Break down the barriers of auto-inflammation: How to deal with a monogenic auto-inflammatory disease and immuno-haematological features in 2022?

In the past few years, the spectrum of monogenic systemic auto-inflammatory diseases (MSAID) has widely expanded beyond the typical recurrent fever. Immuno-haematological features, as cytopenias, hypogammaglobulinemia, hypereosinophilia, lymphoproliferation and immunodeficiency, have been described in association of several MSAID. The objective of this review was to describe these particular MSAID. MSAID must be suspected in front of immuno-haematological features associated with non-infectious recurrent fever, chronic systemic inflammation, inflammatory cutaneous manifestations, arthritis or inflammatory bowel disease. Genes and cellular mechanisms involved are various but some of them are of special interest. Defects in actine regulation pathway are notably associated with cytopenia and immune deficiency. Because of their frequency, ADA2 deficiency and Vacuoles, E1-Enzyme, X-linked, auto-inflammatory, Somatic (VEXAS) syndrome deserve to be noticed. ADA2 deficiency results in polyarteritis nodosa-like presentation with a wide panel of manifestations including cytopenia(s), lymphoproliferation and immune deficiency. Neutrophilic dermatosis or chondritis associated with macrocytic anaemia or myelodysplasia should lead to screen for VEXAS. Of note, most of MSAID are associated with inflammatory anaemia. We proposed here a clinical and pragmatic approach of MSAID associated with immuno-haematological features.

Risk of liver fibrosis induced by methotrexate and other rheumatoid arthritis medications according to the Fibrosis-4 Index.

OBJECTIVES: We aimed to estimate the amount of scarring in the liver with the fibrosis-4 (FIB-4) index in patients with rheumatoid arthritis (RA) with special interest in methotrexate (MTX) influence. METHODS: This was a cross-sectional monocentric study including successive RA patients recruited for a 12-month period. Data on liver function, disease activity, hepatotoxic and cardiovascular risk factors were systematically collected. The FIB-4 index was calculated according the following formula: (age(years)× AST(U/L)/platelet (PLT) (109/L)×√ALT(U/L)). RESULTS: We included 170 patients with established RA: 141 (83%) were women with a mean age of 59±12 years and mean disease duration of 15±11 years. The FIB-4 was low and not significantly different between patients receiving MTX (n=102), patients previously treated with MTX (n=39) and patients never treated with MTX (n=29). No correlation was observed between FIB-4 values and cumulative MTX dose (r=0.09, p=0.271). No relationship was observed between FIB-4 and MTX treatment duration. The FIB-4 index was found significantly increased in patients receiving leflunomide (n=24), (median (range) 1.58 (0.46-3.16) vs. 1.18 (0.54-3.40), p=0.019) and tocilizumab (n=14), (median (range) 1.82 (0.75-3.73) vs. 1.18 (0.54-3.40), p=0.005) compared to patients not receiving DMARDs (n=29). Multivariate logistic regression analyses revealed an independent association between increased FIB-4 (>1.45) and male gender, low disease activity, and treatment with leflunomide and tocilizumab. CONCLUSIONS: RA patients with long-term maintenance MTX therapy have low FIB-4 values suggesting that MTX is not associated with an increased risk of advanced liver fibrosis. Increased FIB-4 values have been detected in leflunomide- and tocilizumab-treated patients, which will deserve dedicated further investigations.

Association between familial Mediterranean fever and multiple sclerosis: A case series from the JIR cohort and systematic literature review.

