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ORIGINAL ARTICLE
Ahead of print publication  

A comparative study of mixed connective tissue disease and overlap syndromes – A single-center study from India


1 Department of Clinical Immunology and Rheumatology, Kalinga Institute of Medical Sciences, KIIT University, Bhubaneswar, Odisha, India
2 Department of General Medicine, Kalinga Institute of Medical Sciences, KIIT University, Bhubaneswar, Odisha, India
3 Department of Pulmonary Medicine, Kalinga Institute of Medical Sciences, KIIT University, Bhubaneswar, Odisha, India

Date of Submission22-Mar-2022
Date of Acceptance23-May-2022
Date of Web Publication18-Aug-2022

Correspondence Address:
Prasanta Padhan,
Department of Clinical Immunology and Rheumatology, Kalinga Institute of Medical Sciences, KIIT University, Bhubaneswar - 751 024, Odisha
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injr.injr_60_22

  Abstract 


Introduction: Mixed connective tissue disease (MCTD) a classical overlap syndrome with four different defining criteria. The present study attempts to compare the clinical features and autoantibodies for MCTD and overlap syndromes.
Methods: In this observational study from October 2018 to August 2020, we included all the patients of MCTD and overlap syndromes. Alarcon–Segovia criteria was used as defining criteria for MCTD patients while the patients meeting diagnostic criteria for more than 1 of 6 classical autoimmune rheumatic diseases were selected in the overlap syndromes group. We compared their clinical features, laboratory parameters, and autoantibody profiles. MS Excel, STATA were used for statistical analysis, and comparison between the groups was done with t-test, Chi-square test, and Wilcoxon rank sum test. P < 0.05 was considered as statistically significant.
Results: The study consisted of 60 consecutive patients (MCTD, n = 30 and overlap syndromes, n = 30) with higher female population in both groups (90% in MCTD and 84% in the overlap syndromes group) compared to males. The incidence of fever (83.3% vs. 46.6%), weight loss (60% vs. 26.6%), trigeminal neuralgia (76.6% vs. 13.3%), and myositis (63.3% vs. 20.0%) was significantly higher in MCTD than overlap syndromes whereas the incidence of cough (66.6% vs. 90.0%) and dry mouth (20.0% vs. 53.3%) was higher in overlap syndromes than MCTD (P < 0.05). Anti-U1 RNP antibodies were seen in all MCTD (100.0%) patients while anti-Scl 70 antibodies (60%) and anti-ribosomal-p-protein antibodies (13.3%) were seen in overlap syndromes.
Conclusion: Fever and weight loss, trigeminal neuralgia, and myositis were more common in MCTD than overlap syndromes. Anti-U1 RNP antibodies seen in MCTD while Anti-Scl 70 antibodies and anti-ribosomal-P antibodies were commonly were seen in overlap syndromes.

Keywords: Autoantibodies, comparative study, mixed connective tissue disease, overlap syndrome, scleroderma-myositis overlap syndrome



How to cite this URL:
Maikap D, Deosale S, Singh P, Panda SS, Padhan P. A comparative study of mixed connective tissue disease and overlap syndromes – A single-center study from India. Indian J Rheumatol [Epub ahead of print] [cited 2022 Oct 3]. Available from: https://www.indianjrheumatol.com/preprintarticle.asp?id=353994




  Introduction Top


Mixed connective tissue disease (MCTD), since its first description in 1972, is generally described as a disease with mixed features of systemic lupus erythematosus, systemic sclerosis, polymyositis/dermatomyositis, and rheumatoid arthritis with high titers of anti-U1-RNP antibody in serum. The anti-U1-RNP antibody has been suggested to have a role in the pathogenesis of MCTD in various studies and titers in serum may correlate with disease activity.[1] IRF7 and IFI44 genes and the HLA region (HLA-DR1 and HLA DR-4) have been shown to exert a genetic risk on MCTD, although their presence itself may not be sufficient to trigger the disease.[2] Several different criteria have been described for the diagnosis and classification of MCTD and while all are comparable in their sensitivity and specificity in various studies, Alarcon–Segovia criteria is widely used.[3],[4],[5] The most commonly described clinical features of MCTD are Raynaud's phenomenon, polyarthritis, puffy hands, sclerodactyly, muscle disease, and esophageal dysmotility along with constitutional symptoms such as fever, arthralgia, myalgia, and fatigue. Some specific antibody associations like anti-cardiolipin antibodies have been associated with pulmonary arterial hypertension (PAH) and anti-angiotensin-converting enzyme (anti-ACE2) antibodies have been associated with constrictive vasculopathy and digital ischemia among MCTD patients.[6],[7] MCTD, although previously thought to have a benign course, has now been shown to have serious complications that can result in mortality including PAH, glomerulonephritis, and rarely central nervous system involvement.[8],[9],[10] Early recognition of the disease and timely interventions to prevent these complications may help in reducing mortality.

