Background

Systemic sclerosis (SSc) is a chronic multisystem connective tissue disease characterised by widespread vascular dysfunction and progressive fibrosis of the skin and internal organs.1 SSc is uncommon, being observed most in women with a female-to-male ratio of 3:1.2 Australia reports one of the highest prevalence of disease worldwide.2 SSc is associated with premature mortality, with significant impact on patient quality of life and healthcare economy.3 The clinical features are distinct from other autoimmune conditions, with sclerodactyly seen almost universally.4 Supportive clinical features include fingertip lesions such as digital ulceration, telangiectasia, nailfold capillary changes, Raynaud’s phenomenon and pulmonary manifestations.4 Interstitial lung disease (ILD) and pulmonary hypertension (pHTN) account for the most common cause of death in patients with SSc.3 Serology for autoantibodies can aid the diagnosis and enable clinicians to predict the clinical course and severity of disease.

The pathogenesis of SSc involves vascular and endothelial changes leading to defective vasoconstriction and angiogenesis.5 Endothelial cell damage is caused by increased levels of circulating inflammatory cytokines and growth factors including endothelin-1, interleukin 1 and 6, interferon-gamma, tumour necrosis factor and transforming growth factor-beta.1 This inflammatory cytokine milieu in combination with intracellular adhesion molecule dysfunction increases vascular permeability, allowing the migration of immune cells into the extracellular matrix.6 Immune dysfunction and the development of a fibrogenic fibroblast population in the extracellular matrix mediate the fibrotic hallmark of SSc.7

Immune dysregulation resulting in autoantibody production is the serological hallmark of SSc with autoantibodies observed in 95% of cases.8 The most frequent antibodies include anti-topoisomerase-1 (20%–45%), anti-centromere (12%–44%) and anti-RNA-polymerase III (5%–31%).9 Anti-topoisomerase-1 positivity is seen more frequently with diffuse subtype SSc, with patients typically displaying increased disease activity with more extensive skin involvement, with an increased risk of developing ILD.7 9 The presence of anti-centromere antibodies is associated with limited cutaneous involvement (CREST phenotype) and type 1 pHTN.9 RNA-polymerase III antibodies correlate with the strongest risk of developing scleroderma renal crisis (SRC).10 An overview of scleroderma-associated antibodies and clinical features is included in table 1.

Case presentation

A female patient in her 40s presented to a general practitioner with new Raynaud’s phenomenon, polyarthralgia of the hands and tightening of the fingers 2 weeks after recovering from a mild COVID-19 illness. The differentials considered at this time included post-viral reactive arthritis and post-COVID-19 autoimmunity. Further investigations revealed a negative rheumatoid factor and anti-cyclic citrullinated peptide (anti-CCP), with a strongly positive anti-nuclear antibody (ANA) in a homogeneous pattern. Systemic corticosteroid therapy was commenced with prednisolone 25 mg daily, and a referral sent for outpatient rheumatology review.

Within 3 weeks of corticosteroid therapy, the patient presented to a regional emergency department with progressive fatigue and dyspnoea, headaches and abdominal pain. The patient had a body mass index of 31, with no other comorbidities, and no personal or family history of autoimmune disease. On examination, there was evidence of sclerodactyly with skin thickening extending above the wrist. Skin thickening was also observed on the trunk and face. The patient had additional findings of digital pulp atrophy and telangiectasia. There was no evidence of active synovitis, rash, calcinosis or digital ulceration. Initial serology revealed an acute kidney injury (creatinine 166 µmol/L), with normal haemoglobin (141 g/L) and platelet count (422×10⁹/L). CT of the abdomen and pelvis was unremarkable. The patient was managed conservatively with intravenous fluids and continuation of prednisolone at 25 mg daily. A complete autoimmune panel was ordered as outlined in table 2.

