Eur J Pediatr DOI 10.1007/s00431-015-2505-9
REVIEW
Treatment of hyperimmunoglobulinemia D syndrome with biologics in children: review of the literature and Finnish experience Svetlana Kostjukovits & Liisa Kalliokoski & Kaisu Antila & Matti Korppi
Received: 12 November 2014 / Revised: 23 January 2015 / Accepted: 10 February 2015 # Springer-Verlag Berlin Heidelberg 2015
Abstract Hyperimmunoglobulinemia D syndrome (HIDS) is an autoinflammatory disorder that is caused by mevalonate kinase deficiency (MKD). Recent advances in the pathogenesis of MKD, including the proposed mechanisms of inflammasome activation, provide the basis for the development of new treatment modalities. So far, feedback on the treatment of HIDS with biological medicines has come from case reports with limited numbers of patients. In this review, we summarize the data that is currently available on the treatment of HIDS in children, with the emphasis on new therapies, and present three Finnish pediatric cases treated with anakinra. Case reports have been published on 33 pediatric HIDS patients who have been treated with biological medicines, and in some cases, they were treated with more than one drug. Of these patients, 21 were treated with anakinra and 16 with etanercept, resulting in complete or partial responses in
90 and 50 % of cases, respectively. A further five patients were treated with canakinumab, with complete or partial responses. Conclusion: The accumulating evidence on the efficacy and safety of biological drugs in pediatric HIDS suggests that the anti-interleukin-1 agent anakinra is the drug of choice for HIDS in children. What is Known: • Various biologic drugs have been tried for the treatment of HIDS. What is New: • Based on the 90 % response rate, anakinra seems to be the drug of choice for HIDS in children.
Keywords Mevalonate kinase deficiency . Hyper IgD syndrome . Autoinflammatory disease . Etanercept . Anakinra . Canakinumab
K. Antila Department of Pediatrics, North Carelia Central Hospital, Joensuu, Finland e-mail: [email protected]
Abbreviations CRP GDP GTP HIDS HMG-CoA IgA IgD IL LPS MKD MVA MVK NLRP3
M. Korppi Pediatric Research Centre, Tampere University and University Hospital, Tampere, Finland e-mail: [email protected]
NSAIDs PAMPs or DAMPs
Communicated by David Nadal Revisions received: 03 January 2015 / 23 January 2015 S. Kostjukovits (*) Department of Pediatrics, Malmi District Hospital, Pietarsaari, Finland e-mail: [email protected] L. Kalliokoski Department of Pediatrics, Kainuu Central Hospital, Kajaani, Finland e-mail: [email protected]
C-reactive protein Guanosine diphosphate Guanosine triphosphate Hyperimmunoglobulinemia D syndrome 3′-Hydroxy-3′-methylglutaryl coenzyme A Immunoglobulin A Immunoglobulin D Interleukin Lipopolysaccharide Mevalonate kinase deficiency Mevalonic aciduria Mevalonate kinase Nod-like receptor family, pyrin domaincontaining protein 3 Non-steroidal anti-inflammatory drugs Pathogen- or damage-associated molecular patterns, respectively
Eur J Pediatr
SAA TNFα WBC
Serum amyloid A Tumor necrosis factor alpha White blood cells
Introduction Mevalonate kinase deficiency (MKD) is an autoinflammatory disorder with autosomal recessive inheritance [22]. Hyperimmunoglobulinemia D syndrome (HIDS) is a milder form of MKD and manifests with recurrent febrile episodes with various combinations of lymphadenopathy, abdominal pain, vomiting, diarrhea, arthralgia/arthritis, headache, skin rashes, mouth ulcers, hepatomegaly, and splenomegaly [51]. The more severe mevalonic aciduria (MVA) has additional features of growth failure, mental retardation, dysmorphisms, and neurological symptoms [18]. Mevalonate kinase (MVK) activity in HIDS patients varies from 1.8 to 28 % [10] as opposed to virtually no active MVK in patients with MVA [21]. In recent years, knowledge on the pathogenesis and treatment options of HIDS has expanded, and an increasing number of children now receive biological medicines. These include the anti-tumor necrosis factor alpha (TNFα) agents infliximab [24, 27], etanercept [53, 54], and adalimumab [15], the anti-interleukin (IL)-1 agents anakinra [5, 7, 15, 27] and canakinumab [15], and the IL-6 antagonist tocilizumab [41]. This paper presents a review of the use of biological drugs in the treatment of pediatric HIDS and the case studies of three Finnish children with HIDS who were treated with anakinra.
