Autoinflammatory disease syndrome of hyperimmunoglobulinemia D

Introduction

Various autoinflammatory diseases (AIDs) are currently being intensively studied. Molecular genetic testing of patients is of great importance for the diagnosis of such diseases, since the basis for their development is pathological mutations that cause disorders in the system of innate (antigen-nonspecific) immunity and the development of inflammation. An expert group consisting of 12 German and Austrian academic specialists has developed a diagnostic algorithm and principles for the treatment of auto-inflammatory processes [1].

Autoinflammation is considered part of the etiopathogenesis of such common diseases as Crohn's disease, erythema nodosum, sarcoidosis, ankylosing spondylitis, vasculitis and vasculitis syndromes, macrophage activation syndrome, monogenic vasculitis (STING-associated vasculitis and type II adenosine-deaminase deficiency (DADA2)), adult Still's disease, systemic lupus erythematosus, systemic juvenile idiopathic arthritis, gouty arthritis, and psoriasis (mutation of the CARD14 gene) [2].

Main AID characteristics:

• absence of autoantibodies;
• frequency of exacerbations;
• particular duration of exacerbations;
• general nature of exacerbations (similar course);
• usually observed intervals without clinical manifestations;
• development of serositis (in almost any form of auto-inflammation);
• arthralgia, which is more common than arthritis (or arthritis with certain syndromes);
• frequent development of amyloidosis (with a late diagnosis);
• high efficiency of anti-interleukin-1 (anti-IL-1) therapy (compared to anti-TNF-α therapy);
• increased level of laboratory markers of inflammation;
• AIDs occur with the same frequency in both men and women;
• positive family history (possibly ethnic in nature)

Nowadays, more than 30 genes are known, mutations in which lead to the development of AIDs; the most common and well-studied are the NLRP3, TNFRSF1A, and MVK genes.

These genes cause the development of the following major monogenic AIDs: cryopyrin-associated periodic syndromes (CAPS); TNF-receptor-associated periodic syndrome (TRAPS); hyper-immunoglobulinemia D-syndrome (HIDS) [3-7].

Modern classification of autoinflammatory diseases:

Hereditary periodic fever (a typical violation of the function of inflammasomes):

1. Familial mediterranean fever (FMF).
2. Hyper-IgD syndrome (HIDS or MKD — mevalonate-kinase deficiency).
3. CAPS (cryopyrin-associated periodic syndromes).
4. TRAPS (periodic syndrome associated with the TNF-α receptor).
5. Deficiency of natural receptor antagonists (IL-1 receptor = deficiency of interleukin 1-DIRA receptor antagonist; IL-36 receptor = deficiency of interleukin 36-DITRA receptor antagonist).

Pyogenic diseases of the skin and bones (possible involvement of inflammasomes and other mechanisms):

1. CRMO (Chronic recurrent multifocal osteomyelitis).
2. SAPHO syndrome (synovitis + acne + pustulosis + hyperostosis and osteitis).
3. PAPA syndrome (pyogenic arthritis + gangrenous pyoderma + cystic acne).

Granulomatous diseases (violation of NF kB activation and signal transmission by IL-10):

1. Crohn's disease with early onset of the disease.
2. Blau syndrome/sarcoidosis with early onset of the disease (children's granulomatous arthritis)

Idiopathic syndromes + other nosological units (unclear pathogenesis, possible involvement of inflammasomes):

1. PFAPA syndrome (periodic fever, pharyngitis, lymphadenopathy, aphthae).
2. Schnitzler syndrome.
3. Still's disease (systemic juvenile idiopathic arthritis).
4. Monogenic forms of vasculitis (DADA 2, STING-associated vasculitis with onset in infancy (SAVI)) [8].

A decrease in the activity of mevalonate kinase leads to a deficiency of geranyl-geranyl-pyrophosphate (GGPP), one of the end products of mevalonic acid involved in the prenylation of intracellular G-proteins, and, as a consequence, leads to excessive activity of procaspase, synthesis of the precursor of interleukin-1 (IL-1)-beta and its active form [5-13].

A milder variant of mevalonate kinase deficiency, also known as hyper-IgD syndrome, is more common and is characterized by recurring episodes of unexplained fever without concomitant infection. Such attacks are accompanied by fatigue, chills, abdominal pain, swelling of the affected lymph nodes (lymphadenopathy), rash, joint inflammation (arthritis), and pain (arthralgia). Additional symptoms include nausea, diarrhea, vomiting, headaches, small mouth ulcers, and abnormal enlargement of the liver and spleen (hepatosplenomegaly). The rash is presented in the form of erythematous spots and papules. Some people have cough and inflammation of the posterior pharyngeal wall (pharyngitis). As a result of the long course of the disease, complications such as kidney amyloidosis, joint contractures, and abdominal adhesions develop [14-16].

The purpose of this study is to present a clinical observation of autoinflammatory disease in a patient.

Materials and methods

Therefore, a clinical case of hyperimmunoglobulinemia D (mevalonate kinase deficiency syndrome) in an 8-year-old girl was analyzed.

Results

Girl R., 8 years old (date of birth – November 24, 2013), born from the 4^th pregnancy against the background of a burdened obstetric history (her mother had 2 miscarriages at an early stage), 2 urgent deliveries. Birth weight — 3660 g, Apgar score — 8/9 points. Preventive vaccinations according to an individual calendar (BCG, V1 against polio, V1–V2 against viral hepatitis B). The child suffered from the following diseases — chickenpox in 1 year 10 months, acute respiratory viral infections, follicular sore throat, acute bronchitis, acute tonsillitis, infectious mononucleosis. The heredity for hematological, immunological, and oncological diseases was not burdened.

