Belimumab treatment in autoimmune hepatitis and primary biliary cholangitis - a case series.

BACKGROUND The majority of patients with autoimmune hepatitis (AIH) achieve complete remission with established treatment regiments. In patients with intolerance or insufficient response to these drugs, the remaining options are limited and novel treatment approaches necessary. In primary biliary cholangitis (PBC), ursodeoxycholic acid (UDCA) and fibrates have improved prognosis dramatically, but there remains a proportion of patients with refractory disease.In patients with refractory AIH and/or PBC, we used a novel treatment strategy with the anti-B cell activating factor, belimumab. The first three patients had concomitant Sjögren's disease. The connecting element between all three diseases is B cell activation, including elevated levels of the B cell activating factor (BAFF). Furthermore, belimumab has been shown to be beneficial in Sjögren's disease. AIMS AND METHODS To retrospectively investigate treatment response in six patients with AIH or PBC with or without concomitant Sjögren's disease treated with the anti-BAFF therapy belimumab at the University Hospital in Bern, Switzerland. RESULTS In all three patients with AIH, belimumab improved disease control and helped by-pass or reduce problematic side effects from corticosteroids and calcineurin inhibitors. In PBC patients (n = 3), there was no clear improvement of liver function tests, despite reduction or normalization of IgM. All patients with concomitant Sjögren's disease (n = 3) had an improvement of sicca symptoms and two out of three patients experienced an initially marked reduction in fatigue, which lessened over time. CONCLUSIONS Belimumab may be a promising treatment option for patients with AIH and further investigations are needed. In PBC however, response was not convincing. The effects on sicca symptoms and fatigue were encouraging

Case Report: Genetic Double Strike: VEXAS and TET2-Positive Myelodysplastic Syndrome in a Patient With Long-Standing Refractory Autoinflammatory Disease.

Somatic genetic mutations involving the innate and inflammasome signaling are key drivers of the pathogenesis of myelodysplastic syndromes (MDS). Herein, we present a patient, who suffered from a long-standing refractory adult-onset autoinflammatory syndrome (AIS), previously interpreted as various distinct rheumatic disorders. Developing pancytopenia and particularly macrocytic anemia prompted the screening for a hematological malignancy, which led to the diagnosis of a TET-2-positive MDS. The impressive and continuously changing range of organ involvement, with remarkable refractoriness to anti-inflammatory treatment, exceeded the common autoinflammatory phenotype of MDS patients. This prompted us to suspect a recently discovered disease, characterized by somatic mutations of the UBA1 gene: the VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome, which was ultimately confirmed by genetic testing. Reevaluation of previous bone marrow biopsies showed the presence of characteristic vacuoles in myeloid- and erythroid progenitor cells. Our case illustrates that the triad of an unresponsive multisystemic autoinflammatory disease, hematological abnormalities and vacuoles in myeloid- and erythroid progenitors in the bone marrow biopsy should prompt screening for the VEXAS syndrome

Quantitative ultrasound to monitor the vascular response to tocilizumab in giant cell arteritis.

OBJECTIVES To characterize the effect of ultra-short glucocorticoids followed by Tocilizumab monotherapy on the intima-media thickness (IMT) in GCA. METHODS 18 GCA patients received 500mg methylprednisolone intravenously on days 0-2, followed by Tocilizumab (8mg/kg) intravenously on day 3 and thereafter weekly subcutaneous Tocilizumab injections (162 mg) over 52 weeks. Ultrasound of temporal (TA), axillary (AA) and subclavian (SA) arteries was performed at baseline, on days 2-3, at week 4, 8, 12, 24 and 52. The largest IMT of all segments and IMT at landmarks of AA/SA were recorded. IMT was scaled by mean normal values and averaged. Each segment was classified according to diagnostic cut-offs. RESULTS 16 patients had TA and 6 had extracranial large artery involvement. The IMT showed a sharp decline on day 2/3 in the TA and AA/SA. In TA, this was followed by an increase to baseline levels at week 4 and a subsequent slow decrease, which was paralleled by decreasing symptoms and achievement of clinical remission. The AA/SA showed a new signal of vasculitis at week 4 in three patients with an IMT increase up to week 8. CONCLUSIONS Glucocorticoid pulse therapy induced a transient decrease of the IMT in TA and AA/SA. Tocilizumab monotherapy resulted in a slow and steady decrease in IMT of the TA and a smaller and delayed effect on the AA/SA. The data strongly support a remission-inducing effect of Tocilizumab and argue for an important role of ultrasound in monitoring disease activity in GCA

