Mixed connective tissue disease and tuberculosis coexistence as a diagnostic dilemma: A case report

Abstract

BACKGROUND

Mixed connective tissue disease (MCTD) is a rare autoimmune disorder characterized by overlapping features of systemic lupus erythematosus, systemic sclerosis, and polymyositis, and presence of anti-U1 ribonucleoprotein antibodies. Coexistence with tuberculosis (TB), a common infectious disease in endemic areas, poses a significant diagnostic challenge due to overlapping clinical and radiological features.

CASE SUMMARY

We report a 35-year-old Pakistani female presenting with oral ulcers, body rash, worsening dyspnea, and a history of joint pains initially treated as rheumatoid arthritis. She was on antituberculous therapy (ATT) for presumed pulmonary TB. Laboratory findings revealed anemia, leukopenia, raised erythrocyte sedimentation rate, positive anti-Sm/RNP, anti-dsDNA, and anti-SSA/Ro antibodies, confirming MCTD with clinical features of systemic lupus erythematosus, Sjogren syndrome, and systemic sclerosis. The patient was also positive for hepatitis C and active TB. Treatment involved corticosteroids alongside continuation of ATT, resulting in significant clinical improvement over 12 days, with resolution of symptoms and improved laboratory parameters. The patient remained stable on follow-up with hydroxychloroquine and prednisolone.

CONCLUSION

This case highlights the diagnostic complexity when autoimmune diseases coexist with TB, particularly in TB-endemic regions. Early recognition and integrated management of both conditions are crucial to improving outcomes. Clinicians should maintain a broad differential diagnosis and perform comprehensive immunological workup in patients with overlapping symptoms.

Key Words: Mixed connective tissue disease; Autoimmune disorder; Mixed collagen vascular disease; Tuberculosis; Case report

Core Tip: Mixed connective tissue disease (MCTD) can mimic infectious diseases like tuberculosis (TB), complicating diagnosis especially in TB-endemic regions. This case highlights the importance of comprehensive immunological testing to differentiate MCTD from TB. Early recognition and tailored treatment improve patient outcomes significantly.

INTRODUCTION

Mixed connective tissue disease (MCTD) is a rare and complex systemic autoimmune disorder marked by elevated levels of anti-U1 ribonucleoprotein (anti-RNP) autoantibodies. It is characterized by overlapping symptoms of systemic lupus erythematosus (SLE), rheumatoid arthritis, scleroderma and polymyositis[1]. It has been reported that patients with MCTD occasionally show an association with tuberculosis (TB)[2-4]. Tuberculosis is a serious, infectious disease caused by Mycobacterium tuberculosis, mainly affecting lungs. Patients of pulmonary tuberculosis present with persistent cough, fever, weight loss and fatigue[5]. We present a rare and complex case of overlap syndrome featuring SLE and tuberculosis, in a 35-year-old Pakistani female patient. The patient’s clinical presentation and laboratory findings revealed a unique overlap of SLE with tuberculosis, Sjogren syndrome and systemic sclerosis, highlighting the complexity of autoimmune disease comorbidities. This case report aims to document the diagnostic approach, treatment strategies, and clinical course of this unusual overlap syndrome, emphasizing the importance of recognizing and managing multiple autoimmune disorders in a single patient.

CASE PRESENTATION

Chief complaints

A 35-year-old Pakistani female presented to the emergency department of a tertiary care hospital with complaints of oral ulcers, body rash, and worsening shortness of breath.

History of present illness

Now, 3 weeks back she developed shortness of breath with exertion which was gradual in onset and progressive in nature. It was associated with dry cough. She was diagnosed with reactivation (secondary) tuberculosis by her GP and had been taking rifampicin, isoniazid, pyrazinamide, and ethambutol for this for 10 days. 10 days back she developed painless ulcers on lips, angles of mouth and inner surface of oral cavity, which started bleeding three days back. 3 days ago, she also developed purpuric rash involving both the extremities and trunk which was non-pruritic.

History of past illness

Before the presentation, the patient had been diagnosed with rheumatoid arthritis due to history of bilateral swelling, redness and pain in small joints of hands and wrists and large joints i.e. elbows and knees for which she had been taking methotrexate 10 mg daily along with folic acid supplementation for 8 months.

Personal and family history

Insignificant.

Physical examination

General physical examination revealed pallor, non-tender oral ulcers with bleeding surface, pinched nose, thinning of lips, and partial skin tightening of distal and middle phalanges. There were reduced breath sounds on right infrascapular region with stony dull percussion note.

Laboratory examinations

Lab investigations showed decreased white blood cells, haematocrit, platelet count, reticulocytes, liver function tests were mildly deranged. Her erythrocyte sedimentation rate (ESR) was raised too, C-reactive protein was not evaluated at this moment. She was found to be hepatitis C virus positive and TB positive. Urine C/E revealed leukocyte esterase 1+, blood 3+, many red blood cells, 6-8 pus cells (Tables 1, 2, 3, 4 and 5).