The patient has been ill since the age of two, when, after chickenpox, a fever attack of up to 40 degrees first appeared, accompanied by an increase in the palatine tonsils, the appearance of purulent plaque on them, and an increase in cervical lymph nodes (Figure 1). This attack was regarded as an infectious process, stopped by antibacterial therapy and the use of nonsteroidal anti-inflammatory medicines (NSAIDs).

However, then such episodes began to recur every 20–30 days with the duration of the attack 5–7 days. There was an intestinal syndrome in the form of abdominal pain, nausea, vomiting, loose stools, arthralgia, and an increase in inflammatory activity of the blood (ESR up to 28 mm/hour) began to join the temperature and increase in the tonsils.

Outside of the attack, the patient showed a satisfactory condition. Her physical development was harmonious according to the mesosomatic type. All the internal organs were without features. Physiological recovery was normal.

During the year, there was a positive effect during attacks in the form of fever relief after taking NSAIDs.

From the age of three, the patient has been observed by an immunologist with a diagnosis of Marshall syndrome; dysgammaglobulinemia was detected as well. During the attacks, she took glucocorticosteroids (GCS) (Prednisone orally 1 mg/kg with a positive effect). At the age of 6, she was consulted by a rheumatologist, therefore, immunological studies were carried out (extractable nuclear antibodies, antibodies to cardiolipin (total), antibodies to single-, double-stranded DNA, antibodies to cyclic citrullinated peptides, antibodies to phospholipids); all the indicators were within normal limits. There was not any data on autoimmune pathology. During the attacks, it was recommended to take GCS (metipred) (1.5 mg/kg). Further, due to a decrease in the response to GCS, the dose of Prednisone was gradually escalated to 2 mg/kg during attacks.

Taking into account the long course of the disease and the short intervals between attacks and the response only to an increase in the dose of GCS to 2 mg/kg at 7.5 years of age, a molecular genetic study was conducted, as a result of which a mutation in the MVK gene was detected in the 11^th exon (V377I) and the 9^th exon (I268T) in a heterozygous state. This confirms the diagnosis of mevalonate kinase deficiency syndrome.

In order to determine further management tactics, the patient was sent to the Department of Immunology of the Federal State Budgetary Institution “National Medical Research Center of Pediatric Hematology, Oncology and Immunology named after Dmitry Rogachev” of the Ministry of Health of Russia, where she was hospitalized in July 2021.

Upon admission, the somatic status was stable, there was moderate hypertrophy of the tonsils (1–2 degrees) with a single plaque.   

Laboratory test results:

• absence of significant deviations in the hemogram, s moderate increase in erythrocyte sedimentation rate (up to 32 mm/hour);
• minimal inflammatory reaction in the biochemical blood test (C-reactive protein — 10.5 mg/l);
• according to the results of the control of immunophenotyping of peripheral blood lymphocytes, there were no signs of impaired maturation of T- and B-lymphocytes;
• the level of mevalonic acid in the urine was moderately elevated (0.97 mM/M, with a norm of 0.1 to 0.7 mM/M).
• confirmation of the mutation by direct sequencing according to Sanger (in the MVK gene of the girl and her father, in exon 11, a replacement of one nucleotide in the heterozygous state of C.1129G>A was found, leading to the replacement of the amino acid p.Val377Ile (V377I).

Results of instrumental research methods:

• electrocardiography and echocardiography showed no pathology;
• ultrasound of the abdominal organs showed signs of minor hepatomegaly and intra-abdominal lymphadenopathy;
• endoscopic colonoscopy — terminal ileitis, lymphofollicular hyperplasia of the terminal part of the ileum; full-thickness colon biopsy was performed – microscopic description: the sample was represented by a fragment of the mucous membrane of the ileum, there was a pronounced lymphoplasmocytic infiltration with a large number of segmented leukocytes, surface erosions. The fragments of the colon mucosa with signs of mild edema, admixture of plasma cells and lymphocytes, few lymphoid follicles were noted as well.

Medical conclusion: the examined biopsy material showed signs of active erosive ileitis, inactive reactive colitis. There were no signs of amyloidosis.

Consultation by an ophthalmologist — OU without pathological changes.

The diagnosis was “Primary immunodeficiency condition: autoinflammatory syndrome — mevalonate kinase deficiency syndrome (mutation in the MVK gene in exon 11 (V377I) and exon 9 (I268T) in a heterozygous state)”.

This disease is chronic in its nature; in the absence of control of inflammatory attacks, the risk of developing kidney amyloidosis and multiple organ failure and other life-incompatible complications is high.

Taking into account the severity of the disease course, as well as the presence of recurrent episodes of high fever in the patient, accompanied by an increase in the palatine tonsils, intestinal syndrome, nausea and arthralgia, as part of achieving and maintaining remission, the girl was prescribed a monoclonal inhibitor IL-1b Kanakinumab (Ilaris) at a dose of 75 mg once every 8 weeks, subcutaneously, according to vital indications.

Already after the first administration of the medicine, the attack-free interval increased to 50 days.

Conclusion

For all the children with periodic fever syndrome, a genetic study is indicated for the timely diagnosis of rare auto-inflammatory diseases and the appointment of pathogenetic therapy to improve the quality of life and prevent complications.