Interstitial lung disease in the context of systemic sclerosis

Die systemische Sklerose (SSc) ist eine seltene autoimmune Multiorganerkrankung, bei der eine immunvermittelte Vaskulopathie, Inflammation und Fibrose betroffener Organe zu deren Funktionsverlust führen können. Ein häufig betroffenes Organ ist die Lunge, deren Beteiligung, insbesondere wenn nicht früh erkannt, mit einer schlechten Prognose einhergeht. Die interstitielle Lungenerkrankung (ILD) ist eine der häufigsten Organmanifestationen, die bereits früh und nicht selten initial asymptomatisch im Krankheitsverlauf auftreten kann. Daher kommt dem Screening mittels HRCT (High-Resolution Computed Tomography) und Lungenfunktionstest eine große Rolle zu. Bei der Früherkennung ist das HRCT dem Lungenfunktionstest überlegen. Nach Diagnosestellung einer ILD wird in Abhängigkeit von Schweregrad und Progressionsrisiko entweder eine Therapie begonnen oder eine abwartende Haltung gewählt. Dabei gilt es zu berücksichtigen, dass ca. 30–40 % der SSc-ILD-Patienten eine Progression erleben werden. Zum regelmäßigen Monitoring eignen sich insbesondere Lungenfunktionsparameter und eventuell auch das HRCT, sofern strahlenreduzierte Protokolle zum Einsatz kommen. Das therapeutische Armamentarium umfasst neben pharmakologischen immunmodulierenden und antifibrotischen Substanzen bei ausgewählten Patienten auch die Option der autologen Stammzelltransplantation oder der Lungentransplantation. Mit dem Wissenszuwachs in der molekularen Pathophysiologie der Erkrankung erwarten wir in der Zukunft Trends für eine personalisierte Medizin basierend auf spezifischen Bio- oder Bildgebungsmarkern und individualisierten Therapieansätzen

Belimumab treatment in autoimmune hepatitis and primary biliary cholangitis – a case series

Background: The majority of patients with autoimmune hepatitis (AIH) achieve complete remission with established treatment regiments. In patients with intolerance or insufficient response to these drugs, the remaining options are limited and novel treatment approaches necessary. In primary biliary cholangitis (PBC), ursodeoxycholic acid (UDCA) and fibrates have improved prognosis dramatically, but there remains a proportion of patients with refractory disease.In patients with refractory AIH and/or PBC, we used a novel treatment strategy with the anti-B cell activating factor, belimumab. The first three patients had concomitant Sjögren's disease. The connecting element between all three diseases is B cell activation, including elevated levels of the B cell activating factor (BAFF). Furthermore, belimumab has been shown to be beneficial in Sjögren's disease. Aims and methods: To retrospectively investigate treatment response in six patients with AIH or PBC with or without concomitant Sjögren's disease treated with the anti-BAFF therapy belimumab at the University Hospital in Bern, Switzerland. Results: In all three patients with AIH, belimumab improved disease control and helped by-pass or reduce problematic side effects from corticosteroids and calcineurin inhibitors. In PBC patients (n = 3), there was no clear improvement of liver function tests, despite reduction or normalization of IgM. All patients with concomitant Sjögren's disease (n = 3) had an improvement of sicca symptoms and two out of three patients experienced an initially marked reduction in fatigue, which lessened over time. Conclusions: Belimumab may be a promising treatment option for patients with AIH and further investigations are needed. In PBC however, response was not convincing. The effects on sicca symptoms and fatigue were encouraging

