigenetic process that can dynamically regulate gene expression [9].

Also, the presence of AITD or RA in family members suggests a higher risk for these conditions due to genetic influences [9]. Notably, the patient's sister suffers from hypothyroidism.

Smoking stands out as the primary environmental factor influencing the progression of AITD and RA. It can escalate the likelihood of developing conditions such as GD and RA, while it may decrease the risk in instances of HT [9].

In GD, a breakdown in immune tolerance initiates a Th1 dominant response, which over time shifts to a Th2 dominant response, significantly influencing B cells to produce thyroid receptor antibodies (TRAb), such as thyroid-stimulating antibodies (TSAb). This process leads to hyperthyroidism and the subsequent suppression of TSH production. The resulting hormonal imbalance manifests as symptoms such as weight loss, tachycardia, irritability, fatigue, thyroid enlargement, bulging eyes, and sleep disturbances [3].

RA, on the other hand, creates an accumulation of immune cells in joints, leading to inflammation, new blood vessel growth, and synovial lining enlargement, damaging bones and cartilage. This inflammation, driven by molecules like TNF and IL-6, results in swelling, pain, and further joint harm. It typically affects smaller joints in the wrists, hands, and feet, specifically the metacarpophalangeal (MCP), metatarsophalangeal (MTP), and proximal interphalangeal (PIP) joints, though it can also affect larger ones, such as the ankles, knees, elbows, and shoulders. RA's hallmark symptoms include joint pain, swelling, stiffness, with the potential for progressive damage and deformity [10].

In this instance, the patient exhibited pain, edema, and stiffness in the PIP joints in both hands, along with systemic symptoms such as exophthalmos, goiter, mood swings, and heat sensitivity. Additionally, fatigue, sweatiness, weight loss, and tachycardia were noted. Later, Rheumatoid Nodules (RNs) appeared on his feet.

RNs are the most prevalent extra-articular feature of RA, often arising in later stages of active disease. Commonly found in areas experiencing repeated stress, these nodules favor the extensor surfaces of the proximal forearm, MCP and PIP joints, as well as the occiput, back, heels, and other foot areas [11].

The 2021 American Thyroid Association (ATA) guidelines for diagnosing GD and the EULAR 2010/2023 update criteria for RA both emphasize early and accurate detection to enable timely treatment [12, 13]. GD diagnosis involves assessing symptoms like weight loss and heat intolerance, measuring thyroid hormone levels and TSH receptor antibodies, and utilizing imaging to confirm increased thyroid activity [12]. Similarly, RA diagnosis uses a scoring method that incorporates joint involvement, serologic markers (RF and ACPA), inflammation indicators (CRP and ESR), and the duration of symptoms. Patients with a score of 6 or more are considered to have definitive RA [13]. Both guidelines serve as structured approaches to diagnosing these distinct autoimmune conditions effectively.

The treatment of RA involves both relieving symptoms and modifying the disease prognosis, which requires a multifaceted approach [14].

Symptomatic treatment, primarily utilizing nonsteroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids, aims to reduce pain and inflammation. In addition, disease-modifying antirheumatic drugs (DMARDs) are pivotal in managing RA. Early initiation of DMARD therapy such as methotrexate is a key for achieving remission and preventing joint degeneration [15].

On the other hand, the treatment of GD involves many therapeutic options such as antithyroid drugs (ATDs) like methimazole and propylthiouracil. Alternative treatments including radioiodine therapy and thyroidectomy may also be considered based on patient preferences or specific indications [16].

Regarding the management implications of RA and GD on each other, a literature review finding [17] indicated that the use of antirheumatic agents in the treatment of RA does not appear to exacerbate autoimmune thyroid disease. Instead, the study found a potential beneficial effect, including a reduction in concentrations of thyroid autoantibodies. Moreover, as suggested by Wu et al. [6], effective management of one condition may potentially benefit the other due to the bidirectional causal relationship between RA and GD. Thus, these two autoimmune diseases could share ideal drugs if the drug target were to show up in the pathogenesis of each disease.

In our case, the patient was commenced on methotrexate to manage his RA. Methotrexate is associated with decreased tT4 levels in patients with rheumatoid arthritis, while glucocorticoids are linked to decreased tT3 levels [18]. Furthermore, it was found that subsequent treatment with methotrexate resulted in marked symptomatic improvement and lowered the thyrotropin receptor antibody level to 24% [19]. Other treatment options for RA, including chloroquine, JAK inhibitors, and iscalimab, may also have great potential for the treatment of GD and Graves' ophthalmopathy [10].

Patient-Reported Outcome Measures (PROMs) are critical for evaluating disease burden and treatment efficacy in RA [20]. However, conventional PROMs often fail to capture the unique challenges faced by younger patients, such as maintaining relationships, using public transportation, and fertility concerns [21].

4 Conclusion

Managing both RA and GD in the same patient and balancing the treatment regimens for both conditions while minimizing potential drug interactions and adverse effects can be challenging. Close monitoring by a multidisciplinary healthcare team, including rheumatologists and endocrinologists, is crucial to tailor a comprehensive treatment plan for such patients.

Author Contributions

Suaad Hamsho: data curation, supervision, writing – original draft, writing – review and editing. Ahmed Aldolly: writing – original draft, writing – review and editing. Mohammed Alaswad: writing – original draft, writing – review and editing.

Ethics Statement

Our institution does not require ethical approval for reporting individual cases or case series.

Consent

Written informed consent was obtained from the patient for their anonymized information to be published in this article.

Conflicts of Interest

The authors declare no conflicts of interest.