INTRODUCTION: Familial Mediterranean fever (FMF) is the most frequent monogenic autoinflammatory disorder; and leads to the uncontrolled production of interleukin (IL)-1ß. Multiple sclerosis (MS) is an inflammatory disease of the central nervous system; and its development seems to be partly correlated with IL-1ß levels. It is hypothesized that FMF could be associated with MS. We aim to describe the features of patients displaying both diseases and to investigate the MEFV mutation rate in MS patients. METHODS: Patients with definite MS were retrieved from the cohort of FMF patients in the Reference Center for Rare Auto-inflammatory Diseases and Amyloidosis (CEREMAIA). We also performed a systematic literature review of articles from PubMed that were published from 1990 to 2020. RESULTS: Twenty-four patients were included in the case series: five patients (1.3%) from our cohort of 364 and 19 patients from the literature. The sex ratio was 2:1. The mean age at diagnosis of FMF was 19 years old; and that for MS was 29 years old. Seven studies investigating the MEFV mutation rate in MS patients were included. Three studies found a higher mutation rate in MS patients than in the control group. CONCLUSION: FMF and MS features were comparable to those of patients with unrelated diseases; and MEFV mutation carriage was not positively correlated with MS. However; MS prevalence in FMF patients was higher than was expected in a healthy population. To a lesser extent; FMF prevalence in MS patients was higher than expected in a healthy population and the difference might not be significant. These data suggest that FMF could be associated with MS; and further studies are needed to investigate a potential causal association.

Amyloid Goiter in Familial Mediterranean Fever: Description of 42 Cases from a French Cohort and from Literature Review.

Our aim was to describe the main features of amyloid goiter in adults with amyloidosis secondary to familial Mediterranean fever. Therefore, we analyzed cases from a French cohort of familial Mediterranean fever patients with amyloidosis and from literature review. Forty-two cases were identified: 9 from the French cohort and 33 from literature review. Ninety percent of patients were on hemodialysis for renal amyloidosis before the development of goiter. The goiter grew up rapidly in 88% of cases; 75.6% of patients were euthyroid, 58% displayed dyspnea, and 44.8% dysphagia. Various features were seen on ultrasound, from diffuse to multinodular goiter. When it was performed, fine-needle aspiration biopsy almost always revealed amyloidosis. Thirty-one patients underwent thyroidectomy: to manage compressive symptoms (72%) or rule out malignancy (27%). Histology showed mature adipose tissue in 64% of cases and lymphocytic infiltration in 21.4%. In conclusion, amyloid goiter in familial Mediterranean fever preferentially occurs in patients with end stage renal failure. Fine-needle aspiration biopsy seems to be a sensitive exam for diagnosis, but thyroidectomy remains sometimes necessary to rule out malignancy or release compressive symptoms.

Disease Activity Score in 28 Joints Using GGT Permits a Dual Evaluation of Joint Activity and Cardiovascular Risk.

OBJECTIVE: To identify the factors potentially associated with serum gamma-glutamyltransferase (GGT) elevation in patients with rheumatoid arthritis (RA). METHODS: This is a cross-sectional monocentric study including RA patients over a 12-month period. Data on liver function, RA disease activity, and hepatotoxic and cardiovascular (CV) risk factors were systematically collected. To provide a simple tool to evaluate both joint disease activity and CV risk factors, we constructed the Disease Activity Score in 28 joints (DAS28)-GGT composite index by replacing erythrocyte sedimentation rate (ESR) with GGT. RESULTS: Among the 129 included patients, 32 (25%) had isolated GGT increase. GGT correlated with age, C-reactive protein (CRP) levels, and body weight and were significantly increased in patients with alcohol intake, type 2 diabetes mellitus, hypertension, dyslipidemia, and metabolic syndrome. GGT levels also gradually increased with the number of CV risk factors and correlated with the Framingham CV risk score. The composite index DAS28-GGT remained a reliable marker of RA disease activity and accurately detected patients with CV risk factors. Conversely to the DAS28 and the DAS28-CRP, the DAS28-GGT steadily increased according to the number of CV risk factors and had an increased diagnostic value compared to the DAS28 and DAS28-CRP for the presence of at least 2 CV risk factors and a Framingham CV risk score greater than 10%. CONCLUSION: GGT may be considered as a marker of systemic inflammation and CV risk in patients with RA. Based on these findings, we herein propose an original index, the DAS28-GGT, which is able to evaluate both joint disease activity and CV risk. This index will deserve further validation in prospective cohorts.