Belimumab in Autoimmune Liver Diseases with associated Sjögren’s Syndrome

Background: Autoimmune hepatitis (AIH) is an auto-inflammatory disease of the liver with, if untreated, a high mortality rate. About 75% of patients are responsive to synthetic disease modifying drugs (sDMARD). Primary biliary cholangitis (PBC) is an inflammatory disease of small and medium sized bile ducts. Despite standard treatments (ursodeoxycholic acid (UDCA), fibrates and obeticholic acid (OCA)), a significant proportion of patients has progressive disease. Twenty percent of PBC patients have Sjögren’s syndrome (SjS). PBC has many features in common with SjS: epidemiology, epithelitis, well-characterized autoantibodies and a poor response to immunosuppressive treatments. Hypothesis: Based on the increased B cell-activating factor (BAFF) levels in AIH, PBC and SjS patients and the similarities between PBC and SjS, we hypothesized that belimumab is effective in AIH and PBC. Methods: Retrospective analysis of treatment responses to belimumab in three female patients with AIH and/or PBC with moderate to advanced liver fibrosis and concomitant SjS. Patient 1: 52y, with AIH, PBC and SjS. Indication: active AIH with intolerance to previous treatments (AZA, MMF, rituximab); belimumab since 01/20. Patient 2: 72y, with PBC and SjS. Indication: refractory PBC despite UDCA and fibrates (OCA declinedby health insurance); belimumab since 11/20. Patient 3: 54y, with PBC (with ductopenia), SjS and erosive rheumatoid arthritis (RA). RA responding insufficiently to all commonly used sDMARDs and biologicals. She was on low dose steroids, HCQ and etanercept. Her PBC was active despite UDCA and fibrates (OCA not tolerated). Indication: refractory PBC; belimumab since 11/20. We discontinued etanercept, when belimumab was started. Results: Patient 1: Remission of AIH under belimumab. Patient 2: Remission of PBC after 6 months of belimumab. Patient 3: Stable cholestasis parameters. Improvement of slightly elevated transaminases and almost normalization of IgM. Improvement of sicca symptoms in all patients. Two patients had a transient improvement in fatigue. RA in patient 3 remained on a level of moderate disease activity. Conclusions: These preliminary findings suggest belimumab as a promising treatment option in AIH and PBC, with so far no safety concerns. Our study shows how the basket of autoimmune diseases can guide us to evaluate new drug candidates in a more efficient way and highlights the strengths of a tight collaboration between hepatology and rheumatology

Belimumab in Autoimmune Liver Diseases with associated Sjögren’s Syndrome

Background: B cell-activating factor (BAFF) levels are elevated in autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC). About 20% of patients with PBC and 5% with AIH have a Sjögren’s syndrome (SjS). PBC and SjS have many features in common. Belimumab (anti-BAFF) shows positive effects in SjS. Methods: Retrospective analysis on treatment response to belimumab in three female patients with AIH and/or PBC with SjS. Patient 1: 52y, with AIH (F2), PBC and SjS. Indication: active AIH with intolerance to standard treatment; belimumab since 01/20. Patient 2: 72y, with PBC (F3) and SjS. Indication: refractory PBC; belimumab since 11/20. Patient 3: 54y, with PBC (F2, ductopenia), SjS and erosive rheumatoid arthritis. Indication: refractory PBC; belimumab since 11/20. Results: Patient 1: AIH in remission under belimumab monotherapy. Patient 2: PBC in remission 6 months after treatment start. Patient 3: Cholestasis stable. Slight decrease of mildly elevated transaminases and almost normalization of IgM. The effects on SjS were overall encouraging in all patients. Conclusions: These preliminary findings indicate belimumab as a promising treatment option in AIH and PBC, with so far no safety concerns. Our study shows how the occurrence of different autoimmune diseases can guide us to further personalize treatment and highlights the strengths of a tight collaboration between hepatology and rheumatolog

