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Clinical Infection & Immunity

Case Report

Volume 1, Number 1, September 2016, pages 11-15

A Case Report of Mixed Connective Tissue Disease Presenting With Fever and Pruritus

The etiology, pathogenesis and diagnosis of the autoimmune diseases are often elusive. Several ongoing studies, looking directly at the molecular level, hopefully will elucidate much on the topic and thus increase our current understanding of these diseases, but for decades, in cases of autoimmune diseases, it has been widely recognized and accepted to use the constellation of the clinical features instead of causes to reach a specific diagnosis, and it is also the basis of internationally accepted diagnostic criteria. We have used the well-known and new both diagnostic criteria for diagnosis [1-6] of a case of mixed connective tissue disease (MCTD) here, who was admitted into a tertiary teaching hospital in Dhaka with rather atypical presentation.

A 50-year-old Bengali female, housewife, Muslim, was admitted into a tertiary teaching hospital in Dhaka with history of fever for 6 months, generalized itching for 6 months, pain in multiple joints for 3 months, and generalized swelling of the body for 7 days. According to the statement of the patient, she was reasonably well 6 months back when she first developed fever which was high grade and continued. The highest recorded temperature was 102 °F without chills and rigor or night sweat and also not associated with chest pain, dyspnea, cough, dysuria or altered bowel habit. Instead, she gave history of generalized itching for 6 months, same duration as the fever, for which she took advice from dermatologist and took antihistamine. She noticed swelling of face and hands (Fig. 1) after that, which she thought was caused by the drugs. There was no history of scanty micturition or high colored urine. The itching was progressive increasing and became generalized thereafter. She also noticed some maculopapular rash in her back and shoulders and small ulcers in the infra-mammary folds, axilla and buttock. She also complained of joint pain, swelling, and stiffness which affected small joints of both hands and feet (Fig. 1) symmetrically and had appeared 3 weeks back. Since 7 days before getting admitted into the hospital, she had noticed that skin over different parts of the body had started to appear hardened (fibrosed, as seen in Fig. 2) and now patient was facing difficulties in mouth opening. Bladder and bowel habit was normal. There was no history of spontaneous abortion, bleeding, venous thrombosis, or convulsion. She was a known case of hypothyroidism, ischemic heart disease, and diabetes mellitus since 3 years back, and had been taking oral levothyroxine (50 μg) since then along with metformin (850 mg bd), aspirin (75 mg od), and nitroglycerine (sustained release, 2.6 mg od). There was no history of connective tissue disease in her family. She was a non-smoker and non-alcoholic. On general examination, she was ill looking, anemic, non-icteric, not cyanosed, no clubbing, koilonychia and leukonychia. She was edematous, with puffy face and mildly anemic, and there were some maculopapular rash involving face, inframammary folds, axilla and buttock, and ulcerations over the same area with blackening and skin tightening involving face, hands and feet (Fig. 1) with difficulty in opening the mouth. Later she also complained of extreme weakness and generalized body ache. Her pulse, blood pressure, respiratory rate, and jugular venous pressure all were within normal limits, and there was bilateral ankle edema and bilateral crepitation. There was no sign of clubbing, thyromegaly or lymphadenopathy. Respiratory system examination revealed bilateral basal crepitation. Abdominal examination revealed presence of maculopapular rash and blackening of the skin (Fig. 2). On palpation, there was no organomegaly apart from mild ascites, and shifting dullness was positive. Musculoskeletal system examination revealed swollen and tender wrist, metacarpophalangeal and interphalangeal joints of both hands without any deformity. There was not significant proximal