Overlap syndrome involving rheumatoid arthritis and systemic sclerosis complicated by Hashimoto’s thyroiditis and interstitial lung disease detected in primary care: a case report

Introduction

Overlap syndrome (OS) is an autoimmune condition characterized by clinical features that meet the diagnostic criteria for at least two connective tissue diseases (CTDs), which can arise simultaneously or develop sequentially (1). The CTDs encompass rheumatoid arthritis (RA), systemic sclerosis (SSc), systemic lupus erythematosus (SLE), polymyositis, dermatomyositis and Sjögren’s syndrome (1). Diagnosing OS is challenging due to the overlapping symptoms among these conditions (2). Current diagnostic approaches to OS generally involve detecting specific antibodies alongside characteristic symptoms or identifying distinct clinical patterns, even without particular antibodies (3).

OS is associated with various autoimmune disorders, including autoimmune thyroid disease (4,5). A retrospective study revealed that individuals with autoimmune thyroid diseases, especially Hashimoto’s thyroiditis, are at increased risk of developing other CTDs like RA and SSc and vice versa (6). Interstitial lung disease (ILD) is another condition frequently occurring in OS, adding complexity to its clinical presentation (7). Given the presence of multiple conditions in OS, it is crucial to obtain a comprehensive medical history and perform a detailed physical examination to facilitate early detection of these conditions.

This case report describes a patient with OS, involving RA and SSc, complicated by Hashimoto’s thyroiditis and ILD. The patient presented with a diverse range of symptoms, examination findings, and imaging abnormalities, illustrating the complexity of the clinical presentation. This case highlights the importance of early diagnosis and timely management in such complex conditions and the need for a coordinated multidisciplinary approach to ensure optimal patient care. Effective collaboration among primary care physicians, rheumatologists, endocrinologists, respiratory physicians and radiologists is crucial to achieving the best outcomes for the patient. We present this article in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-2025-66/rc).

Case presentation

A 48-year-old Malay woman, employed as a teacher, visited a university primary care clinic in June 2022, reporting a 1-year history of intermittent joint pain, swelling, and morning stiffness in both hands and fingers. The symptoms had a gradual onset and were more noticeable in the morning or after prolonged inactivity. She described the joint pain as dull and aching, with a pain score of 4 out of 10, indicating a mild to moderate level of discomfort. There was no specific factor which aggravated the joint pain, and it was partially relieved by oral paracetamol and over-the-counter painkillers. Her morning stiffness typically lasted between 30 minutes to 1 hour, and she experienced no relief from any specific actions or treatments. These symptoms were accompanied by skin thickening on her fingers, extending to her upper arms. However, there were no additional symptoms such as fever, oral ulcers, rashes, difficulty swallowing, gastro-esophageal reflux, dry mouth, dry eyes, or limb weakness. Despite the symptoms, she could still write, teach students, and perform activities of daily living. She did not smoke, consume alcohol, or use any illicit drugs, and she had no other significant health issues. Additionally, she is married and blessed with two healthy children.

On examination, she was a medium-built, middle-aged woman with normal vital signs. Examination of the hands revealed bilateral swelling of the proximal interphalangeal joints. Notably, the skin over the swollen joints appeared normal, with no signs of erythema. On palpation, the skin temperature over the swelling area was not warm to touch and non-tender. However, the range of motion of the bilateral hands was restricted due to swelling and stiffness. Additionally, examination revealed sclerodactyly, characterized by thickened skin extending from distal areas to the metacarpophalangeal joints to the proximal arms. No other findings such as Raynaud’s phenomenon or digital pulp atrophy were detected. A neurological examination of both hands showed no abnormalities, and the sensation was preserved. Both the respiratory and cardiovascular examinations were also normal.

The patient’s clinical presentation and physical examination findings were highly suggestive of CTDs, particularly RA and SSc. Several differential diagnoses were considered at this stage which included osteoarthritis (OA), psoriatic arthritis, and gouty arthritis. OA was deemed unlikely because of her overlapping clinical presentation of having skin thickening. Psoriatic arthritis was excluded due to the absence of psoriasis-related rashes. Additionally, gouty arthritis was ruled out because there were no signs of inflammation, such as redness, warmth to touch, or tenderness on palpation.

The hematological workup revealed normal full blood count parameters. The hemoglobin level was 12.6 g/dL, the white blood cell count was 7.7×10⁹/L, and the platelet count was 382×10⁹/L. However, the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels were elevated at 44 mm/h and 7.5 mg/L, respectively. The results of the liver function, kidney function, and urinalysis tests were all unremarkable. Autoantibody testing detected rheumatoid factor (RF) at 40 IU/mL, anti-cyclic citrullinated peptide (anti-CCP) at 60.2 U/mL, anti-DNA topoisomerase I (Scl-70) antibodies, and anti-Ro (SS-A) antibodies. X-rays of bilateral hands revealed subchondral sclerosis of both distal radii with mild joint space narrowing of both radiocarpal joints as shown in Figure 1.

