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Overview of Autoinflammatory Syndromes

Steven Spalding, MD

 

Overview

Autoinflammatory conditions constitute a broad range of genetically mediated conditions characterized by recurrent attacks of systemic inflammation with primary physical manifestations of primarily fever, rash, serositis, lymphadenopathy, and musculoskeletal symptoms. Genetic mutations that usually cause some dysregulation of the innate immune system underlie the etiology of the autoinflammatory syndromes.

Common autoinflammatory conditions are shown on table 1. Novel autoinflammatory conditions and molecular alterations resulting in these conditions are being discovered every year.

Table 1. Types of autoinflammatory diseases
Common Uncommon
Familial Mediterranean fever Blau syndrome
Hyperimmunoglobulin D syndrome Pyogenic arthritis, pyoderma, acne
TNF receptor-associated periodic syndrome Majeed syndrome
Deficiency of IL-1 antagonist
Cryopyrin-associated periodic syndromes  
Familial cold autoinflammatory syndrome  
Muckle-Wells syndrome  
Neonatal onset multisystem inflammatory disease  

Figure 1 shows many of the dysfunctions characterized in the autoinflammatory conditions. The common pathophysiologic pathway for all of these conditions is usually an increase in production of interleukin-1 (IL-1), one of the three major proinflammatory cytokines. This increase in IL-1 drives the inflammatory symptoms experienced by patients and observed by physicians. For example, in a patient with familial Mediterranean fever (FMF), mutations in the pyrin protein cause loss of function and an increase in procaspace-1 activity, which increases production of IL-1. For the TNF receptor-associated periodic syndrome (TRAPS), ineffective cleavage of the extracellular portion of the TNF receptor can result in continued transmission of a proinflammatory signal to the cell nucleus and inappropriate production of proinflammatory cytokines, TNF and IL-1. Blau syndrome has a mutation that affects NF-kappaB, a protein which modulates production of proinflammatory cytokines. Regardless of the autoinflammatory condition, genetic abnormalities drive disordered regulation of the proinflammatory cytokine pathway and physical manifestations of systemic inflammation.

figure 1
Figure 1.Pathways in autoinflammatory dysfunction syndromes.

Table 2 provides an overview of different autoinflammatory syndrome features. The clinical features and duration of attack can help categorize the patient’s condition. For example, with FMF, fever attacks are mostly short lived, usually lasting less than 72 hours. Patients with FMF have intense serositis, arthritis, and rashes. With hyperimmunoglobulin D syndrome (HIDS), the duration of symptoms is longer, usually 3 to 5 days. Patients with TRAPS have episodes that can last weeks. The symptoms in cryopyrinopathies (CAPS) can span the spectrum, lasting from one day (Familial Cold Autoinflammatory Syndrome; FCAS) to infants who develop nearly continuous symptoms on their first day of life (Neonatal Onset Multisystem Inflammatory Disease; NOMID).

Therapeutic options are also listed in Table 2. Response to cytokine-specific immunomodulatory agents can provide important diagnostic clues in the evaluation of patients with potential autoinflammatory conditions. For example, if based on phenotype, a patient is suspected to have FMF and responds to therapy known to be uniquely effective for FMF (eg, colchicine),this positive response could be an important clue as to the underlying cause of symptoms. There could be cross-over response between conditions (ie, response to IL-1 inhibition between FMF and CAPS).

In the long term, the sequelae of the conditions are truly dependent on the specific autoinflammatory syndrome. One of the most serious complications of the autoinflammatory conditions is amyloidosis. In the United States, the incidence of amyloidosis is not as high as in some other countries such as Israel or Turkey. A patient’s amyloidosis risk is partially dictated by their genetic mutation.

Interestingly, amyloidosis risk is also affected by where the person is living, not where they were born. For example, consider the case of a patient living in Turkey who is homozygotic for MEFV gene and is considered at high risk for developing amyloidosis. If that patient moves from Turkey to the United States, their amyloidosis risk would decrease.

Additionally, patients with autoinflammatory conditions have reported lower scores on quality of life or other general measures of health status. The cryopyrinopathy conditions can result in sensory neural hearing loss, chronic meningitis, and structural changes to the skeleton. Ultimately, the long-term outcome is likely most dependent on early recognition and initiation of definitive therapy for these rare conditions.

Table 2. Features of autoinflammatory syndromes.
Syndrome Clinical features Duration of attacks Mode of inheritance Gene Therapy Amyloidosis risk
FMF Serositis
Arthritis
Rash
<72 hrs Recessive MEFV Colchicine
IL-1 inhibition
+++
HIDS Cervical adenopathy
Rash
Arthritis
Headache
Triggered by
vaccine
3 - 5 days Recessive MVK Prednisone
Etanercept
IL-1 inhibition
IL-6 inhibition
-
TRAPS Myalgia
Serositis
Periorbital edema
Traveling rash

7 - 10 days Dominant TNFRS1A Prednisone
Etanercept
IL-1 inhibition IL-6 inhibition
++
Cryopyrin-associated periodic syndromes (CAPS)
-FCAS Urticaria
Arthralgia
<24 hrs Dominant NLRP3 Cold avoidance -
-MWS Urticaria
Arthritis
Headache
Hearing loss
5 -7 days Dominant NLRP3 IL-1 inhibition ++
-NOMID Urticaria
Arthritis
Headache
Hearing loss
Papilledema Bony changes
Constant Dominant NLRP3 IL-inhibition ++

