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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.

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

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.

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]