Abatacept and tofacitinib in refractory sarcoidosis: drug survival, safety, and treatment response.

OBJECTIVES: To describe drug survival, safety and treatment response in sarcoidosis patients treated with abatacept or tofacitinib in routine care. METHODS: We identified 41 sarcoidosis patients treated with abatacept and 12 patients treated with tofacitinib. Of the patients treated with tofacitinib 83% had previously been treated with abatacept. Drug survival and reasons for discontinuation of treatment was investigated. Treatment response was evaluated at least once within the first 6 months of treatment by at least one trained clinician and classified as responder or non-responder. No direct comparison of drugs was made. RESULTS: Median (range) disease duration was 3.5 (1-27) and 3 (1-16) years for abatacept and tofacitinib. The patients had previously received a median of 1 DMARD and 1 biological DMARD in both groups. Nearly all patients had been treated with at least one TNFi (95%/92 %). After 6 months, 90% (95%CI 85-90%) of the 41 patients in the abatacept group and 89% (79-99%) of the 12 patients in the tofacitinib group-maintained treatment. At 12 months, it was 80% (73-87%) and 74% (58-90%). No serious adverse events were recorded. For abatacept and tofacitinib 71% and 67% of patients were characterised as responders. In both treatment groups, there was a significant reduction in prednisolone dosage and levels of soluble IL2-receptor at all time points. CONCLUSIONS: Sarcoidosis patients treated with abatacept and tofacitinib had long drug survival, achieved high response rates. Both drugs represent good and safe therapeutic options in sarcoidosis patient's refractory to previous TNFi therapy.

Characteristics of cardiovascular autonomic dysfunction and association with quality of life in patients with systemic lupus erythematosus.

OBJECTIVES: Cardiovascular autonomic neuropathy (CAN) may affect the clinical course of SLE leading to reduced quality of life. CAN is assessed by heart rate variability (HRV) measures and cardiovascular autonomic reflex tests (CARTs). In patients with SLE, we aimed to determine the characteristics of CAN and if CAN associates with health-related quality of life (HRQoL). METHODS: Patients with SLE and healthy controls (HCs) were CAN tested with 5 min HRV and three CARTs to determine parameters reflecting parasympathetic and mixed sympathetic-parasympathetic function. Subjects were classified as having no, early or definitive CAN by having none, one or more than one abnormal CART, respectively. HRQoL as determined by the Short Form 12 (SF-12) was assessed in SLE. RESULTS: Of 111 patients with SLE, 92 answered the SF-12 and 54 were matched with 54 HCs for characterisation of CAN. Definitive CAN was present in 24.1% (95% CI 15% to 37%) patients with SLE and 1.9% (95% CI 0.3% to 9.8%) HCs (OR 16.8, 95% CI 2.1 to 133.8, p=0.008). The corresponding prevalences of any CAN were 53.7% (95% CI 41% to 66%) and 22.6% (95% CI 13% to 35%). SLE patients with definitive CAN showed signs of mixed sympathetic-parasympathetic dysfunction, whereas patients without CAN primarily presented with impaired parasympathetic activity. Signs of parasympathetic as well as sympathetic-parasympathetic dysfunction were associated with low physical SF-12 component score (all: ß>0.211, p<0.05). The mental SF-12 component score was not associated with any CAN indices. CONCLUSIONS: CAN was a frequent finding in SLE and associated to self-report on impaired physical HRQoL. Even patients without CAN showed signs of impaired parasympathetic function compared with controls.

Smoking associates with distinct clinical phenotypes in patients with systemic lupus erythematosus: a nationwide Danish cross-sectional study.

OBJECTIVES: SLE displays large clinical heterogeneity that beyond genetic factors may be determined by environmental exposures. In this Danish nationwide study, we aimed to determine if clinical subsets of SLE were associated with smoking history. METHODS: At each of six participating centres, incident or prevalent inpatients and outpatients with SLE were consecutively included. Manifestations forming the basis of SLE classification were registered in an electronic chart system. Patients also provided questionnaire-based data on environmental exposures, including smoking history. Hierarchical cluster analysis was conducted to determine and characterise subsets of patients with similar traits of disease manifestations. Levels of smoking exposure by pack-years were correlated to the identified SLE subsets, as well as discrete SLE manifestations. RESULTS: The cohort consisted of 485 patients (88% women and 92% Caucasian) with SLE of which 51% were ever smokers. Common disease manifestations comprised non-erosive arthritis (81%), malar rash (57%), lymphopenia (55%), photosensitivity (50%) and persistent proteinuria (41%). We identified three distinct phenotypic clusters characterised by their preponderance of (A) neurological, serosal and mucosal involvement; (B) renal, haematological and immunological disorders; and (C) acute and chronic skin manifestations. Cluster B was the youngest and had the lowest level of smoking exposure. Age-adjusted regression analyses showed that compared with never smokers a smoking history of >20 pack-years was associated with neurological disorder (OR=3.16), discoid rash (OR=2.22), photosensitivity (OR=2.19) and inversely with haematological disorder (OR=0.40), renal disorder (OR=0.40) and non-erosive arthritis (OR=0.45), p<0.05 for all. CONCLUSIONS: Our findings support that SLE presents in varying clinical phenotypes and suggest that they may have differentiated associations with smoking history.

The study of interactions between genome and exposome in the development of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a systemic inflammatory autoimmune disease characterized by a broad spectrum of clinical and serological manifestations. This may reflect a complex and multifactorial etiology involving several identified genetic and environmental factors, though not explaining the full risk of SLE. Established SLE risk genotypes are either very rare or with modest effect sizes and twin studies indicate that other factors besides genetics must be operative in SLE etiology. The exposome comprises the cumulative environmental influences on an individual and associated biological responses through the lifespan. It has been demonstrated that exposure to silica, smoking and exogenous hormones candidate as environmental risk factors in SLE, while alcohol consumption seems to be protective. Very few studies have investigated potential gene-environment interactions to determine if some of the unexplained SLE risk is attributable hereto. Even less have focused on interactions between specific risk genotypes and environmental exposures relevant to SLE pathogenesis. Cohort and case-control studies may provide data to suggest such biological interactions and various statistical measures of interaction can indicate the magnitude of such. However, such studies do often have very large sample-size requirements and we suggest that the rarity of SLE to some extent can be compensated by increasing the ratio of controls. This review summarizes the current body of knowledge on gene-environment interactions in SLE. We argue for the prioritization of studies that comprise the increasing details available of the genome and exposome relevant to SLE as they have the potential to disclose new aspects of SLE pathogenesis including phenotype heterogeneity.