Table 1 Complete blood count.

Test	Reference value, %	Result, %
WBC	4-11 × 109/L	2.3 × 109/L
RBC	3.5-5.5 × 1012/L	2.31 × 1012/L
HGB	12-15 g/dL	5.1 g/dL
Hct	36-46	17.8
MCH	76-96 pg	22.3 pg
MCHC	31.5-34.5 g/L	29.9 g/L
Platelets	150-450 × 109/L	35 × 109/L
MPV	40-80	9.6
Neutrophils	20-40	42.7
Lymphocytes	2-8	18.7
Eosinophils	1-5	0.2
MCV	27-31 fL	77.4 fL
Reticulocyte count	12.2-16.1	1
ESR	0-20 mm/hours	79 mm/hours

MCH: Mean corpuscular haemoglobin; MCHC: Mean corpuscular haemoglobin concentration; MCV: Mean corpuscular volume; WBC: White blood cells; RBC: Red blood cells; ESR: Erythrocyte sedimentation rate.

Table 2 Liver function test liver function tests.

Test	Reference	Result
AST	10-40 IU/L	131 IU/L
ALT	10-40 IU/L	51 IU/L
Alkaline phosphatase	44-147 IU/L	427 IU/L
Total bilirubin	0.1-1.20 mg/dL	0.36 mg/dL
Renal function panel RFTs
Serum urea	10-50 mg/dL	18 mg/dL
Serum creatinine	0.7-1.20 mg/dL	0.89 mg/dL
Electrolytes
Sodium	135-145 mEq/L	137 mEq/L
Potassium	3.5-5.2 mEq/L	3.6 mEq/L
Chloride	96-106 mEq/L	116 mEq/L
Albumin
Albumin	3.5-5.5 g/dL	2 g/dL

AST: Aspartate transaminase; ALT: Alanine transaminase; RFT: Renal Function Tests.

Table 3 Urine complete examination.

Physical examination
Test	Reference	Result
Colour	Normal/pale yellow	Pale yellow
Turbidity	Clear	-
Chemical examination
pH		6.0
Specific gravity	1.003-1.030	1.010
Leukocytes esterase	-	+
Nitrite	Negative	-
Protein	Negative	-
Ketone	Negative	-
Bilirubin	Negative	-
Glucose	Nil	-
Blood	Nil	+++
Urobilinogen	Nil	-
Microscopic examination
Pus cell	Negative	6-8
Crystals	Negative	-
Casts	Negative	-
Epithelial cells	Negative	-
RBC	Nil	Many
Bacteria	Nil	-
Yeast	Nil	-

RBC: Red blood cells.

Table 4 Arterial blood gas analysis.

Test	Result
pH	7.407
pO2	70
pCO2	23
K+	3.8
HCO3-	14.5
SpO2	94.4%

RESULT: Respiratory Alkalosis with metabolic compensation.

Table 5 Serum markers.

RA factor	Negative	U/mL
ANA	Positive	1:5120	Speckled pattern
Anti-nucleosome	Positive	84	SLE
Anti-dsDNA	Positive	86
Anti-histones	Positive	21
Anti-Sm	Positive	90
Anti-Sm/RNP	Positive	93	MCTD
Anti-SSA/Ro 60kD	Positive	92	Sjogren syndrome

RA: Rheumatoid arthritis; ANA: Antinuclear antibody; SLE: Systemic lupus erythematosus; MCTD: Mixed connective tissue disease.

Imaging examinations

Chest X-ray showed right sided pleural effusion and right lower zone homogenous opacity (Figure 1). Ultrasound chest showed 150 mL of fluid on right side. Her ABG’s revealed respiratory alkalosis with metabolic compensation.

Figure 1  Chest X-ray anteroposterior view.

FINAL DIAGNOSIS

Based on all these findings she was diagnosed with mixed connective tissue disease (Systemic lupus erythematous, Sjogren, systemic sclerosis) with coexistence of TB.

TREATMENT

She was admitted in ward and her treatment was started. The patient was thoroughly informed about her condition. Education regarding the treatment and its side effects was provided to the patient. She was encouraged to follow the recommended treatment plan to manage the symptoms effectively. She was given injection methylprednisolone 1 g IV once daily (OD) for 3 days, tab potassium chloride, oral vitamin D and calcium supplements, inf dextrose, sodium chloride 1 L IV OD, nebulization with ipratropium bromide and beclomethasone, tab folic acid 5 mg OD, miconazole oral gel, Tab betamethasone in water gargles, inj. calcium folinate 12.5 mg QID (4 times a day), Injection meropenem 500 mg IV TDS (three times a day), Tab prednisolone 40 mg daily along with continuation of a combination of rifampicin, isoniazid, ethambutol and pyrazinamide.