weakness, but overall, she was extremely weak, and her muscle power on all limbs was 3/5. There were violaceous papules noted on the extensor aspect of the metacarpophalangeal joints of both hands (Fig. 1). All other system examinations were unremarkable. Her complete blood count (CBC) showed Hb was 10.8 g/dL (12 - 15.5 g/dL), total white blood cell (WBC) was 7,500/mm³ (4,000 - 11,000/mm³) and differential count was N 63% (40-80%), L 34% (20-40%), E 0.2% (1-6%), M 0.1% (2-10%), and erythrocyte sedimentation rate (ESR) was 25 mm at first hour (less than 30 mm in elderly female). After 1 week, her CBC showed Hb was 9.6 g/dL (12 - 15.5 g/dL), total WBC was 10,500/mm³ (4000 - 11,000/mm³), and differential count was N 66% (40-80%), L 24% (20-40%), E 0.8% (1-6%), M 0.2% (2-10%), and ESR was 40 mm at first hour. Again 1 week after that, her CBC showed Hb was 10.0 g/dL (12 - 15.5 g/dL), total WBC was 10,000/mm³ (4,000 - 11,000/mm³) and differential count was N 50% (40-80%), L 20% (20-40%), E 25% (1-6%), M 0.5% (2-10%), and ESR was 25 mm at first hour. There was evident progressive eosinophilia, and treatment with antihelminthic did not improve the condition, and there was no allergic manifestation. Her peripheral blood film on admission showed microcytic hypochromic anemia with eosinophilia. A repeat peripheral blood film after 1 week showed normocytic normochromic anemia with eosinophilia and thrombocytosis. Her thyroid profile just 2 weeks before admission showed that thyroid stimulating hormone (TSH) was > 30.24 U/mL (0.3 - 5.0 U/mL), and the patient seemed hypothyroid, probably from not taking her thyroid medication regularly. But after admission and after she had got treatment for 2 weeks, TSH was 0.12 U/mL (0.3 - 5.0 U/mL), then after another 1 week was 0.95 U/mL (0.3 - 5.0 U/mL) and the patient was euthyroid. Despite being euthyroid, her generalized or local neither type of edema improved. On admission, free triiodothyronine (FT3) was 3.15 pmol/L (3.5 - 6.5 pmol/L) and free thyroxine (FT4) was 24.10 pmol/L (10 - 23 pmol/L). Her liver and renal biochemistry were completely normal, so any cause of edema could not be attributed to either liver or renal cause. The 24-h urinary total protein was 0.08 g/day (0.001 - 0.014 g/day). Her serum creatinine was 0.6 mg/dL (0.1 - 1.1 mg /dL). Serum electrolyte was normal. Urinary microalbumin was 14 mg/L, serum albumin was 25 g/L (35 - 55 g/L), HbA1C was 7% (< 7%), and urine R/M/E was normal. Fasting lipid profile was normal. ICTs for malaria and kala-azar were negative. HbsAg, anti-HCV, anti-HIV (1+2) all were negative. Ultrasonography of whole abdomen showed only mild fatty liver and no other abnormality. Serum bilirubin was 0.7 mg/dL (0.1 - 1.1 mg/dL), serum glutamic pyruvic transaminase (SGPT) was 88 U/L (< 40 U/L), and serum glutamic-oxaloacetic transaminase (SGOT) was 46 U/L (< 40 U/L). Upper GI endoscopic findings were reflux esophagitis/gastritis, esophageal candidiasis and presence of antral erosions. Colonoscopic findings were normal. Chest X-ray PA view suggested interstitial opacity in both lungs, newly developed shadows which could be infiltration. MDCT of upper abdomen showed lesions at bases of both lungs, possibly due to infiltration, and splenomegaly was also seen. Rapid urease test of H. pylori was negative. Creatine phosphokinase (CPK) was 1,398 U/L (19 - 155 U/L). After 1 month of admission, her serum albumin was 31 g/L (25 - 35 g/L), aspartate aminotransferase (AST)/SGOT was 136 U/L (< 40 U/L), alanine aminotransferase (ALT)/SGPT was 96 U/L (< 40 U/L), troponin T was 0.344 ng/mL (< 0.014), and lactate dehydrogenase (LDH) was 437 U/L (140 - 280 U/L). Findings of nerve conduction studies and EMG reports were compatible with inflammatory myopathy, mild sensory-motor polyneuropathy. Skin biopsy taken from right arm showed thickening of the dermis and the fibrous septa of the subcutaneous tissue .The thick dermis was composed of thick and sclerotic collagen fibers. The peri-appendageal fat was absent. There was mild perivascular lympho-histiocytic infiltrate in the thick dermis and it was commented to be congruent with histopathological change of scleroderma.

