Mixed Connective Tissue Disease: A Rare Disease with Many Faces

Introduction

Mixed connective tissue disease (MCTD) is a rare systemic autoimmune disorder characterized by an overlap of several connective tissue diseases, notably systemic lupus erythematosus and systemic sclerosis, in the presence of high-titer anti-U1- RNP antibodies [1-3]. Its clinical presentation is heterogeneous, frequently involving articular, muscular, cutaneous, pulmonary, or digestive manifestations, which often complicates and delays diagnosis [4]. Despite advances in the field, MCTD remains a clinical entity with still ill-defined boundaries, necessitating deeper insight to enhance patient management. The objective of this study is to report the experience of the Internal Medicine Department at Ibn Rochd University Hospital Center in Casablanca regarding this pathology over a five-year period.

Methods

This retrospective descriptive study was conducted from January 2020 to December 2024. The analysis included 9 female patients diagnosed with MCTD according to Kasukawa’s criteria. Data were collected through a thorough review of the patients’ medical records encompassing hospital admissions.

Results

Demographic Data

Among the 1921 patients followed in internal medicine during the study period, 9 cases of MCTD were identified, representing a prevalence of 0.4%. All patients were female, with a mean age at diagnosis of 41.3 years.

Clinical Presentation

The most frequent inaugural presentation was Raynaud's phenomenon accompanied by puffy fingers (33.3%). Other notable clinical signs observed included (Figure 1):

- Exertional dyspnea (Grade 3 on the modified Medical Research Council (mMRC) scale): 2 patients

- Orthopnea with abundant pericardial effusion: 1 patient - Malar rash (erythema in vespertilio): 1 patient

- Non-scarring alopecia: 1 patient

- Non-erosive polyarthritis: 1 patient

Associated Autoimmune Diseases

The presence of other autoimmune comorbidities was significant (Figure 2):

- Hashimoto's thyroiditis: 6 patients (66,6%)

- Sjögren's disease: 2 patients (22.2%)

- Immune thrombocytopenia: 1 patient (11,1%)

- Antiphospholipid syndrome (APS): 1 patient (11,1%)

Figure 2 : Autoimmune Diseases Associated to Mixed Connective Tissue Diseases in Our Series

Ancillary Investigations

In capillaroscopy, all patients exhibited distal microangiopathy, with severe findings (e.g., capillary deserts, hemorrhages) in 33.3% of cases (Figure 3).

Immunologically, antinuclear antibodies (ANA) were positive in 100% of patients (titer ≥ 1/640). The immunofluorescence pattern was speckled in 66.6% and a mixed homogeneous and speckled pattern in 33.3% (Figure 4). Anti-U1RNP antibodies were positive in 100% of patients, with strong positivity noted in 33.3% (Figure 5).

Organ Involvement

8 patients presented with pulmonary hypertension (PHT) in echocardiogram (Figure 6). Whereas confirmed PHT was present in only 2 patients. Thoracic computed tomography scan revealed no involvement in 33.3% of cases, non-fibrosing interstitial lung disease in 33.3%, and pulmonary fibrosis in 33.3% (Figure 7). Pulmonary function tests indicated restrictive ventilatory defects in 22.2% and mixed ventilatory defects in 22.2%.

Therapeutic Management

All patients received a calcium channel blocker. In addition, the following treatments were administered:

-Corticosteroids and mycophenolate mofetil: 55.5%

-Hydroxychloroquine: 44.4%

Evolution and Prognosis

The disease course demonstrated varied differentiation patterns (Figure 8):

- Differentiation towards systemic sclerosis: 33.3% (including one paraneoplastic case)

- Differentiation towards systemic lupus erythematosus: 44.4%

- Not individualized MCTD: 22.2%

The overall outcome was favorable in 88.8% of cases. Unfortunately, one patient (11.1%) succumbed to the disease, specifically due to a paraneoplastic form of systemic sclerosis.

Discussion

MCTD, also called Sharp’s syndrome, is an autoimmune entity defined by the coexistence of symptoms belonging to several systemic connective tissue diseases (systemic lupus erythematosus, systemic sclerosis, polymyositis) and by the presence of anti- U1RNP antibodies. Diagnosis is based on criteria sets such as those by Sharp, Kasukawa, Alarcón-Segovia, Kahn and Tanaka (Table 1) [1,5- 8].

Table 1 : The different diagnostic criteria for MCTD based on established classifications from the literature. Abbreviations: RP: Raynaud’s Phenomenon ; Anti-nRNP: Anti-U1 ribonucleoprotein antibodies ; PAH: Pulmonary arterial hypertension ; SLE: Systemic lupus erythematosus ; SSc: Systemic sclerosis ; PM/DM: Polymyositis/Dermatomyositis ; DLCO: Diffusing capacity for carbon monoxide ; CPK: Creatine phosphokinase.

