Primary biliary cirrhosis associated with systemic sclerosis: A milder disease?

Polyautoimmunity is a frequent condition in systemic sclerosis (SSc) affecting one quarter of SSc-patients. Among SSc-associated autoimmune diseases, primary biliary cirrhosis (PBC) affects 3% of the patients both in our European cohort and in a worldwide meta-analysis. PBC is a slowly progressive cholestatic liver disease characterized histologically by a chronic destructive non suppurative granulomatous/ lymphocytic cholangitis affecting the small and medium-sized bile ducts and by the presence of the highly disease-specific anti-mitochondrial antibodies (AMA), which are present in 90-95% of the patients and in less than 1% of healthy controls. Although the prevalence of PBC among SSc-patients has been estimated to 3%, about 25% of SSc-patients are positive for AMA. In these patients, long-term monitoring of signs and symptoms of cholestatic liver disease should be performed as the presence of AMA can precede clinical symptoms. Anticentromere antibodies (ACA) have been found in up to 30% of PBC patients and 80% of patients with a PBC/SSc overlap syndrome. But ACA are also observed in patients with PBC without SSc and seem to be associated with severe bile duct injury and portal hypertension. The prognosis of PBC/SSc overlap is unclear. Whereas some case reports have suggested that these patients had a slower rate of liver-disease progression compared to matched patients with PBC alone, others had suggested a worse prognosis. Regarding SSc, in our European cohort, SSc-PBC overlap patients had a milder disease, with association with the limited cutaneous subtype (OR 2.1,95% CI 1.5-2.8) and the presence of ACA (OR 6.2, 95% CI 2.3-16.5). We present the case of a 65-years old woman, with SSc-associated PBC. The patient presented a Raynaud phenomenon appeared 10 years ago with secondary digital ulcers and calcinosis appeared in 1991 revealing limited cutaneous-SSc with positivity for ACA. There was no cardiopulmonary involvement. She was treated with calcium channel blockers. In 1993 appeared liver tests abnormalities with a 5-fold increase in transaminase. Liver biopsy revealed lesions compatible with diagnosis of PBC and AMA were present at high titers. PBC led to a liver transplantation in 1999. Following transplantation, an immunosuppressant therapy by tacrolimus was introduced. In 2000, the patient suffered from dyspnea. The pulmonary tests revealed a decrease in DLCO/VA at 50%. No further exploration was performed. In 2005, the patient was admitted to our unit: symptoms and pulmonary tests remained unchanged. Echocardiography revealed an increase in PAPs at 45 mmHg and a diagnosis of pulmonary arterial hypertension (PAH) was confirmed at RHC in 2007. Treatment by sildenafil was introduced in 2007 and ambrisentan was added in 2010 because of worsening of PAH. In 2012 appeared a non-compressive pericardial effusion. In 2014, pericardial effusion was increased with worsening of dyspnea and of PAPs (80mmHg). Surgical drainage was performed with improvement of dyspnea and decrease in PAPs (55 mmHg). This case demonstrates that the prognosis of SSc-associated PBC remains unclear and that some cases may develop severe SSc complications. It is also of interest to discuss about the development of PAH in the context of profound immunosuppression required by the transplantation. Further studies are warranted to better identify the prognosis or the different profiles of SSc-associated PBC and to determine prognostic factors of a severe disease.