INTRODUCTION
Systemic sclerosis (SSc) is a connective tissue disease characterised by skin thickening, vascular abnormalities and visceral organ involvement. While serologic markers aid in diagnosis, there exists a subset of patients who present with characteristic clinical features but lack these typical antibodies. This poses a unique challenge and requires careful clinical evaluation. We present a case of a 63-year-old woman presenting with scleroderma renal crisis (SRC), who was found to have atypical scleroderma.
CASE DESCRIPTION
A 63-year-old female with a past medical history of non-ischaemic cardiomyopathy, type 2 diabetes mellitus, hypertension, dyslipidaemia and bilateral carpal tunnel syndrome presented to the hospital for worsening renal function and progressive dyspnoea. Preceding this hospitalisation, the patient was being evaluated for progressive dyspnoea. Computerized tomography (CT) imaging ruled out pulmonary embolism but showed bibasilar consolidation with prominent bilateral axillary lymph nodes, concerning for pneumonia. She completed a course of doxycycline, but her symptoms did not improve. Subsequent pulmonary function tests revealed a severely reduced ‘forced expiratory volume in 1 second’ test at 45%, with a ratio to forced vital capacity of 82%, total lung capacity of 38% and severely reduced diffusing capacity for carbon monoxide at 25%, consistent with restrictive lung pathology. During this work-up, her creatinine was noted to be 1.78 mg/dl (baseline 0.8–1.0 mg/dl). Despite discontinuation of her sacubitril-valsartan and empagliflozin, repeat testing two weeks later showed worsening creatinine at 4.92 mg/dl and she was recommended for inpatient evaluation.
Upon presentation, she also reported an unintentional 15-pound weight loss, dyspepsia and fatigue. Additionally, she reported tightness and discoloration of bilateral hands without joint swelling or pain. She denied photosensitivity, dry eyes or mouth, abdominal pain or urinary symptoms, but did note a decrease in daily urine output. She denied occupational exposures to dangerous inhalants, and a personal or family history of autoimmune diseases. She was afebrile (37.2°C), hypertensive (200/107 mmHg), tachypnoeic (30/min), without tachycardia (86/min) or desaturation. Physical examination was significant for diffuse end-inspiratory fine crackles without wheezing. Mild finger oedema with early sclerodactyly changes were seen, and digital pitting and tenderness were noted on the right fifth digit. Her hands were cool with dusky discoloration, but her feet were warm without oedema. Admission laboratory investigations are noted in Table 1. Ultrasound of the kidneys and bladder was without obstructive uropathy, and a CT scan of the abdomen and pelvis was unremarkable. A high-resolution chest CT (HRCT) scan showed worsening intralobular septal thickening, patchy ground glass opacities in the upper lobes and areas of dense consolidation more prominent in the lower lobes, concerning for interstitial lung disease. Given multisystem involvement of the pulmonary and renal systems, the differential diagnosis included systemic sclerosis, vasculitis, amyloidosis and sarcoidosis. An anti-nuclear antibody (ANA) test returned with a high titre of 1:1280.
(click to enlarge)
Table 1. Laboratory investigations.
During hospitalisation, the patient’s blood pressure remained elevated despite aggressive medical management. Within 48 hours, she developed acute hypoxic respiratory failure from flash pulmonary oedema, thought to be provoked by a hypertensive emergency. A transthoracic echocardiogram (TTE) revealed significantly reduced ejection fraction (EF) to 25–30% (a TTE one month previously showed an EF of 40%), global hypokinesis and circumferential pericardial effusion without tamponade physiology. She underwent right heart catheterisation showing right atrial pressure 12 mmHg, pulmonary artery pressure 44/21 mmHg, pulmonary capillary wedge pressure 22 mmHg, thermodilution cardiac output 3.4 l/min, thermodilution cardiac index 2.1 l/min/m2 and pulmonary vascular resistance of 2.1 Wood units. Her renal dysfunction was out of proportion to the cardiac index and filling pressures, suggesting cardiogenic aetiology alone. She did not have equalisation of chamber pressures to suggest obstructive shock from tamponade. These findings along with clinical examination and elevated ANA titre prompted further autoimmune work-up. She underwent cautious diuresis and quickly weaned back to nasal canula the next day.