Although recognized since the 1970s , MCTD remains uncommon, representing less than 2% of systemic connective tissue diseases in most series . In our study, it accounted for 0.4% of patients followed in internal medicine, confirming its rarity. The female predominance is well-established: in the large cohort by Burdt et al. (n = 91), 92% of patients were women, as was the case in the Norwegian study by Gunnarsson et al. (n = 147), with 89% female patients [9,10]. Our series is consistent, with 100% female patients. The mean age at diagnosis generally ranges between 30 and 50 years [9,10]. In our series, the mean age at diagnosis was 41.3 years, falling within this range.

Raynaud’s phenomenon is often the inaugural sign, reported in 80 to 100% of cases. In our study, it was present in one-third of patients at onset. It is frequently associated with capillaroscopic abnormalities, as we also observed in all of our patients. Severe forms (microangiopathy, capillary dropout) were present in 33.3%, comparable to what Cutolo et al. report in systemic connective tissue diseases with early vascular involvement [11].

Arthralgias and non-erosive polyarthritis occur in 50 to 80% of cases, often rheumatoid-like but without joint destruction [12]. In our cohort, only one patient (11%) presented with arthropathy. Malar rash (11%) and non-scarring alopecia (11%) are more characteristic manifestations of lupus, also found in our series.

The coexistence of autoimmune diseases is frequent. Autoimmune thyroiditis is found in about 30 to 40% of MCTD cases [13,14]. In our study, this proportion was even higher (66.6%), which might reflect a specificity of our population or a recruitment bias. Sjögren’s syndrome is also reported in MCTD, found in 22.2% of our patients [15].

Antinuclear antibodies (ANA) positivity is constant in MCTD, generally at high titers (≥1/640), with a speckled or mixed pattern [16]. Our data confirm this tendency: all cases were positive, with 77.7% having a titer of 1/1280. The anti-U1RNP antibody is the central immunological marker [17]. It was strongly positive in all our patients, in line with Kasukawa’s criteria. Other autoantibodies (anti-dsDNA, anti-Ro/SSA, anti-Scl70) may be transiently present but are not specific (Table 2) [18,19].

                                                                           Table 2: Clinical/Diagnostic Notes of Autoantibodies in MCTD

Pulmonary involvement is the main cause of death in MCTD. Pulmonary fibrosis (PF) is found in 20 to 40% of cases depending on the series, with a strong association to scleroderma-like progression [20]. In our study, one-third of patients already had PF at diagnosis, demonstrating the potential severity of respiratory involvement. Restrictive or mixed ventilatory defects, found in 44% of our patients, are also well described in pulmonary function tests of patients with MCTD.

Pulmonary arterial hypertension (PAH) affects 10 to 20% of patients in various series (up to 40% in advanced forms). PAH is the most serious life-threatening complication, making regular screening for this condition crucial [21]. Its detection via echocardiography and confirmation by right heart catheterization is essential [22]. In our cohort, 22.2% of patients had confirmed PAH.

Prevalence of cardiac involvement varied from 13% to 65% in MCTD cases, and pericarditis is the most common cardiac diagnosis with a prevalence of 30% and 43% [23]. One of our patients presented with orthopnea and a large pericardial effusion, which is consistent. Neurological and renal involvements are rarer and were not found in our series.

A major feature of MCTD is its nosological instability. Several longitudinal studies show that about 30 to 70% of patients evolve over time toward a differentiated connective tissue disease, most often systemic lupus or systemic sclerosis [24,25]. In our series, 77.7% of patients had already evolved: 44.4% toward lupus, 33.3% toward systemic sclerosis (including one paraneoplastic case), and 22.2% remained undifferentiated. This progression suggests that MCTD could represent an intermediate or early state of other connective tissue diseases rather than a stable entity. This hypothesis is reinforced by the clinical, immunological, and therapeutic evolution observed over time.

Treatment for MCTD depends on the type of manifestations. Corticosteroids are widely used to control inflammatory phases, often combined with immunosuppressants (azathioprine, mycophenolate mofetil, methotrexate) depending on organ involvement [26]. In our study, 55.5% received corticosteroids and mycophenolate. Hydroxychloroquine is recommended for mild articular or cutaneous involvement [27].

For interstitial lung disease, particularly early or moderate forms, several studies have demonstrated the efficacy of mycophenolate mofetil and cyclophosphamide in stabilizing respiratory function and even improving functional parameters [28].

Conclusion

MCTD is a rare and complex autoimmune disorder that poses significant diagnostic challenges due to the absence of highly specific criteria. Enhancing the standardization of immunological and clinical assessment tools is essential to enable earlier detection. Physician’s main goal remains improving patient monitoring and better anticipating potential complications. Looking ahead, ongoing research hold promise for more precise diagnostic methods and targeted therapies, offering hope for management of MCTD in the future.

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 are in accordance with the ethical standards of the institutional and/or national research comittee(s). Written informed consent was obtained from the patients for publication of this case series.

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