Overlap syndromes are identified as entities satisfying criteria for more than one of any of the classic autoimmune connective tissue diseases (systemic lupus erythematosus [SLE], SSc, polymyositis/dermatomyositis [PM/DM], rheumatoid arthritis [RA], and Sjogren's syndrome). Features of two diseases can occur concomitantly or sequentially. The groups of patients with similar overlap clinical features have been studied by several researchers to identify the specific autoantibodies that aid in defining some overlap syndromes and in facilitating the disease management.[11],[12] Overlap syndromes usually have a milder form of the disease. Autoimmunity in overlap syndromes is often antigen-driven by RNA-associated components and may direct against spliceosomal components, nucleosomal components, or proteasomal components.[13],[14] A variety of scleroderma overlap syndromes, lupus overlap syndromes and myositis overlap syndromes and their associations with specific antibodies have been described. Overlaps of PM with scleroderma are even more common than pure forms of PM.[15]

A distinction between MCTD, a classical overlap disease, and other overlap syndromes may have a prognostic significance and may help in the prediction and even prevention of specific complications associated with MCTD. Hence, this study was undertaken to differentiate their autoantibody profiles and clinical features.


  Methods Top


This prospective observational study was conducted from October 2018 to August 2020 in the Departments of General Medicine and Clinical Immunology and Rheumatology of Kalinga Institute of Medical Sciences, Bhubaneswar, India. Institute's Ethics Committee approval was undertaken (KIMS/KIIT/IEC/118/2018) and all consecutive patients of MCTD and overlap syndromes presenting to outpatient and inpatient departments were included in the study. Alarcon–Segovia criteria was used as defining criteria for MCTD patients. For the overlap syndromes group, the patients meeting diagnostic criteria for more than 1 of 6 classical autoimmune rheumatic diseases were included.

Patients with undifferentiated connective tissue disease, connective tissue disease other than MCTD, and patients with other chronic comorbid conditions such as diabetes mellitus, chronic liver disease, and chronic renal failure were excluded from the study. Sixty consecutive patients were considered as study subjects. In each group, there were 30 patients.

Written informed consent was obtained from each patient and data were recorded in a pro forma. Organ involvements were assessed by clinical examination of the organ systems and supported by investigations such as liver function tests, kidney function tests, pulmonary function tests, chest X-ray, and high-resolution computed tomography (HRCT) thorax for lungs, nerve conduction studies for nerve involvement, two-dimensional-echocardiogram for the evaluation of the cardiac status, and serum creatine phosphokinase (CPK) for muscle involvement.

For Gastroesophageal reflux disease (GERD) evaluation, we used a validated gastrointestinal symptom scale known as GerdQ. The GerdQ is a six-item, self-administered questionnaire in which patients specify how many days in the past week they have experienced heartburn, regurgitation, nausea, sleep interference, upper abdominal pain, and need for medication.

For the case definition of ILD, the following parameters were used:

Pulmonary function test screening: forced vital capacity (FVC) <70%; Medical Research Council dyspnea scale ≥ Grade 2; HRCT thorax: NSIP/UIP pattern.

For the case definition of PAH: we used the following criteria.

TR Velocity >3 m/sec with any 2 echocardiographic findings.

  1. Early diastolic pulmonary regurgitation velocity >2.2 m/s
  2. Right ventricular outflow Doppler acceleration time <105 ms and/or mid systolic notching
  3. PA diameter >25 mm
  4. Right atrial area (end-systole) >18 cm2
  5. Tricuspid annular plane systolic excursion of <18 mm
  6. Pulmonary artery systolic pressure PASP is >50 mmHg.


For the evaluation of peripheral neuropathy case definition, we used the following 3 findings with or without nerve biopsy findings.

  1. Symptoms of weakness, sensory loss (numbness), and/or positive sensory symptoms such as paresthesia, pain, or burning sensations
  2. Examination of signs of sensory deficit or motor weakness
  3. Electrodiagnostic clue of axonal or demyelinating neuropathy.


Statistical software, including MS Excel and STATA and others, were used for analysis. Quantitative data were presented as mean ± standard deviation. Qualitative data was presented as frequency and percentage tables. Comparison between the study groups was done with a two-sample t-test. Association among the study groups was tested by student's t-test, Chi-square test, and Wilcoxon-rank-sum test. A P < 0.05 was considered statistically significant.


  Results Top


Of all patients 90% of patients in MCTD, and 83% of patients in overlap syndrome groups were female. No significant difference was found in gender between both the groups (P value: 0.448). The mean age at the time of diagnosis for MCTD and overlap syndrome was 41.3 ± 13.08 years and 34.4 ± 14.1 months, respectively. There was no statistical difference between the mean duration of disease and mean time (in years) to diagnose the disease MCTD versus overlap syndrome (4.81 ± 3.04 vs. 5.04 ± 3.84; 3.17 ± 2.50 vs. 3.13 ± 2.37).