Within 48 hours of admission, the patient deteriorated developing hypertensive crisis with oliguric renal failure (creatinine 758 µmol/L), new anaemia (haemoglobin 101 g/L) and thrombocytopenia (platelets 64×10⁹/L). Systolic blood pressure was consistently recorded between 220 and 240 mm Hg. Microangiopathic haemolytic anaemia was suspected, confirmed by the presence of schistocytes on blood film, with an undetectable haptoglobin and negative direct anti-globulin test. The primary differential at this time was SRC with secondary thrombotic microangiopathy caused by uncontrolled hypertension. Differentials such as thrombotic thrombocytopenic purpura (TTP) were also considered. The patient was intubated and transferred to the intensive care unit (ICU) following a cluster of tonic–clonic seizures presumed secondary to hypertensive encephalopathy. The patient was commenced on captopril and a nitroprusside infusion for blood pressure control, plasma exchange until TTP was excluded, haemofiltration and levetiracetam for seizure control. Corticosteroids were discontinued due to their recognised effect of precipitating SRC.

With treatment, blood pressure control improved and subsequently the degree of haemolysis. ADAMS-T13 was not suggestive of TTP. CT of the chest revealed bilateral pleural effusions without evidence of fibrotic lung changes. Transthoracic echocardiogram noted elevated pulmonary arterial pressures (50–55 mm Hg); however, in the setting of pulmonary congestion, this was thought to be wedge driven. Scleroderma-related antibodies were positive for anti-topoisomerase-1 as seen in table 2. The remainder of the autoimmune and vasculitis screen was negative including RNA-polymerase III. The diagnosis of diffuse SSc was based on the presence of sclerodactyly, with skin thickening extending proximal to the metacarpophalangeal joints. Supportive clinical features included telangiectasia, Raynaud’s phenomenon, scleroderma-related antibodies and corticosteroid-induced hypertensive crisis. The modified Rodnan Skin Score at this time was 19/51.

The patient transitioned to intermittent haemodialysis via Permcath and underwent renal biopsy. Histopathology showed accelerated hypertensive endothelial injury and ischaemic glomerulopathy, with sclerosis to 2/20 glomeruli. Over the following 2 months, the patient’s urine output improved, and with consistent blood pressure control, the patient was successfully weaned from renal replacement therapy.

In the weeks that followed cessation of haemodialysis, the patient re-presented with worsening dyspnoea and was found to have a new pericardial effusion thought to be a cardiac manifestation of SSc. Corticosteroid therapy was re-initiated, which achieved resolution of the effusion. Unfortunately, this again triggered SRC. The patient was transferred to a quaternary hospital ICU for rheumatology review and haemofiltration to manage acute renal failure and fluid overload. Repeat CT of the chest showed no evidence of ILD; however, pulmonary function testing showed a severely reduced diffusion capacity of 35% consistent with pulmonary vascular disease. Repeat transthoracic echocardiogram showed persistently elevated pulmonary artery pressure with severe tricuspid regurgitation. Once euvolemic, type 1 non-wedge-driven pHTN was confirmed on right heart catheterisation. Sildenafil was commenced with good response, with bosentan discontinued due to adverse effects. A timeline of key investigations is outlined in table 3.

The patient remained oliguric and dialysis dependent via newly formed arteriovenous fistula with ACE inhibitor therapy continued. Renal transplantation currently is not a viable consideration due to progression of pHTN and intolerance of corticosteroids.

The patient continued to experience refractory nausea and abdominal discomfort. Coeliac serology was unremarkable. The patient underwent endoscopy, followed by Barium swallow and gastric emptying study. Barium swallow identified oesophageal dysmotility likely secondary to SSc, with significant impact on quality of life and management decisions. In the setting of recurrent aspiration events, initiation of immunosuppression has been delayed and the patient remains off disease-modifying therapy.

Given the complexity of the case with multiple systems affected, the patient will be followed up by several specialty units including nephrology, rheumatology, respiratory and gastroenterology. Future management decisions will require a multidisciplinary approach.