Despite respiratory improvement, the patient’s urine output continued to decrease, and her creatinine continued to rise, ranging from 5.65–8.46 mg/dl. She subsequently underwent renal biopsy and was initiated on haemodialysis by hospital day 5. The biopsy showed thrombotic microangiopathy (TMA) involving multiple arterioles, normocellular glomerular without specific immunoreactivity, no significant globally sclerosed glomerular and interstitial fibrosis, and mild-to-moderate arterial sclerosis. By this time, her autoimmune serology was non-specific (Table 2). However, her biopsy findings were consistent with scleroderma-associated renal disease. Due to her renal pathology, steroids and mycophenolate mofetil were not initiated. She was started on captopril 25 mg twice daily for SRC which stabilised her blood pressure and improved symptoms. She was discharged to a rehabilitation centre with plans for outpatient haemodialysis and specialist follow-up.
(click to enlarge)
Table 2. Autoimmune laboratory investigations.
DISCUSSION
Systemic sclerosis (SSc), also known as scleroderma, is an immune-mediated rheumatic disease with high morbidity and mortality[1]. It is associated with chronic inflammatory infiltration in numerous organs – commonly the lungs, heart, kidneys and gastrointestinal tract[2]. Per the 2013 classification criteria for systemic sclerosis by the American College of Rheumatology, our findings on history, physical examination, imaging and kidney biopsy led to a clinical diagnosis of scleroderma, despite the lack of supportive laboratory data[3].
In patients with SSc, a clinically relevant ANA titre of 1:80 or more has been reported in 75–95% of patients, with a sensitivity of 85% and specificity of 54% on immunofluorescence[1]. For anti-centromere (ACA) this has been shown to be 33% sensitive and 99.9% specific, and anti-topoisomerase I (ATA) has a sensitivity of 34% and a specificity of 99.6%. Similarly, anti-RNA polymerase III (anti-RNAP) has a low sensitivity at 10–20% with a high specificity of 98.8%[4]. In our patient, tests for ACA, ATA and anti-RNAP III antibodies were negative, making it a rare presentation of systemic sclerosis with SRC[5].
SRC occurs in about 10% of all patients with scleroderma. Most commonly, it is characterised by malignant hypertension and progressive renal failure. However, about 10% of SRC cases may present with normal blood pressure, known as normotensive renal crisis[6]. Although the pathogenesis of SRC remains unclear, it is thought that intimal proliferation from an endothelial insult leads to luminal narrowing of small renal arteries and arterioles[5]. Common risk factors for renal involvement include diffuse skin disease, use of systemic steroids and the presence of anti-RNAP III[5]. Cases of seronegative SSc may be associated with malignancy, or as paraneoplastic manifestations of secondary malignancies[1,3]. Our patient’s serologic and radiographic work-up for malignancy was negative, making this case of further interest.
The pathogenesis of SRC includes activation of renin-angiotensin-aldosterone-system (RAAS)[7]. Since the advent of angiotensin converting enzyme inhibitors (ACE-I), the prognosis of SRC has improved drastically by reducing the 1-year mortality from 85% to 24%, and they remain the mainstay of treatment[6,7]. A short-acting ACE-I such as captopril is used initially and once blood pressure has stabilised, long-acting ACE-I can be substituted in equivalent doses. Diuretics must be avoided as this may stimulate RAAS further[7]. Although ACE-I have improved outcomes in such patients, they do not have a role in prevention[7]. Continued therapy with ACE-I is recommended as about half of these patients may have renal recovery over 3 to 18 months and may be able to discontinue dialysis[7].
CONCLUSION
This case of severe SRC despite with manifestations including multi-organ systems, illustrates the importance of clinical diagnosis, even when laboratory data might indicate otherwise. The patient underwent HRCT and renal biopsy with findings consistent with scleroderma interstitial lung disease and SRC. It is important for clinicians to promptly recognise atypical scleroderma presentations to make a timely diagnosis and prevent complications.