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Frequent Symptoms

The most common and frequent symptoms of MCTD that can occur during a flare are dependent upon which overlap syndrome your disease course more closely follows. Almost all patients with MCTD will experience joint pain.

You may also have inflamed muscles that cause weakness and soreness around the shoulders and hips. Having swollen hands and fingers is common, as is a butterfly-shaped rash on the cheeks and bridge of the nose.

Similar symptoms or flares are seen in undifferentiated connective tissue disease, an autoimmune disorder with similar overlap syndromes but which doesn’t fulfill enough criteria to reach a specific diagnosis of lupus, MCTD, or any other connective tissue disease.

Classic Symptoms of MCTD

Though MCTD is often difficult to diagnose because of its overlap with other syndromes, four classic symptoms are characteristic of the disease:

• Raynaud’s phenomenon: Often the first sign of the disease, this constriction of the blood vessels in the fingers and sometimes toes causes loss of feeling and color changes.
• Swollen fingers are sometimes temporary but can progress into a state of hardened skin with limited movement.
• Inflamed joints and muscles may be present.
• Pulmonary hypertension may be noted, which is high blood pressure in the blood vessels of the lungs.

Nearly half of all MCTD patients may experience lung involvement at some point, leading to difficulty breathing. This difficulty in breathing can be caused by pulmonary hypertension or interstitial lung disease.

Introduction

What was known?

Mixed connective tissue disease (MCTD) is a distinct entity, closely resembling overlap syndrome. The skin manifestations of MCTD are different from those of overlap syndrome. There is suboptimal recording of cutaneous manifestations of this disease In India and none from eastern India.

Mixed connective tissue disease (MCTD) is a specific condition in which two or more connective tissue disorders are associated with the presence of antibody against a specific uridine-rich U1 ribonucleoprotein (U1RNP).[1] Clinical manifestations are usually those of systemic lupus erythematosus (SLE), scleroderma, and inflammatory myositis. First described by Sharp[2] in 1972, this disease is now known to have characteristic cutaneous features. Overlap syndromes present a combination of at least two collagen vascular diseases without necessarily demonstrating antibody against U1 RNP. MCTD has been observed to eventually develop into scleroderma, SLE, or dermatomyositis by some authors and so they prefer to use the term “undifferentiated connective tissue disease.”[3] Others have firmly established the entity as MCTD, setting forth criteria for demarcating this disease.[4] There is a paucity of data regarding the skin manifestations of MCTD from India and none from eastern India. This led to study the predominant skin lesions of this disease prevalent among MCTD patients from this region. A comparison of the dermatological manifestations occurring in overlap syndromes with those of MCTD was another of our objectives. We also sought to evaluate our data with similar research from other parts of our country and that from the West.

Results

Out of the 23 MCTD patients, 20 (86.96%) were females and 3 (13.04%) were males. In comparison, of the 22 recruits of “overlap syndrome,” 20 (90.91%) were females and 2 (9.09%) males. The patients’ ages ranged from 18 to 41 years in the MCTD group. In this group, the youngest female was only 18 years and the youngest male was 39 years. The overlap syndrome patients were between 15 years and 56 years of age. The youngest female with features of overlap was only 15 years old and the youngest male was 25 years old. Mean age of presentation of MCTD and overlap syndrome participants were 31.22 ± 7.4 years and 34.23 ± 12.3 years, respectively, with no significant difference between the two (P = 0.32). No significant difference existed between mean duration of disease of the patients with MCTD and overlap syndrome on presentation, which was 32.43 ± 25.9 months and 41.95 ± 44.9 months, respectively (P = 0.39).

Table 1

Clinical signs and symptoms of MCTD and overlap syndrome

Puffy fingers in a patient with mixed connective tissue disease

MCTD subject with erythematous malar rash in butterfly distribution

Vasculitic lesions over hand and foot in another MCTD patient

Emotional

Feeling sad, discouraged, maybe even mad after your MCTD diagnosis is normal and to be expected. Getting a diagnosis is a major life event. Experiencing symptoms like pain or swelling of your joints or fatigue that limit your daily activities can be extremely upsetting.

Adjusting to life with the disease can take time. While you’re adjusting to your new normal, you will experience ups and downs. There might be some relief to know what’s wrong and to finally have a treatment plan, but you might also be disappointed to find that some of your symptoms prevent you from enjoying the things you used to enjoy.

You may also find that you feel anxious about your treatment plans and wonder if they’re going to work or cause side effects. You might also fret about possible future symptoms. All of these feelings are normal and to be expected. Talking to friends, family, and healthcare professionals can help you work through these feelings.