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Figure 1. Skin changes over hand, including sclerodactyly, and swelling of joints and Gottron’s papules.

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Figure 2. Fibrotic changes of skin in the abdomen.

Antinuclear antibody (ANA) was strongly positive, in speckled pattern, and titer was 1:5,120. Anti-ds-DNA was negative, anti-U1-RNP was positive, anti-Sm was negative, and anti-Ro-52 were positive. p-antineutrophilic cytoplasmic antibody (ANCA) was < 2 RU/mL (< 20 RU/mL), c-ANCA was 33.3 RU/mL (< 20 RU/mL), and anti-TG was > 1,000 IU/mL (0 - 4.11 IU/mL). Cancer screening, ENT evaluation and mammogram were unremarkable.

She received pulse methylprednisolone 1 g for 3 days. Later, she was put on prednisolone 60 mg/day PO, hydroxycloroquine 400 mg/day PO, and azathioprine 100 mg/day PO. Then her skin ulcer gradually healed and itching improved.

In our case, the initial presentation was fever and generalized itching, but the exact pathology behind any of the presenting symptoms could not be found, even after thorough evaluation of all the symptoms and physical signs and laboratory investigations. But as the suffering of the patient continued, more and more signs and symptoms began to appear which gave clues that a rheumatologic disease could be responsible. In diagnosis and classification of connective tissue diseases, the clustering of symptoms and signs into readily recognizable groupings has an important historic precedence. In some cases when diagnosis of a specific connective tissue disease is not always obvious, this is often referred to as undifferentiated connective tissue disease (UCTD) [7]. In their early stages, many autoimmune connective tissue diseases (AICTDs) are not clinically well differentiated and then they belong to UCTD group. About 50% of UCTDs remain undifferentiated also later in the course and never resemble any specific autoimmune disease. The diagnosis of well differentiated AICTD is usually readily apparent without recourse to extensive investigations. Again, in some cases, features of multiple autoimmune diseases are found. The term “overlap syndrome” has been to describe patients who have signs of two or more connective tissue diseases simultaneously [8].

In our patient, different clinical features were found that belong to more than one rheumatologic disease. Systemic lupus erythematosus (SLE) was suspected in this patient, and it was evident from the clinical features reported that this patient has got 1) maculopapular rash, 2) bilateral and symmetrical small joint arthritis in both hand and both feet which show typical more than 30 min of morning stiffness, 3) serositis in form of ascites, 4) ANA positivity in high titer (1:3,120) and in speckled pattern staining and also 5) anti-Sm antibody positivity.

The collection of the above mentioned features fulfill required four criteria out of 11 criteria mentioned in 1997 Update of the 1982 Revised American College of Rheumatology Classification Criteria for SLE [9]. Here it is a point of interest that this patient has ascites as a form of serositis which is not usually seen in contrast to commonly found pericarditis and pleural effusion [9]. However, ascites in SLE patients, although extremely rare, yet have been reported in existing literature [10, 11]. The newly proposed Systemic Lupus International Collaborating Clinics in 2012 (SLICC-12) criteria [2, 12, 13] require presence of four or more criteria of which one must be clinical and one must be laboratory findings, which are also fulfilled by this patient. So, it can be concluded that this patient got SLE.

This patient showed skin thickening proximal to the metacarpophalangeal joints in both hands. According to American College of Rheumatologists (ACR) criteria, this feature alone is sufficient to make a diagnosis of scleroderma [1]. Moreover, biopsy taken from inner arm further confirms it along with other typical features like hand edema, difficulty in mouth opening and so on, which together proves the case to be diffuse cutaneous systemic sclerosis (DCSS) [14].

The patient was extremely weak from the beginning, and complained of pain at different sites of her body. Her AST/SGOT, LDH and CPK values were very much high, which raised the possibility of presence of myositis, and electromyogram and nerve conduction studies supported this with findings consistent with inflammatory myopathy. There were Gottron’s papules seen on the extensor aspect of the metacarpophalangeal and interphalangeal joints of both hands, which is a hallmark sign of dermatomyositis (DM) [15, 16]. She also had maculopapular rash, plenty in a shawl like distribution, over the back and neck. The findings together confirm she also had DM.