Literature review Pathogenesis MKD results in insufficient mevalonate phosphorylation in the sterol biosynthesis pathway (Fig. 1). The excess mevalonate does not contribute to inflammatory attacks in HIDS, but the deficiency of isoprenoids downstream in the MVK pathway does [14, 29]. In particular, the lack of geranylgeranyl-phosphate leads to caspase-1 activation through Rac1 signaling [25]. Caspase-1 then processes the IL-1β precursor to an active IL-1β [9], which initiates cytokine secretion. The currently available biological medicines include anakinra and canakinumab, which are both anti-IL-1 agents. The events take place within the nod-like receptor family, pyrin domain-containing protein 3 (NLRP3) inflammasome, also known as cryopurin [38], a complex network of intracellular molecular signaling pathways that form the basis of innate immune responses [32]. Inflammasomes are activated by pathogen-associated molecular patterns (PAMPS) or damageassociated molecular patterns (DAMPS), such as lipopolysaccharides (LPS) or signals from injured cells [33], and this can explain why infections, vaccines, and stress trigger inflammatory attacks in HIDS. NLRP3 is overexpressed in MVKdeficient patients, and stimulation with LPS in a cellular model of MKD resulted in the induction of NLRP3 and caspase-1 [50]. The complex interplay of cytokines in HIDS is not yet fully understood. Experimental evidence suggests that IL-6 may have reciprocal interactions with IL-1 [45], and anti-IL-6-targeted treatment may be an option in some HIDS patients [41].
Fig. 1 Hypothetical pathogenesis of HIDS. Adapted from Normand et al. [35]. HMG-CoA 3′-hydroxy-3′-methylglutaryl coenzyme A; PP pyrophosphate, GDP guanosine diphosphate, GTP guanosine triphosphate, IL interleukin
Eur J Pediatr
New insights into the pathogenesis of HIDS pave the way for novel therapeutic options, such as inhibition of Rac-1 or administration of the deficient geranylgeraniol, which have both been shown to decrease IL-1β secretion in cellular models [25, 50]. These options result in an inhibition of the overactivation of innate immunity, whereas currently available drugs only suppress the influence of the storm of innate immunity mediators. Complications HIDS attacks are accompanied by acute phase responses, presenting with leukocytosis and elevated C-reactive protein (CRP) and serum amyloid A (SAA) [52]. Only five cases of amyloidosis have been reported in HIDS patients, presenting as nephrotic syndrome at 19 to 29 years of age [26, 28, 36, 43]. Recently, renal amyloidosis was found in a 7-year-old boy with HIDS [54], emphasizing the potential importance of early suppression of inflammatory responses. Other reported complications are abdominal adhesions, presumably caused by repeated peritonitis during inflammatory attacks, and joint symptoms, which range from arthralgia to erosive arthritis and may lead even to joint contractures [2, 51]. Whether these long-term consequences of HIDS can be prevented by early anti-inflammatory treatment is not known. Treatment A number of medicines have been used to treat HIDS but with no, or marginal, efficacy. These include azathioprine, colchicine, cyclosporine, dapsone, methotrexate, montelukast, salazopyrin, tacrolimus, thalidomide, ranitidine, and immunoglobulins [51]. Paracetamol, non-steroidal anti-inflammatory drugs (NSAID) and corticosteroids may relieve symptoms and shorten the duration of febrile attacks, but the effects are inconsistent [47] and, as is well-known, long-term corticosteroid treatment has many side effects. HMG-CoA reductase inhibitors (statins) have a theoretical potential therapeutic effect on HIDS, as they block the MVK pathway and decrease mevalonate production [37]. However, a pediatric trial that used lovastatin to treat MVA was stopped because of disease exacerbation in two children [21]. A placebo-controlled randomized cross-over trial with simvastatin resulted in a positive clinical effect in five out of six adult patients with HIDS [44]. However, statins did not prove sufficiently effective in later studies [2, 51]. There is an anecdotal report of disease resolution with oral alendronate, which was initially prescribed to treat osteoporosis in a 14-year-old boy with HIDS [8]. Bisphosphonates inhibit the already compromised MVK pathway [38] and are, therefore, considered as contraindicated in HIDS. The normalization of SAA levels and complete resolution of attacks