While feeling scared, sad, and upset are all normal feelings when living with a chronic illness, if they persist it is important to seek the help of your healthcare provider. If your feelings last for a long period of time and you start to feel hopeless, irritable, or begin to purposely withdraw from friends, family, or activities you love, you may be dealing with depression.

Depression is more common in people who live with chronic illness. Depression is treatable and treatment can even help improve some symptoms of your MCTD.

In a study of lupus patients, it was noted that those who had depression and anxiety had worse outcomes with the disease. Those whose depression was treated had better outcomes. Taking care of your mental health along with your physical health can help tremendously when living with MCTD.

Discussion

Cutaneous manifestations of MCTD may be the presenting signs of the disease. These have been included by researchers as important markers while defining criteria to identify this disease. Overlap syndromes are a combination of signs and symptoms of at least two connective tissue diseases with specific serological parameters. Antibody to RNAse-sensitive extractable nuclear antigen is rarely found in overlap disorders in contrast to MCTD. This antigen has been identified as polypeptides on the U1 ribonuclear protein component of the splicesosome (U1RNP).[5] The U1 small nuclear ribonucleoprotein element (snRNP) is a target of autoreactive B cells and T cells in MCTD.[6]

Entity of MCTD is more common among women. In a pioneering study by Sharp,[2] 21 (84%) were females and 4 (16%) were males out of 25 patients recognized as suffering from MCTD. Haroon and associates noticed only 1 male and rest 12 (92.30%) females among their set.[8] These figures corroborated with our research (86.96% females). The age group that is usually affected is 30-50 years. Median age of onset of disease was 36 years in a study from south India.[8] The age range in the original study from the West[2] was 13-66 years with a mean of 36 years. This was similar to our study (mean = 31.22). All were adults (youngest respondent was 18 years) in our group of MCTD subjects. The mean age at diagnosis of adult-onset MCTD was found to be 37.9 years by others.[9] MCTD has been identified in children by Tiddens.[9]

Uncommon features such as edema of the forehead, trigeminal neuralgia, and juxta articular calcinosis may suggest possibility of MCTD.[4] Periorificial numbness was seen in four of our patients due to trigeminal neuralgia. Others have noted this sign in a patient with MCTD who was also suffering from Sjogren's syndrome.[19] None of those in the overlap group complained of this difficulty. Two of our MCTD cases presented with discoid erythematosus (DLE) like rash. One lesion over the scalp had been present for 4 years and the other over the forehead was present for 2 years. Both were positive for ANA and anti-U1RNP. Similar lesions of DLE were observed by other scientists studying the cutaneous features of MCTD, but in their research one individual was found to have developed MCTD 10 years after onset of a DLE rash.[20]

Materials and Methods

Patients diagnosed as overlap syndrome demonstrating the features of at least two connective tissue disorders.

Exclusion criteria included:

A rheumatologist's opinion was taken whenever necessary. It was a cross-sectional observational study. Permission of the ethical committee of the institution was taken prior to the start of the research and an informed consent of each participant was obtained.

Patients were subjected to detailed history taking, and a thorough clinical examination was then carried out on each subject with emphasis on the cutaneous system. Routine laboratory investigations including complete hemogram, erythrocyte sedimentation rate (ESR), X-rays of chest and hands, C-reactive protein, rheumatoid factor, estimation of antinuclear antibody (ANA), antitopoisomerase-1, anticentromere antibody, and anti-U1RNP as well as creatinine phosphokinase were performed in all of the cases. Antibody against double-stranded DNA, pulmonary function test, electromyography, echocardiography, histopathology, ultrasonography, Coombs test, high-resolution computerized tomography (HRCT) of the chest, and complement 3 levels were tested when indicated. The ANA was tested using the indirect immunofluorescence technique on HEp-2 cells. Antibody against U1RNP was also measured using the indirect immunofluorescence test. The observed parameters were transcribed to MS Excel from the source. Statistical analysis was done using SPSS version 17 manufactured by IBM, and MedCalc manufactured by MedCalc, version 11.6. The categorical data were described using absolute and relative frequency. The numerical data were observed for the distribution pattern, first using Kolmogorov–Smirnov test (KS test), the parametric data were observed with mean and standard deviation (SD), and nonparametric data were observed with median and interquartile range (IQR). Categorical variables of MCTD and overlap syndromes were compared using the Fisher's exact test and numerical variables of the same were compared using independent sample t test.