OUTCOME AND FOLLOW-UP

Patient stayed in ward for 12 days, during this time her platelet count and haemoglobin levels improved. Her ESR levels and C-reactive protein decreased. Oral ulcers, dyspnoea and haematuria settled. Patient was discharged after 12 days on Tab Hydroxychloroquine, prednisolone and Anti-Tuberculous regimen with follow-up on outpatient department basis. At the time of discharge, she was again encouraged to follow her treatment plan, and educated about the lifestyle modifications that should be made in order to manage her symptoms effectively. Initially the patient was followed up monthly then after 6 months. She was compliant and adhered to her medication and had good tolerability for it. She had no flare-ups till the last follow-up.

DISCUSSION

MCTD is a complex autoimmune condition with overlapping features of systemic lupus erythematosus, systemic sclerosis, and polymyositis, which often leads to diagnostic dilemmas, particularly in patients with comorbidities such as pulmonary TB. This overlap can complicate both the clinical presentation and the diagnostic process, as seen in our patient who presented with chronic respiratory symptoms. Pulmonary involvement in MCTD commonly manifests as interstitial lung disease, which shares clinical and radiological features with TB, including dyspnoea, chronic cough, and lung infiltrates[6,7]. The potential for these features to be mistaken for TB, especially in regions where TB is endemic, underscores the diagnostic challenge[8].

Pakistan ranks among the top five countries globally with the highest burden of TB, including multidrug-resistant TB (MDR-TB). A population-based study in Khyber Pakhtunkhwa reported that TB prevalence increases significantly with age, and Pakistan is the 4^th highest globally in MDR-TB cases, indicating a growing public health concern[8]. Additionally, a study among livestock farmers in Lahore revealed a high prevalence of zoonotic tuberculosis (Mycobacterium tuberculosis complex), especially among abattoir workers and animal handlers, emphasizing occupational risk and the need for One Health interventions[8,9].

The interaction between MCTD and TB extends beyond clinical similarities, as TB can exacerbate underlying autoimmune symptoms and complicate treatment protocols. For instance, immunosuppressive therapies used in MCTD, such as corticosteroids and disease-modifying antirheumatic drugs (DMARDs), can suppress the immune response, increasing susceptibility to TB reactivation. This was evident in our case, where the patient had a previous misdiagnosis of rheumatoid arthritis and was treated with methotrexate, a DMARD known to increase TB risk[10,11]. The patient’s worsening respiratory symptoms initially led to a presumptive TB diagnosis, yet further investigation revealed a strong immunological profile indicative of MCTD, with specific antibodies such as anti-Sm/RNP, which is a hallmark of this disease[7,12].

The misdiagnosis of MCTD as TB or other infectious diseases is not uncommon in the literature, as autoimmune manifestations in MCTD patients can resemble infections, particularly TB. For example, it is reported that MCTD patients presenting with lung symptoms are frequently misdiagnosed with respiratory infections, as clinical overlap and similar radiological findings create challenges in differential diagnosis[13]. Additionally, in a study by Pratap et al[14], approximately 20% of MCTD patients with pulmonary involvement were initially treated for respiratory infections before MCTD was identified, suggesting that routine TB treatment may delay appropriate immunosuppressive therapy and worsen prognosis.

This case underscores the critical importance of comprehensive immunological workup when standard TB treatment fails to resolve symptoms. Specific autoantibody profiles, including anti-Sm/RNP, play a crucial role in confirming MCTD in cases where clinical presentation alone may be misleading[6,12]. Further, serological markers are valuable in distinguishing MCTD from other autoimmune conditions, such as rheumatoid arthritis, which can present with similar initial symptoms like joint pain and swelling. The misdiagnosis of MCTD as rheumatoid arthritis or systemic sclerosis occurs frequently, further complicating the course of disease in the absence of targeted treatment[15].

Treatment strategies in cases of suspected MCTD should be carefully balanced, particularly when TB is part of the differential. Current guidelines for MCTD management emphasize corticosteroids and hydroxychloroquine, both of which led to significant improvement in our patient’s symptoms once the correct diagnosis was made[11,16]. Studies support that corticosteroids reduce systemic inflammation effectively, while hydroxychloroquine manages skin and joint manifestations, as seen in our case[9,11]. However, clinicians must remain cautious, as immunosuppressive therapies can increase TB susceptibility, making it essential to rule out or concurrently treat TB in endemic regions[14].

CONCLUSION

Our case demonstrates the importance of a broad differential diagnosis in patients with overlapping autoimmune and infectious disease features. Recognizing the potential for misdiagnosis between MCTD and TB, especially in endemic areas, is essential. This case adds to the literature supporting comprehensive serological testing and a nuanced approach to treatment, considering the risks associated with immunosuppression in TB-endemic regions.