Introduction:
Autoinflammatory syndromes are a group of rare disorders that have distinct features. They are characterized by episodes of fever along with inflammation in the skin, mucous membranes, serosa, and joints. Unlike common infections or autoimmune diseases, these disorders are not caused by germs or the body attacking itself. Instead, they happen because of a genetic issue that leads to problems with the body's natural defense system, causing too much inflammation. These disorders usually respond to specific substances like interleukin (IL)-1 or tumor necrosis factor (TNF)-α rather than general immune-suppressing medications. Symptoms include recurring fevers, rashes, inflammation in body tissues, enlarged liver and spleen, swollen lymph nodes, high levels of certain blood markers, an increase in a type of white blood cell called neutrophils, and a long-term risk of a condition called secondary amyloidosis. Autoinflammatory conditions are infrequent, and their occurrence is contingent on the genetic makeup of the population. Familial Mediterranean fever (FMF) stands out as the most prevalent autoinflammatory disease, particularly among individuals with roots in the eastern Mediterranean region, encompassing Turks, Jews (mainly non-Ashkenazi), Armenians, and Arabs. FMF can be identified with lower frequency in other ethnicities bordering the Mediterranean and, less commonly, beyond it. The prevalence of FMF exhibits notable disparities across different geographical areas. In Turkey, reported prevalence rates range from 0.0027 percent to 0.82 percent, while in Arabs, it is estimated to be approximately one in 25. The carrier frequency in the broader eastern Mediterranean region can be as high as one in five to one in three individuals. Tumor necrosis factor (TNF) receptor-associated periodic syndrome is likely the most prevalent autosomal dominant autoinflammatory disease, with documented cases in families and over 200 sporadic cases reported in Central America, Australia, and Europe. The knowledge of genetic origin rapidly advances the understanding of the mechanism of autoinflammatory syndrome. However, there are some points where rheumatologists need to differentiate rheumatological conditions from autoinflammatory syndromes. This article reviews the impact of autoinflammatory syndromes in rheumatology practice.
What Are Autoinflammatory Conditions?
The term autoinflammatory syndrome was introduced by Mc Dermott et al. in an article detailing the identification of mutations in the TNFRSF1A gene (TNF receptor superfamily 1A) within several families exhibiting a dominantly inherited periodic fever syndrome. This condition was subsequently labeled TNF receptor-associated periodic fever syndromes (TRAPS). Originally, autoinflammatory syndromes denoted a set of inflammatory diseases, hence the term 'inflammatory,' characterized by a robust genetic foundation determined by Mendelian inheritance, hence the term 'auto.' This phrase also conveys another concept, as it indirectly contrasts with the commonly used term 'autoimmunity.' It implies that syndromes and diseases vying for recognition as autoinflammatory disorders lack autoimmune abnormalities such as specific auto-antibodies or auto-reactive T-lymphocytes.
This primary category consists of four diseases, with familial Mediterranean fever (FMF) being the most prevalent among them. The other three conditions are TNF receptor-associated periodic fever syndromes (TRAPS), the group of mevalonate kinase deficiencies (MKD), which includes mevalonic aciduria (MA) and hyper immunoglobulin D and periodic fever syndrome (HIDS); and a fourth subgroup featuring three independently described syndromes: Muckle-Wells syndrome (MWS), familial cold urticaria (FCU), also known as a familial cold-associated syndrome (FCAS), and chronic infantile neurological cutaneous and articular (CINCA) syndrome, alternatively referred to as neonatal-onset multisystem inflammatory disease (NOMID) syndrome. Two additional syndromes meeting these initial criteria have been subsequently identified: nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain (NLRP12)-associated syndrome and deficiency of the interleukin (IL)-1–receptor antagonist (DIRA). Intriguingly, the defining feature of this initial group, particularly the first three entities, is the intermittent manifestation of clinical symptoms, often described as disease attacks, sharply contrasting with the genetically determined and, therefore, permanent nature of the underlying defect. The clinical symptoms primarily involve intermittent inflammatory attacks with both general and localized manifestations. General symptoms include mild to severe fever accompanied by blood neutrophilia and a consistent acute-phase response typically assessed through serum amyloid A (SAA) or C-reactive protein (CRP). Local symptoms predominantly affect three areas: the abdomen, skin, and the musculoskeletal system. New discoveries about how these disorders develop and the genes involved have made it possible to do tests. These tests might help find out if someone has one of these uncommon disorders in the end.
What Are the Impact of Autoinflammatory Syndromes in Rheumatology Practice?
Autoinflammatory syndromes, a group of rare disorders characterized by recurrent febrile episodes and inflammatory manifestations, have a significant impact on the field of rheumatology.
The following are key aspects highlighting the impact of autoinflammatory syndromes in rheumatology practice:
1. Diagnostic Challenges:
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Autoinflammatory symptoms overlapped with rheumatological conditions, making it a diagnostic challenge.
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Rheumatologists need to differentiate between syndromes such as fever and pain, which are more common in rheumatological conditions.
2. Genetic Basis and Molecular Pathways:
The knowledge of genetic basis is important for rheumatologists to understand the mechanism of autoinflammatory syndromes. This understanding gives the details of immune response and cytokine secretion and provides extra insight for the targeted therapeutic treatment.
3. Treatment Strategies:
Autoinflammatory syndromes typically respond to specific cytokine inhibitors such as interleukin (IL)-1 or tumor necrosis factor (TNF)-α. Rheumatologists play a key role in selecting and monitoring the effectiveness of these targeted therapies, which differ from traditional immunosuppressive treatments.
4. Collaboration With Other Specialties:
As autoinflammatory syndromes have a multisystem nature, collaboration with specialists from various fields, including dermatology, immunology, and genetics, is crucial. Rheumatologists need to work in tandem with other healthcare professionals to provide comprehensive and multidisciplinary care.
5. Long-Term Complications:
Rheumatologists must be vigilant about potential long-term complications, such as secondary amyloidosis, associated with autoinflammatory syndromes. These complications should be monitored and managed during the patient's treatment.
6. Educational Initiatives:
As autoinflammatory syndromes are rare and complex, rheumatologists play a role in educating healthcare professionals about recognizing and managing these conditions. The awareness within the rheumatology community should be increased so as to thwart misdiagnosis and for the best patient outcome.
Conclusion:
Autoinflammatory disorders can be a big challenge for different types of doctors, such as pediatricians, internists, primary care physicians, dermatologists, rheumatologists, and infectious disease specialists. People with these disorders often show either noticeable signs of fever without a clear cause or have confusing episodes of fever and skin issues without any signs of infection or cancer. The impact of autoinflammatory syndromes on rheumatology practice underscores the need for ongoing education, collaboration across specialties, and a nuanced approach to diagnosis and treatment. Rheumatologists are at the forefront of addressing the challenges posed by these disorders, ultimately enhancing the quality of care for patients with autoinflammatory syndromes.