Figure 1 Radiographs of both hands in posteroanterior view (A) and ball-catcher view (B) showed subchondral sclerosis of both distal radii with mild joint space narrowing of both radiocarpal joints in keeping with degenerative changes (green arrows). L, left; R, right.

Therefore, the diagnosis of RA and suspected SSc was initially made in primary care. She was subsequently referred to a rheumatologist, and the diagnosis OS involving RA and SSc was confirmed. The patient was initially prescribed methotrexate (MTX) tablets at a dosage of 10 mg per week and diclofenac tablets at 50 mg as needed. Later, hydroxychloroquine 200 mg once daily (OD) and sulfasalazine 500 mg twice daily were also added to control disease activity.

At a follow-up visit, the patient reported experiencing intermittent lethargy, dry skin, constipation, and a dry cough for the past six months which preceded the initiation of disease-modifying antirheumatic drugs (DMARDs) by the rheumatologist. However, she did not experience fever, weight loss, night sweats, chest pain, shortness of breath, neck swelling, cold intolerance, or any other systemic symptoms. The neck, abdominal, cardiovascular, and respiratory examinations were unremarkable. However, thyroid function test (TFT) demonstrated low level of T4 at 7 mmol/L and elevated thyroid-stimulating hormone level at 6.28 mIU/L. Additionally, the blood tests showed positive anti-thyroid peroxidase (TPO) antibodies, indicating an autoimmune response. Based on these findings, the patient was diagnosed with Hashimoto’s thyroiditis and subsequently referred to an endocrinologist for further management. Treatment was initiated with a starting dose of 12.5 mcg of levothyroxine OD, which was later increased to 25 mcg OD to address her symptoms of hypothyroidism. She was scheduled for follow-up appointments every 2 to 3 months, during which her TFT would be reassessed. This approach aimed to ensure that the thyroid hormone levels were adequately managed to alleviate her symptoms.

Her chest X-ray (CXR) revealed normal findings with clear lung fields and no evidence of consolidation, effusion, or other abnormalities. Echocardiogram findings demonstrated a normal estimated pulmonary artery systolic pressure of 22 mmHg. Spirometry revealed a restrictive lung disease pattern with low forced expiratory volume in one second (FEV1) at 64%, low forced vital capacity (FVC) at 62%, a high FEV1/FVC ratio of >0.7, and a low diffusing capacity of the lungs for carbon monoxide (DLCO) at 56.6% (normal is over 80%). Additionally, a 6-minute walk test (6MWT) revealed no desaturation.

Due to the high suspicion of ILD, the primary care physician requested a high-resolution computed tomography (HRCT) scan, which showed fine reticular opacities in the posterior regions of both lower lobes of her lungs and a ground-glass nodule (GGN) in the apical segment of the right upper lobe, with some subpleural sparing, as illustrated in Figure 2. The patient was subsequently referred to a respiratory physician, who diagnosed early ILD associated with OS. She was managed with regular follow-ups to monitor disease progression using lung function tests and HRCT. The prognosis of the condition and the potential need for immunosuppressive therapy in the future were discussed with the patient.

Figure 2 HRCT of the thorax in axial (A,B) and coronal (C) views, showed a ground glass nodule in the apical segment of the right upper lobe (green arrows). Fine reticular opacities in the posterior aspects of the bilateral lower lobes with relative subpleural sparing (blue arrows) were suggestive of CTD-ILD. CTD-ILD, connective tissue disease-associated interstitial lung disease; HRCT, high-resolution computed tomography.

All procedures performed in this study were in accordance with the ethical standards of the institutional research committees and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

This is a challenging case of OS involving RA and SSc, further complicated by Hashimoto’s thyroiditis and ILD, initially identified in primary care. The prevalence estimates of OS presenting with RA and SSc is around 6.4% to 32% (8,9). OS is difficult to diagnose in primary care due to the presence of overlapping symptoms among the CTDs (8). The underlying mechanisms of OS remain poorly understood, further complicating their diagnosis (2).

In this case, the diagnosis of RA was initially made in primary care according to the American College of Rheumatology and the European League Against Rheumatism (ACR/EULAR) 2010 criteria (10), and the Malaysian Clinical Practice Guidelines on RA (11). According to these criteria, a score of ≥6 is classified as definite RA. Her clinical symptoms of bilateral proximal interphalangeal joint pain, involving 10 small joints, high-positive anti-CCP antibodies, raised ESR, and a duration of symptoms persisting for more than 6 weeks scored her 8 points, which confirmed the diagnosis of RA. However, this patient also exhibited skin thickening in addition to RA symptoms, which led the primary care physician to refer her to a rheumatologist, considering SSc as a possible concurrent condition. Although SSc is less commonly encountered in primary care, primary care physicians need to have a high index of suspicion of SSc in patients presenting with skin thickening.