during alendronate treatment are a paradoxical finding, which deserves further research. Biological agents Our current knowledge on the use of biologic medicines to treat HIDS has been derived from published case reports. This is because the number of diagnosed and registered HIDS patients is very low, at around 200 [47]. We searched PubMed for the phrases “mevalonate kinase deficiency,” “mevalonic aciduria,” and “hyper-immunoglobulin D (IgD) syndrome.” This identified 21 publications in English that contained information on biological therapy in 31 children, ranging in age from birth to 18 years, with genetically confirmed HIDS. In order to avoid double inclusion of the cases, we checked for the ages/dates of birth of reported patients whenever publications were from the same country. We evaluated the cases and classified their responses to treatment using six categories: (1) none (no change in symptoms), (2) complete (resolution of inflammatory attacks), (3) partial (improvement of symptoms during inflammatory attacks), (4) positive (reported as effective, but detailed data are not provided), (5) negative (worsening of symptoms), and (6) not specified (ns). The results of the 33 HIDS patients, including the two Finnish patients not published earlier, are presented in Table 1. Anakinra is a recombinant IL-1 receptor antagonist that can be administered purely on-demand during fever attacks or as continuous regular injections, usually on a daily basis. The drug has been used in 21 children with HIDS, with a complete response in four patients (19 %), partial or positive responses in 15 patients (71 %), including the four supplied with the drug on-demand, and no response in one child (5 %) (Table 1). It is important to point out that patient 16 experienced worsening of symptoms after a single anakinra injection, and this patient was then successfully treated with tocilizumab [34]. Patient 1 was treated with a dose of 5 mg/kg/ day, with a partial response, and followed up for 13 months. In this patient, the combination of adalimumab with anakinra had no additional benefits, and the disease was partially controlled after switching from anakinra to canakinumab [15]. Side effects of anakinra have included pain at the injection site [5], neutropenia [24], bacterial pneumonia [15], and herpes zoster infection [7]. Etanercept is a TNFα receptor fusion protein, which has been used in 16 children with HIDS, with a complete response in three patients (19 %), partial response in five patients (31 %), and no response in four patients (25 %) (Table 1). According to the retrospective data from the international registry that includes both adults and children, more patients responded to anakinra (24/27, 89 %) than to etanercept (11/17, 65 %) [47]. Susceptibility to respiratory infections was interpreted as a side effect of etanercept in two HIDS patients
Eur J Pediatr Table 1 Case reports of biological medicines in pediatric patients with HIDS
a
Supplemented with additional data provided by Caroline Galeotti ns not specified
Patient number
Country and reference
Age (years)
Treatment
Regimen
Response
Follow-up (months)
1
France [15]
8
2 3
France [15] France [15]
3 4
4 5
France [15] France [15]
17 18
Adalimumab Anakinra Canakinumab Etanercept Anakinra Anakinra Canakinumab Anakinra Anakinra Canakinumab
ns Continuous Continuous ns Continuous Continuous Continuous On-demand Continuous Continuous
None Partiala Partial ns Partiala Completea Completea Partial Partiala Completea
ns 13 21 ns 19 2 12 2 39 18
6
France [27]
1
7 8
France [27] Italy [39]
0.25 7
9 10 11 12
Italy [34] Netherlands [5] Netherlands [5] Netherlands [48]
1.5 12 17 ns
13 14 15
Portugal [7] Portugal [7] Turkey [16]
3 5 2
16
UK [42]
13
17
USA [4]
ns
Etanercept Anakinra Infliximab Anakinra Anakinra Etanercept Anakinra Anakinra Anakinra Anakinra Etanercept Anakinra Anakinra Anakinra Etanercept Anakinra Etanercept Anakinra
ns Continuous Continuous Continuous Continuous Continuous Continuous Continuous On-demand Continuous Continuous Continuous Continuous Continuous Continuous Continuous Continuous ns
ns Complete Partial Positive Partial None Partial Complete Partial None None Partial Partial Positive None Negative Negative Positive
ns 6 2 7 18 ns 12 8 ns 3 6 7 17 ns 6 5 days 9 weeks ns
18 19 20 21 22 23
Portugal [40] Finland [23] Finland Finland France [15] France [15]
3 1.5 10 1 3 5
Anakinra Anakinra Anakinra Anakinra Canakinumab Canakinumab
Continuous Continuous On-demand On-demand Continuous Continuous
Partial Complete Partial Partial Partial Partiala
36 48 36 24 11
6 4 12 3 6 1.5 7 10 ns 14
Etanercept Etanercept Etanercept Etanercept Etanercept Etanercept Etanercept Etanercept Etanercept Etanercept Infliximab
ns Continuous Continuous Continuous Continuous Continuous Continuous Continuous Continuous Continuous Continuous
ns Partial None Complete Partial Complete Partial Complete Partial Partial Positive
24 25 26 27 28 29 30 31 32 33
Denmark [53] Italy [31] Italy [6] Turkey [1] Turkey [11] Turkey [49] Turkey [54] USA [46] USA [46] USA [24]
[46]. When etanercept therapy fails, anakinra may be effective and vice versa [51]. In the pediatric HIDS cases reviewed
16 ns 6 3 24 12 12 17 ns 24 36 12
here, anakinra also performed better than etanercept, with complete or partial responses in 90 and 50 %, respectively.