[Table 1] shows the clinical features recorded among patients of both groups. Symptoms such as fever, weight loss, and trigeminal neuralgia were more commonly found in the MCTD group whereas the overlap group had more symptoms of cough, and dry mouth [Table 1]. Myositis was observed more in MCTD (63%) than overlap syndrome patients (20%), (P = 0.00045). There was a higher mean erythrocyte sedimentation rate (ESR) and total leukocyte count (TLC) count in the overlap group compared to the MCTD group. Results of PFT in both groups were similar. ILD was more commonly seen in the overlap group in comparison to the MCTD group (P = 0.012). Among MCTD patients, ILD was present in 18 patients (60%) with NSIP (nonspecific interstitial pneumonia) in ten patients and UIP (unique interstitial pneumonia) pattern in eight patients. In the overlap syndrome group, ILD was seen in 27 patients (90%) with NSIP in 20 patients and UIP in seven patients). PAH was seen in 12 patients with MCTD and 14 patients with overlap syndromes (P = 0.235).
Table 1: Demographic characteristics of patients

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ANA was positive in all MCTD and overlap syndrome patients. All MCTD and nine overlap syndrome patients (30%) had anti-U1 snRNP antibody positivity. Anti-Scl-70 antibody positivity was seen in 18 Overlap syndrome (60%) patients (P < 0.001). Four patients with overlap syndrome had anti-ribosomal-p-protein antibody. Rheumatoid factor was positive in eight patients with MCTD (26.6%) and 15 patients (50%) with overlap syndromes. Anti-CCP was positive in one patient with MCTD (3.3%) and seven patients with overlap syndrome (23%) [Table 2].
Table 2: Comparison of autoantibody profile of cases of mixed connective tissue disease and overlap syndromes

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  Discussion Top


Our study suggests a female predominance among both groups, consistent with various other studies. Estimated female-to-male ratios vary approximately from 3:1 to 16:1.[16] Age groups affected in both groups were similar. John et al. have reported the mean age at presentation to be 39.3 ± 11.6 years in MCTD.[17]

In this study, the most commonly observed clinical features among the MCTD group were Raynaud's phenomenon (RP) followed by GERD, fever, trigeminal neuralgia, symmetric arthritis, disturbed sleep, and cough, and weight loss. Other features such as vasculitic rash, peripheral neuropathy, depression, puffy fingers, and sicca symptoms were observed less commonly. Among the overlap syndrome group, the most common features were RP, cough, GERD, symmetric arthritis, and disturbed sleep. Fever, weight loss, cough, and trigeminal neuralgia were more common in MCTD, while sicca symptoms were more common in overlap syndromes. There was no deforming arthritis in either group; which could be due to early diagnosis and treatment. On the other hand, Sen et al. reported a significant difference for synovitis as a presenting feature in the MCTD group (87%) compared to the overlap syndrome group (31.8%).[18] Other findings in their cohorts (MCTD and overlap syndrome) included swollen hands, acrosclerosis, puffy fingers, significant malar rash, and vasculitis. Nedumaran et al. and Sen et al. reported much lower rates of trigeminal neuralgia (16% and 17%, respectively) in MCTD than our study.[18],[19] High prevalence in our study could be a chance finding in our cohort. Other skin manifestations of MCTD such as telangiectasias, calcinosis, photosensitivity, a rash of dermatomyositis, DLE, and leg ulcers were not observed in our study.[20],[21],[22]

Myositis was seen more commonly in the MCTD group as compared to the overlap syndrome group in our study with predominant proximal muscle involvement among both groups (P < 0.001). Sen et al. have reported myositis in 52% of cases in their study with predominant proximal muscle involvement.[18] Myositis may be the predominant and presenting feature, with muscle weakness, raised CPK, and abnormalities on the electromyogram. Hence, anti-RNP antibody testing should be an important part of the evaluation of any patient having myositis.

In our study, anemia was common in both groups without any significant difference. Most patients had anemia of chronic disease. Immune thrombocytopenia was observed in one-third of MCTD patients and was not observed in the overlap syndromes group. Anemia, thrombocytopenia, and leukocytopenia have all been described in MCTD.[23] ESR values were higher in the overlap syndrome group compared to the MCTD group.