SSc can be challenging to diagnose due to the absence of established local guidelines and its potential to resemble other CTDs (9). In this case, the rheumatologist confirmed the diagnosis of SSc based on the ACR/EULAR 2013 classification criteria (12). According to this classification, patients with a total score of more than 9 are classified as having definite SSc. This patient scored a total of 14 points (9 points for skin thickening on both fingers extending proximal to the metacarpophalangeal joints, 2 points for the presence of ILD, and 3 points for the presence of positive anti Scl-70 antibodies).

Patients with SSc can be classified into limited cutaneous systemic sclerosis (lcSSc) and diffuse cutaneous systemic sclerosis (dcSSc), depending on the extent of skin involvement (12). Patients with lcSSc have skin thickening limited to the digits, hands, and forearms. On the other hand, patients with dcSSc have more extensive skin involvement extending to the proximal hands and trunk (12). This categorization is important for the future prognosis of SSc (12).

Nailfold videocapillaroscopy (NVC) is typically a core component of SSc diagnostic workup (13). However, a normal NVC was obtained in this case. While NVC is important, its results must be interpreted within the broader clinical context. A normal NVC in the presence of other supporting clinical features of dcSSc, does not negate the overall diagnosis (13,14). The diagnosis of diffuse SSc in this patient was supported by characteristic widespread skin involvement and positive autoantibody test results. These findings, in conjunction with a normal NVC, allowed for a confident diagnosis (13). A normal NVC in SSc patients has been associated with less severe skin involvement, consistent with the patient’s presentation (13,14). The overall clinical picture, therefore, justified the diagnosis.

In this case, it can be argued that the patient’s joint symptoms could represent arthritic manifestations within the context of SSc rather than an overlap with RA. However, the diagnosis of OS in this patient was made by the rheumatologist based on the coexistence of RA and dcSSc, supported by characteristic clinical features and high titers of anti-CCP antibodies and anti-Scl 70 antibodies. The rheumatologist’s consideration of OS (RA and dcSSc) in this case stems from the patient meeting the ACR/EULAR classification criteria for both conditions concurrently. By definition, OS involves the simultaneous or sequential occurrence of multiple CTDs. In this instance, the patient exhibits symptoms of both SSc and RA simultaneously.

The detection of a positive anti-CCP result with a titer of 60.2 U/mL in this case holds significant clinical weight, especially in the context of differentiating between various autoimmune conditions. Research indicates a strong association between high levels of anti-CCP antibodies and OS involving RA and SSc. A study demonstrated that approximately 64% of patients with such OS exhibited elevated anti-CCP antibody levels (15). The presence of a high anti-CCP antibody titer, combined with other clinical and laboratory data, contributed to the rheumatologist’s diagnosis. The absence of other positive autoantibodies is also clinically relevant and considered in the overall evaluation. The nuanced interpretation of both positive and negative test results, along with clinical findings, is essential for accurate diagnosis in this complex autoimmune condition (3,15).

To complicate the situation further, this patient experienced symptoms of fatigue, dry skin and constipation for a duration of six months during her regular follow-up in primary care. With the recent diagnosis of OS, the primary care physician suspected a possible association between OS and an autoimmune thyroid disorder. As a result, the patient was subsequently referred to an endocrinologist, who confirmed the diagnosis of Hashimoto’s thyroiditis through the presence of positive anti-TPO antibodies. Literature has shown that Hashimoto’s thyroiditis is often associated with RA and SSc (4). This association is believed to be due to shared genetic susceptibility that increases the likelihood of developing multiple autoimmune conditions, further adding to the complexity of this case (4).

During the primary care follow-up, the patient also reported experiencing intermittent dry cough and lethargy for the past 6 months. In primary care, these symptoms are common and can have multiple differential diagnoses. In this case, the patient reported these symptoms prior to the initiation of DMARDs by the rheumatologist, making the diagnosis of MTX-induced ILD unlikely. The recent diagnosis of OS heightened the suspicion of ILD associated with OS of RA and SSc (7). Although the CXR was normal, this suspicion prompted the primary care physician to request for a spirometry and pulmonary function tests.