Abbreviations: FCAS = Familial cold autoinflammatory syndrome; FMF = Familial Mediterranean fever; HIDS = Hyperimmunoglobulinemia D syndrome; MWS = Muckle-Wells syndrome; NOMID = Neonatal onset multisystem inflammatory disease; TRAPS = Tumor necrosis factor receptor-associated periodic syndrome

Identifying AutoinflammatorySyndromes

A key to the diagnosis of the autoinflammatory syndromes is obtaining a detailed history to fully understand the pattern of symptoms associated with attacks. For example, a patient may experience discrete, recurrent episodes of fevers accompanied by stereotypic symptoms that vary by episode. In some attacks there could be significant, isolated lymphadenopathy, while in subsequent attacks, lymphadenopathy and arthritis or lymphadenopathy and serositis could occur. However, fevers are a virtual sine qua non in the autoinflammatory syndromes.

The episodes do not have to be predictable or have a fixed frequency. Attacks may occur six times one year and five times the year prior with varying time intervals between attacks. While febrile attacks are not predictable, they are usually relatively discrete, self-limited episodes. The evaluation of patients for possible malignancies and infections as a cause of these episodes is crucial, and those diagnostic considerations should be ruled out before settling on a diagnosis of an autoinflammatory syndrome.

Patient history

The diagnosis of an autoinflammatory condition is primarily clinical, and relies heavily on the patients’ history. Accuracy of the data requires practitioners to ask the right historical questions and to spend the necessary time with the patients and their families to understand the patient’s symptoms — and whether other family members are affected. Symptom onset can start during the first, second, or third decade of life, but they can start later. Chronic conditions start acutely, although many patients do not present until they have 3 or 4 months of symptoms and are often misdiagnosed with recurrent viral infections, thus delaying diagnosis and initiation of treatment.

Lab values

Laboratory test values and acute phase reactants are going to be elevated in all the patients, especially during attacks, thus providing limited value for disease differentiation. Inflammatory markers may remain persistently elevated, although typically lower than during attacks, inbetween episodes. Mevalonic acid, an organic acid, can be found in the urine of patients who have hyper-IgD syndrome, especially during attacks and can be used as both a marker of disease activity and as a diagnostic tool.

Biopsy

Biopsies have a limited role in the evaluation of patients for autoinflammatory syndromes beyond their use in determining whether symptoms are related to malignancy or infection. A skin biopsy of areas affected by rashes can identify neutrophilic infiltrates, but it is a relatively generic finding and will not differentiate between the various autoinflammatory syndromes. Genetic sequencing can be helpful but should not be used as definitive diagnostic testing. Numerous studies have demonstrated that between 30% and 40% of patients who meet phenotypic classification of an autoinflammatory condition do not have a definable genetic mutation. Other studies have found that the likelihood of identifying a genetic mutation associated with an autoinflammatory condition varies depending on the patient population, patient ethnicity, or presence of a family member with a genetic mutation. Thus, it is important to consider genetic results in the context of the patient’s symptoms.

Therapy

Results from different therapeutic interventions can provide diagnostic data. For example, Colchicine therapy is effective for FMF but has limited efficacy for other autoinflammatory conditions. Both TNF alpha and IL-1 have efficacy for the hyper-IgD syndrome. Etanercept and IL-1 are effective for the tumor necrosis factor receptor-associated periodic syndrome (TRAPS).Both the Muckle-Wells syndrome and Neonatal onset multisystem inflammatory disease respond to IL-1. Because most autoinflammatory conditions are characterized by elevated levels of IL-1, response to an IL-1 inhibitor does indicate existence of an autoinflammatory condition but not always a specific autoinflammatory condition. Nevertheless, a positive response to IL-1 inhibition is an important finding, especially when evaluating those patients with suspected autoinflammatory conditions but negative genetic testing.

There are several methods to leverage these therapies as diagnostic aids, including incorporation of “hard stops” or “dose pushes.” For example, while waiting for genetic testing results, practitioners could escalate doses ofa short-acting IL-1 inhibitor during a 2-week period. If symptoms respond to therapy, it could indicate certain disease considerations. If symptoms do not respond, that could also eliminate certain autoinflammatory diseases.

Children frequently require higher doses of cytokine inhibitors when compared to adults. For example, some children with Muckle-Wells syndrome will require doses of IL-1 inhibitors several times greater than published dosing regimens. During an attack, greater doses can be required to control symptoms. Fortunately, IL-1 inhibitors have a relatively short half-life, which helps avoid untoward adverse effects. This relatively benign pharmacologic profile allows practitioners to utilize these therapies as a diagnostic tool.

Summary

The autoinflammatory syndromes are an evolving group of phenotypically similar conditions unified by a disordered regulation of the innate immune system. Diagnosis is based on the patient’s historical factors and supported by laboratory findings. Therapy is focused on providing regulation of cytokine abnormalities that are derived from the genetic changes.

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