There are six AICTDs, namely [17], 1) SLE; 2) scleroderma (Scl); 3) polymyositis (PM); 4) DM; 5) rheumatoid arthritis; and 6) Sjogren’s syndrome.

All of the above are descriptive syndromes without gold standard for diagnosis [17]. In up to 25% of patients with rheumatological diseases, criteria for more than one rheumatic disease are found, and are consequently diagnosed as overlap syndrome [18]. To define an overlap syndrome, it is necessary to identify a constellation of distinctive features that constitute a true syndrome. SLE rarely occurs with scleroderma [19]. In this case, this rare combination has been found, with rather atypical presentations like ascites.

MCTD is a prototypical overlap syndrome combining features of SLE, systemic sclerosis, and myositis together with the presence of antibodies to U1-RNP [20, 21]. This overlap is not seen at the onset of MCTD, rather it often takes several years to develop. The prevalence of overlap syndromes, especially MCTD, is unknown, and PM and DM are regarded as very rare rheumatic diseases [22]. Only in Japan, the reported prevalence of MCTD is 2.7 per 100,000 [17]. The first clue to diagnosing MCTD is usually a positive ANA with a high titer speckled pattern. The titer is often greater than 1:1,000 and sometimes greater than 1:10,000. This finding should point to measurement of antibodies to U1-RNP, Sm, Ro and La. Antibodies to dsDNA, Sm and Ro are occasionally seen as a transient phenomenon in patients with MCTD [23]. This patient showed all the components of MCTD, namely, SLE, scleroderma and myositis, and anti-U1-RNP antibody was positive. For diagnosing MCTD, there are four sets of criteria, proposed by Sharp, Alarcon-Segovia, Kahn, and Kasukawa [3-6]. Out of these four sets of criteria, only Sharp’s criteria do not absolutely demand the presence of high titers of U1-RNP antibodies to diagnose MCTD, although for the diagnosis of definite MCTD, anti-U1-RNP antibodies are necessary and at the same time Sharp’s criteria require absence of anti-Sm antibody [5]. In this case, anti-U1-RNP antibody was positive but anti-Sm antibody was negative. So, this case fulfils or satisfies any of the diagnostic criteria for MCTD, yet known in available literature. Here it can be also added that despite presence of at least four sets of criteria, there remains no universally accepted definition of the condition [24].

From the very beginning this patient complained of extensive pruritus. Pruritus can be originated from the scleroderma component of the MCTD [25, 26].

Systemic rheumatologic disease can hide behind rather non-specific and seemingly unrelated symptoms and signs. We therefore recommend holding a high degree of suspicion in the susceptible individuals, and always consider the possibility of presence of any autoimmune pathology where needed, because these diseases, as evident from the discussion before, can present with uncommon features and even mimic some other trivial conditions initially. But it is always necessary to diagnose early in order to decrease morbidity, and disease-related complications. Example of this very rare combination is scarce in available literature, and especially for this ethnicity or region.

Competing Interests

The authors declare that they have no competing interests.

Author Contributions

PH contributed in writing, editing, literature review and overall preparation of this manuscript and in diagnosis of the patient, AK contributed greatly in diagnosis and management of the patient, AS contributed in diagnosis of the patient and also preparation of the manuscript, and SR contributed in management of the patient.

Consent

Written informed consent was obtained from the patient for publication of this case report and any accompanying images.

Abbreviations

DMCH: Dhaka Medical College Hospital; WBC: white blood cell; CBC: complete blood count; ESR: erythrocyte sedimentation rate; Hb: hemoglobin; TSH: thyroid stimulating hormone; FT3: free triiodothyronine; FT4: free thyroxine; CPK: creatine phosphokinase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; SGPT: serum glutamic pyruvic transaminase; SHOT: serum glutamic-oxaloacetic transaminase; LDH: lactate dehydrogenase; ANCA: antineutrophilic cytoplasmic antibody; ANA: antinuclear antibody; UCTD: undifferentiated connective tissue disease; MCTD: mixed connective tissue disease; SLE: systemic lupus erythematosus; ACR: American College of Rheumatologists; SLICC-12: Systemic Lupus International Collaborating Clinics in 2012

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