[Interstitial Lung Disease associated with Connective Tissue Diseases]. / Interstitielle Pneumopathien bei Konnektivitiden.

INTRODUCTION: Interstitial Lung Disease associated with Connective Tissue Diseases Abstract: Interstitial lung diseases (ILD) are in up to one-third of cases associated with connective tissue diseases (CTD). In systemic sclerosis, rheumatoid arthritis, polymyositis/dermatomyositis, Sjögren's syndrome, and mixed connective tissue disease, an associated ILD significantly increases morbidity and mortality. The diagnostic workup for suspected CTD-ILD includes a range of functional, radiological, laboratory, and, if necessary, invasive tests. A thorough medical history and physical examination with targeted rheumatological diagnosis is particularly important. Also, patients with unclassified ILDs should be evaluated thoroughly for any underlying CTD. Pharmacological treatment options for CTD-ILD differ significantly from those for other ILDs. In addition to short-term glucocorticoids, antimetabolites and biological agents are often used. Antifibrotic drugs have also been successfully used in CTD-ILDs. The decision on whether and which immunosuppressive and/or antifibrotic therapy is indicated depends on the underlying disease, disease activity, extrapulmonary manifestations, severity of organ involvement, ILD progression, comorbidities, and patient preferences. Complex treatment decisions are ideally made in multidisciplinary expert teams.

Phenotyping by persistent inflammation in systemic sclerosis associated 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.

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.

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: Eighteen GCA patients received 500 mg for 3 consecutive days (total of 1500mg) i.v. methylprednisolone on days 0-2, followed by i.v. Tocilizumab (8 mg/kg) on day 3 and thereafter weekly s.c. Tocilizumab injections (162 mg) over 52 weeks. US of temporal (TAs), axillary (AAs) and subclavian (SAs) arteries was performed at baseline, on days 2-3, and at weeks 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: Of the 18 GCA patients, 16 patients had TA and 6 had extracranial large artery involvement. The IMT showed a sharp decline on day 2/3 in the TAs and AAs/SAs. In TAs, 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 AAs/SAs showed a new signal of vasculitis at week 4 in three patients, with an IMT increase up to week 8. CONCLUSION: Glucocorticoid pulse therapy induced a transient decrease of the IMT in TAs and AAs/SAs. Tocilizumab monotherapy resulted in a slow and steady decrease in IMT of the TAs and a smaller and delayed effect on the AAs/SAs. The data strongly support a remission-inducing effect of Tocilizumab and argue the case for US having an important role in monitoring disease activity in GCA. TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT03745586.

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.

Tocilizumab monotherapy after ultra-short glucocorticoid administration in giant cell arteritis: a single-arm, open-label, proof-of-concept study.

BACKGROUND: Two randomised controlled trials showed a glucocorticoid-sparing effect of tocilizumab in patients with giant cell arteritis. In the GUSTO trial we aimed to evaluate the efficacy and safety of tocilizumab monotherapy after ultra-short-term glucocorticoid treatment in patients with new-onset giant cell arteritis. METHODS: This investigator-initiated, single-arm, single-centre, open-label, proof-of-concept trial with a Simon's two stage design was done at University Hospital Bern, Bern, Switzerland. We enrolled patients aged older than 50 years newly diagnosed with giant cell arteritis (within 4 weeks before the screening visit) satisfying the American College of Rheumatology criteria or with large vessel vasculitis-associated polymyalgia rheumatica. The participants received 500 mg methylprednisolone intravenously for 3 consecutive days. Thereafter, glucocorticoid treatment was discontinued and a single infusion of tocilizumab (8 mg/kg bodyweight) was administered intravenously, followed by weekly subcutaneous tocilizumab injections (162 mg) until week 52. The primary endpoint was the proportion of patients who had remission within 31 days and showed no relapse at week 24. The secondary endpoints were the proportion of patients with complete relapse-free remission of disease at weeks 24 and 52, and time to first remission, first relapse (after induction of remission), and first partial remission. This study is registered with ClinicalTrials.gov, NCT03745586. FINDINGS: From Nov 23, 2018, to Sept 22, 2019, 18 patients were enrolled (12 of 18 were female, 18 of 18 were White) with a median age of 72 (IQR 67-75) years. Overall, 15 of 18 patients had cranial symptoms, ten of 18 had polymyalgia rheumatica symptoms, and 13 of 18 showed a positive histopathology. At the interim analysis, three (25%) of 12 patients were in remission. The null hypothesis could not be rejected, and the study was futile with respect to the primary endpoint. However, 14 (78%) of 18 patients had remission within 24 weeks (mean time to first remission 11·1 weeks, 95% CI 8·3-13·9) and 13 of 18 showed no relapses up to 52 weeks (72%, 47-90). Mean time to first partial remission was 6·2 [3·7-8·7] weeks. Time to first relapse (after induction of remission) could not be estimated as there was no relapse after induction of remission. Overall, three of 18 patients did not respond to treatment and two of 18 discontinued the study due to an adverse event (hepatopathy [one] and diverticulitis [one]). Anterior ischaemic optic neuropathy occurred in one patient. INTERPRETATION: The data show a slow remission-inducing and a lasting remission-maintaining effect of tocilizumab after an ultra-short pulse of glucocorticoids in patients with newly diagnosed giant cell arteritis. As a proof-of-concept study, our data do not allow us to propose clinical recommendations. FUNDING: Bern University Hospital, University of Bern, and F Hoffmann-La Roche.