Phenotyping by persistent inflammation in systemic sclerosisassociated interstitial lung disease: a EUSTAR database analysis

BACKGROUND: Systemic sclerosis (SSc) is a heterogeneous disease with frequently associated interstitial lung disease (SSc-ILD). We aimed to determine the prognostic potential of phenotyping patients with SSc and SSc-ILD by inflammation and to describe disease trajectories stratified by inflammation and immunosuppressive treatment. METHODS: Patients from the European Scleroderma Trials and Research (EUSTAR) group cohort were allocated to persistent inflammatory, intermediate and non-inflammatory phenotypes if C-reactive protein (CRP) levels were ≥5 mg/L at ≥80%, at 20-80% and at <20% of visits, respectively. Cox regression models were used to analyse mortality risk and mixed effect models to describe trajectories of FVC and diffusing capacity for carbon monoxide (DLCO) %-predicted stratified by inflammation and immunosuppressive treatment. RESULTS: 2971 patients with SSc and 1171 patients with SSc-ILD had at least three CRP measurements available. Patients with SSc-ILD with a persistent inflammatory phenotype had a 6.7 times higher risk of mortality within 5 years compared with those with a persistent non-inflammatory phenotype (95% CI 3 to 15). In the inflammatory phenotype, FVC %-predicted was declining without (-1.11 (95% CI -2.14 to -0.08)/year), but stable with immunosuppressive treatment (-0.00 (95% CI -0.92 to 0.92)/year). In the non-inflammatory phenotype, patients with and without immunosuppressive treatment had a significant decline in FVC %-predicted, which was more pronounced in those with immunosuppressive treatment (-1.26 (95% CI -1.87 to -0.64) and -0.84 (95% CI -1.35 to -0.33)/year, respectively). CONCLUSIONS: Phenotyping by persistent inflammation provides valuable prognostic information, independent of demographics, disease duration, cutaneous subtype, treatment and SSc-ILD severity. The findings from this study support early immunosuppressive treatment in patients with SSc-ILD with persistent inflammation

Phenotyping by persistent inflammation in systemic sclerosisassociated interstitial lung disease: a EUSTAR database analysis.

BACKGROUND Systemic sclerosis (SSc) is a heterogeneous disease with frequently associated interstitial lung disease (SSc-ILD). We aimed to determine the prognostic potential of phenotyping patients with SSc and SSc-ILD by inflammation and to describe disease trajectories stratified by inflammation and immunosuppressive treatment. METHODS Patients from the European Scleroderma Trials and Research (EUSTAR) group cohort were allocated to persistent inflammatory, intermediate and non-inflammatory phenotypes if C-reactive protein (CRP) levels were ≥5 mg/L at ≥80%, at 20-80% and at <20% of visits, respectively. Cox regression models were used to analyse mortality risk and mixed effect models to describe trajectories of FVC and diffusing capacity for carbon monoxide (DLCO) %-predicted stratified by inflammation and immunosuppressive treatment. RESULTS 2971 patients with SSc and 1171 patients with SSc-ILD had at least three CRP measurements available. Patients with SSc-ILD with a persistent inflammatory phenotype had a 6.7 times higher risk of mortality within 5 years compared with those with a persistent non-inflammatory phenotype (95% CI 3 to 15). In the inflammatory phenotype, FVC %-predicted was declining without (-1.11 (95% CI -2.14 to -0.08)/year), but stable with immunosuppressive treatment (-0.00 (95% CI -0.92 to 0.92)/year). In the non-inflammatory phenotype, patients with and without immunosuppressive treatment had a significant decline in FVC %-predicted, which was more pronounced in those with immunosuppressive treatment (-1.26 (95% CI -1.87 to -0.64) and -0.84 (95% CI -1.35 to -0.33)/year, respectively). CONCLUSIONS Phenotyping by persistent inflammation provides valuable prognostic information, independent of demographics, disease duration, cutaneous subtype, treatment and SSc-ILD severity. The findings from this study support early immunosuppressive treatment in patients with SSc-ILD with persistent inflammation