In this patient, the spirometry findings revealed a restrictive pattern with a low DLCO, consistent with ILD (16). This low DLCO inversely correlates with lung parenchymal inflammation and predicts ILD progression (14). In restrictive lung disease, spirometry typically shows reduced total lung capacity (TLC) and vital capacity (VC). The combination of reduced DLCO, low lung volumes, and the restrictive pattern strongly supports the diagnosis of ILD in this case. Importantly, the DLCO test is valuable for early ILD detection, often identifying the condition before spirometry shows abnormalities. It also helps monitor disease progression, assess treatment response, and predict mortality (17).

Given the strong suspicion of ILD, the primary care physician ordered an HRCT scan of the chest to confirm the diagnosis and evaluate its severity. HRCT is regarded as the gold standard to detect ILD because of its high sensitivity (18). In this case, the scan results revealed bilateral reticular opacities and GGN, indicating early changes of ILD, prompting referral to a respiratory physician for further evaluation. It can be argued that ILD is a well-recognized manifestation of SSc and not necessarily a complication or related to OS. However, in this case, ILD was manifested in the presence of both SSc and RA, supporting the diagnosis of OS.

ILD is a recognized manifestation of both SSc and RA, making HRCT-confirmed ILD a diagnostic challenge (18). The clinical presentation, including the temporal relationship between symptom onset and the diagnoses of RA and SSc, along with laboratory findings, were considered in determining etiology. Because the relative contributions of each condition to the disease process are often difficult to discern, the respiratory physician diagnosed the ILD as related to an OS instead of ILD related to specific SSc or RA.

Regarding the diagnosis of ILD, studies have indicated that, following the onset of respiratory symptoms, the average time to diagnosis is approximately 14.36±15.3 months (19), with some cases taking up to 2 years (20). Concerning this case, ILD was detected early, almost simultaneously with the OS diagnosis. This is important because a delay in diagnosis can lead to more advanced fibrosis and can potentially worsen the patient’s prognosis (20). If ILD is detected early, the 5- and 10-year survival rates are around 87.9% and 81.5%, respectively (21), highlighting the importance of early detection and prompt referral to a respiratory physician.

During respiratory follow-ups, the 6MWT results were within normal limits, and subsequent DLCO readings were also normal, indicating stable lung function. The 6MWT and DLCO are non-invasive and reliable methods for assessing disease-related disability (22) and are recommended to track disease progression during follow-up assessments (23).

Monitoring OS is complex because each CTD has a distinct antibody profile that can help to predict the progression of the disease and its prognosis (9). In RA, the presence of RF and high levels of anti-CCP antibodies indicate a more severe disease manifestation, earlier onset of ILD, and poorer long-term outcomes (24-26). In contrast, in SSc, the presence of anti-Scl-70 antibodies can predict disease progression (27). A recent study showed that over 81% of SSc patients with anti-Scl-70 antibodies ultimately developed ILD (27). In this case, the patient had positive RF, anti-CCP antibodies, and anti-Scl-70 antibodies, all of which are strongly linked to the development of ILD (12,27).

Managing this complex case of OS, complicated by Hashimoto’s thyroiditis and ILD, required a dedicated multidisciplinary team involving primary care physicians, rheumatologists, endocrinologists, respiratory physicians, and radiologists. The treatment for OS in this case involved a regime of DMARDs such as MTX, hydroxychloroquine, and sulfasalazine to control disease activity, in line with current clinical practice guidelines (28). However, treating ILD associated with OS is challenging due to the lack of established, evidence-based guidelines (29). Some experts recommend using immunosuppressive agents such as mycophenolate mofetil or cyclophosphamide to potentially slow the progression of ILD, although the supporting evidence is limited (29). In this case, the patient was closely monitored by a respiratory physician, who regularly conducted lung function tests and HRCT of the chest. However, no treatment for ILD was initiated at this stage, as the patient remained clinically stable with preserved lung function. The patient also has regular follow-up appointments with a rheumatologist, endocrinologist, and primary care physician.

Conclusions

In summary, this case demonstrated the complexity of managing OS involving RA and SSc, further complicated by Hashimoto’s thyroiditis and ILD. These associated conditions significantly influenced the progression of OS and impacted the patient’s quality of life. Primary care physician plays a crucial role in taking detailed histories, conducting thorough physical examinations, maintaining a high degree of clinical suspicion for associated conditions, facilitating timely specialist referrals, ensuring early diagnosis, and appropriate management. This case also highlights the importance of a multidisciplinary approach involving primary care physicians, rheumatologists, endocrinologists, respiratory physicians, and radiologists to deliver optimal care for such a complex case. Regular follow-ups and monitoring are crucial to track disease progression and adjust management strategies as the patient’s condition evolves.

Acknowledgments

We would like to thank the patient for giving her permission to publish this case report.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-2025-66/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-2025-66/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-2025-66/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional research committees and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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