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Familial Mediterranean Fever (FMF) and psoriatic arthritis: a higher risk than expected

Article title: Increased risk of psoriatic arthritis in patients with familial Mediterranean fever: a population-based cohort study.

First author: Amir Haddad

Journal: Rheumatology (Oxford)

Author of the abstract: Dr Rim Bourguiba


FMF et rhumatisme psoriasique : un risque plus élevé qu’attendu

Summary


Familial Mediterranean Fever (FMF) is the most common monogenic autoinflammatory disease worldwide. It is associated with mutations in the MEFV gene and characterized by excessive activation of the interleukin-1 (IL-1)β pathway. Psoriatic arthritis (PsA) is a chronic inflammatory disease belonging to the spectrum of spondyloarthritis, whose pathophysiology notably involves the IL-23/IL-17 pathways and Th17 lymphocytes. Data concerning the association between FMF and PsA have remained limited until now.


This retrospective population-based cohort study was conducted using the database of the main Israeli health insurance organization (Clalit Health Services), covering approximately 4.9 million individuals, between 2010 and 2023. The authors identified 9,736 adults with FMF treated with colchicine, with no history of PsA, matched by age and sex to 97,360 non-FMF controls. Participants were followed until the occurrence of PsA, death, or the end of the study period.


The incidence of PsA was significantly higher in FMF patients than in controls (3.26 vs 0.9 per 1,000 person-years). After adjustment for demographic factors and comorbidities, FMF was associated with a more than three-fold increased risk of developing PsA (HR 3.52; 95% CI 2.48–5.0). Other factors independently associated with PsA in FMF patients were age, smoking, and high socioeconomic status. The presence of psoriasis was, as expected, the major predictive factor.


The clinical characteristics and therapeutic strategies of PsA were overall similar in patients with or without FMF, with the exception of more frequent use of targeted synthetic DMARDs in FMF-PsA patients.


These results suggest an increased susceptibility to PsA in FMF patients, possibly related to common immunopathological mechanisms involving IL-1β and Th17 activation. They highlight the need for increased clinical vigilance regarding inflammatory joint manifestations in FMF patients.


In practice, this work encourages active screening for symptoms suggestive of psoriatic arthritis (persistent joint pain, enthesitis, dactylitis) in patients with FMF, particularly in cases of psoriasis or associated risk factors.

 
 
 

New variants of the MRTFA gene broaden the spectrum of actinopathy with low white blood cell counts and inflammation

Article title: Des nouveaux variants de MRTFA expandent le phénotype de cette actinopathie avec neutropénie et manifestations autoinflammatoires
First author: Wendao Li
Journal: Pediatric Allergy and Immunology
Author of the abstract: Philippe Mertz

De nouvelles variantes du gène MRTFA élargissent le spectre d’une actinopathie avec baisse des globules blancs et inflammation

Three key points to remember:


  1. MKL1 deficiency was known to cause major disruption of the actin cytoskeleton and severe primary immunodeficiency with phagocyte defects.

  2. The authors report here the first case of composite heterozygous variants in MRTFA, broadening the known phenotypic spectrum with major autoinflammatory manifestations and abnormalities in neutrophil number and function at the forefront.

  3. As illustrated here, the full phenotype of actinopathies remains to be discovered, highlighting the importance of accurate diagnosis and in-depth functional investigations.


The MRTFA gene encodes the Megakaryoblastic Leukemia 1 (MKL1) protein, a regulator of the SRF transcription factor that induces the transcription of genes involved in actin cytoskeleton homeostasis, cell migration, and adhesion in multiple cell types. Normally, G-actin polymerization releases MKL1, allowing it to enter the nucleus to coactivate SRF-targeted genes.

The MKL1 defect was initially described in 2015 in three patients who presented with a phenotype of actinopathy with combined immunodeficiency, including a defect in the number and function of phagocytes. These earlier cases, from consanguineous families, had homozygous variants leading to the complete absence of the MKL1 protein. The classic clinical picture included increased susceptibility to severe bacterial infections, poor wound healing, and thrombocytopenia.

This article reports the fourth patient with MKL1 deficiency and the first reported case associated with composite heterozygous variants in the MRTFA gene (NM_020831; p.Q377X/p.C684X). These two variants are located in critical domains of the MKL1 protein, resulting in the complete absence of the protein in PBMCs and neutrophils, and therefore of its function as a regulator of actin metabolism gene transcription factors.

The patient, aged 3 years and from a non-consanguineous family, presented her first symptoms at the age of 2 months. She suffered from early infections, intermittent neutropenia, and thrombocytopenia, with a nadir of 55 G/L. Unlike the cases initially described in the literature, the infections observed in this patient were relatively less severe. However, she had marked autoinflammatory manifestations, characterized by recurrent febrile episodes associated with multiple erythematous and papular skin lesions affecting the face and limbs, as well as swelling of the hands and feet. She also had intermittent bloody diarrhea, rectal ulcers, colitis, and colonic lymphoid follicular hyperplasia, as confirmed by endoscopy.


Multiple erythematous rashes on the patient's face and legs and swelling of the fee

Figure extraite de l’article

The authors conducted several functional explorations to understand the impact of these variants:


The absence of MKL1 caused marked dysfunction of the actin cytoskeleton, characteristic of actinopathies. A significant reduction in filamentous actin (F-actin) content was observed in neutrophils, monocytes, and, to a lesser extent, T and B lymphocytes. Similarly, F-actin polymerization in response to stimulation (fMLF) was reduced.


Major neutrophil dysfunction:

Migration: greatly reduced chemotactic response

ROS production and oxidative burst: The production of ROS (reactive oxygen species), whether intracellular or extracellular, and the production of H₂O₂ (assessed by DHR) were reduced in response to stimulation. This contrasts with previous reports that did not note any defects in ROS production.


NETs (Neutrophil Extracellular Traps): The formation of NETs, a crucial immune defense mechanism requiring intact actin cytoskeleton rearrangement, was impaired.

Transcriptomic analysis of neutrophils provided support for the clinical inflammatory observations, revealing downregulation of cytoskeletal genes but, concomitantly, upregulation of inflammatory pathways, including the NFkB pathway, TNFα, and a signature typical of inflammatory bowel disease (IBD). These results may partly explain the inflammatory manifestations observed in the patient.


In conclusion, the authors report here the first case of MKL1 deficiency associated with composite heterozygous variants, significantly broadening the known phenotypic spectrum. The association of a marked autoinflammatory phenotype with a less severe immune deficiency highlights the diversity and complexity of actinopathies. As illustrated here, the full phenotype of these diseases probably remains to be discovered, justifying further clinical and functional investigations.



 
 
 
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