Asymptomatic elevation of liver enzymes was observed in one patient in each of both groups. Liver disease in systemic autoimmune diseases could be the consequence of various factors such as fatty infiltration, drug toxicity, superadded infection by hepatotropic viruses, vascular thrombosis, and diffuse nodular regenerative hyperplasia,[24] or overlap with autoimmune hepatitis.[25] Most of the patients may develop a subclinical liver involvement with mild transient abnormal liver function tests during their disease course.[26] Histopathological examination of the liver may help in ruling out drug-induced liver damage.[27] The clinicians should be aware of the possibility of liver involvement as they may occur concomitantly or serially.[28]

A significant association of Anti-U1-RNP antibodies with MCTD as compared to overlap syndromes was observed. On the other hand, anti-Scl-70 and anti-Ribosomal-P-Protein antibodies were found to be associated with overlap syndromes. These findings were consistent with the studies of John et al. (anti-U1-RNP positivity in all MCTD patients).[17] In another study, Sen et al. reported ANA with a speckled pattern in >90% of MCTD patients and with a homogeneous pattern in 63% of overlap syndrome patients.[18]

The prevalence of anti-dsDNA, rheumatoid factor, anti-Ro/SS-A, and anti-La/SS-B was much lower in MCTD compared to overlap syndrome. Anti-ds DNA and anti-Smith antibodies were only transiently positive in MCTD whereas a diagnosis of SLE is strongly recommended if these highly specific autoantibodies are found to be dominant and persistent. In our study, all patients were negative for ant-dsDNA or anti-Smith in the MCTD group on follow-up. In MCTD, RF and anti-CCP have been associated with arthritis. Anti-CCP was found in just 9% of MCTD patients. Anti-U1 RNP levels may indicate a more aggressive form of erosive arthritis. We had 50% of patients who were positive for RF in overlap syndrome and 26.6% in MCTD patients despite having a similar number of arthritis patients in each group. However, the prevalence of anti-CCP positivity is higher in overlap syndrome compared to MCTD patients.

Restrictive lung disease was frequently seen in both MCTD and overlap syndromes According to Ciancio et al. Diffusing capacity for carbon monoxide (DLCO) is more sensitive than FVC for ILD among patients of scleroderma spectrum disorders and idiopathic inflammatory myopathies.[29] Inflammatory involvement of the diaphragm and other respiratory muscles may also be responsible for a restrictive respiratory pattern. However, we could not measure DLCO in our patients due to its high cost and nonavailability in our center. In our study, ILD was more commonly seen in the overlap syndrome group. NSIP was the more common pattern in both the groups. Reiseter et al. have reported that risk factors of ILD are high titers of anti-U1RNP antibodies, absence of arthritis, and increasing age among MCTD patients.[30]

PAH was present among patients in both groups with similar prevalence. Severe PAH with right heart failure was seen in 3 MCTD and 4 overlap syndrome patients. Nimelstein et al. have reported PAH and congestive heart failure as the most common causes of death in MCTD.[31] According to the “registry to evaluate early and long-term pulmonary arterial hypertension disease management (REVEAL)” study, 1-year survival rates and discharge rates are lower for patients having PAH due to MCTD as compared to patients of PAH attributable to RA, SLE, and scleroderma.[32]

During the follow-up, all patients with MCTD continued to meet the criteria for MCTD and did not show any new features nor did their disease show evolution. The patients in the overlap syndromes group included 23 patients with scleroderma overlap syndromes and the most common overlap of scleroderma was with RA (23%). Other overlaps seen were SLE with Sjogren's syndrome and systemic sclerosis, DM overlaps with SLE and systemic sclerosis. The patients in the overlap syndromes group also continued to meet the criteria used to diagnose them at the end of the study period. According to Rasmussen et al., 44 (45%) out of 97 patients with anti-RNP antibodies could meet the criteria for SSc, SLE, PM/DM, or RA. Most patients had a benign and unchanged course for a mean of 9 years. They established the validity of the term MCTD and the acronym SRA (swollen fingers, RP, and arthritis) should be preferred over MCTD.

The precedence of the development of autoantibodies to clinical manifestations of MCTD suggests their involvement in pathogenesis.[33],[34] Numerous clinical correlations with specific autoantibodies have been reported and further research for the identification of these associations is warranted to determine prognosis and predict outcomes.

Long-term studies have shown that the spectrum of MCTD may range from mild self-limited disease to severe organ involvement and even mortality. The worst prognosis is associated with PAH. Standardization of treatment of MCTD and overlap syndromes will require randomized controlled trials. For now, specific clinical manifestations may be addressed as per recommendations to treat the same manifestations in other diseases.[35] Despite interesting findings, the limitations of our study were small sample size, single centered study and short follow-up duration.


  Conclusion Top


Constitutional symptoms such as fever and weight loss, cough, dry mouth, trigeminal neuralgia, and myositis were more common in MCTD than in overlap syndromes. Anti-U1 RNP antibodies showed a strong association with MCTD while anti-Scl70 antibodies and anti-Ribosomal-p-protein antibodies were commonly seen in overlap syndromes. The recognition of the existence of overlap syndromes and their differences from MCTD may be a necessary step in prognosticating the patients, further evaluation and management.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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