Eur J Pediatr
Infliximab treatment led to the resolution of keratopathy in patient 33 and had a partial effect on the gastrointestinal symptoms of patient 6 but did not have an impact on their other symptoms. An alternative to anakinra, which is rapidly eliminated with a serum half-time of 4 to 6 h, is canakinumab, a monoclonal anti-IL-1β receptor antagonist. The half-time of canakinumab is 22 to 25 days, meaning that it only needs to be administered once every 8 weeks [12, 13]. Canakinumab showed promising results in five pediatric patients followed up for 11 to 21 months, with complete responses in three children and partial responses in the remaining two (Table 1). The reported side effects were inflammatory reactions at the injection site, recurrent pharyngitis, and transient hepatitis [15]. Other anti-IL-1 agents not yet been trialed in patients with HIDS are rilonacept and gevokizumab. Rilonacept, a soluble receptor fusion protein binding both IL-1α and IL-1β, has been used successfully in cryopurin-associated periodic syndromes [20] and familial Mediterranean fever [19]. Gevokizumab, a monoclonal recombinant anti-IL-1β antibody, has shown promising results in Bechcet’s disease [17] and generalized pustular psoriasis [30].
Finnish cases Patient A (number 20, Table 1) was born in 2000 and is the second child of healthy unrelated parents. From the age of 2 days, she presented with repeated episodes of fever every 1 to 6 weeks, and these were accompanied by elevated CRP, white blood cells (WBC), and various symptoms, including skin rashes, mouth ulcers, febrile seizures, loose stools, abdominal pain, and a distended abdomen. The fever usually continued for 1 to 7 days, and the other symptoms disappeared more slowly and gradually. Extensive investigations, including immunological and autoimmune studies, could not establish any diagnosis in infancy. Intravenous antibiotics did not shorten the duration of the fever or other symptoms, and intravenous immunoglobulins did not prevent the symptomatic episodes. A single dose of oral prednisolone stopped the fever episode on one occasion but was ineffective after that. A tonsillectomy at 10 months of age had no effect on the febrile attacks. A diagnosis of HIDS was considered at 15 months of age. Serum IgD concentrations were 24–79 mg/l (normal
REVIEW
Treatment of hyperimmunoglobulinemia D syndrome with biologics in children: review of the literature and Finnish experience Svetlana Kostjukovits & Liisa Kalliokoski & Kaisu Antila & Matti Korppi
Received: 12 November 2014 / Revised: 23 January 2015 / Accepted: 10 February 2015 # Springer-Verlag Berlin Heidelberg 2015
Abstract Hyperimmunoglobulinemia D syndrome (HIDS) is an autoinflammatory disorder that is caused by mevalonate kinase deficiency (MKD). Recent advances in the pathogenesis of MKD, including the proposed mechanisms of inflammasome activation, provide the basis for the development of new treatment modalities. So far, feedback on the treatment of HIDS with biological medicines has come from case reports with limited numbers of patients. In this review, we summarize the data that is currently available on the treatment of HIDS in children, with the emphasis on new therapies, and present three Finnish pediatric cases treated with anakinra. Case reports have been published on 33 pediatric HIDS patients who have been treated with biological medicines, and in some cases, they were treated with more than one drug. Of these patients, 21 were treated with anakinra and 16 with etanercept, resulting in complete or partial responses in
90 and 50 % of cases, respectively. A further five patients were treated with canakinumab, with complete or partial responses. Conclusion: The accumulating evidence on the efficacy and safety of biological drugs in pediatric HIDS suggests that the anti-interleukin-1 agent anakinra is the drug of choice for HIDS in children. What is Known: • Various biologic drugs have been tried for the treatment of HIDS. What is New: • Based on the 90 % response rate, anakinra seems to be the drug of choice for HIDS in children.
Keywords Mevalonate kinase deficiency . Hyper IgD syndrome . Autoinflammatory disease . Etanercept . Anakinra . Canakinumab
K. Antila Department of Pediatrics, North Carelia Central Hospital, Joensuu, Finland e-mail: [email protected]
Abbreviations CRP GDP GTP HIDS HMG-CoA IgA IgD IL LPS MKD MVA MVK NLRP3
M. Korppi Pediatric Research Centre, Tampere University and University Hospital, Tampere, Finland e-mail: [email protected]
NSAIDs PAMPs or DAMPs
Communicated by David Nadal Revisions received: 03 January 2015 / 23 January 2015 S. Kostjukovits (*) Department of Pediatrics, Malmi District Hospital, Pietarsaari, Finland e-mail: [email protected] L. Kalliokoski Department of Pediatrics, Kainuu Central Hospital, Kajaani, Finland e-mail: [email protected]
C-reactive protein Guanosine diphosphate Guanosine triphosphate Hyperimmunoglobulinemia D syndrome 3′-Hydroxy-3′-methylglutaryl coenzyme A Immunoglobulin A Immunoglobulin D Interleukin Lipopolysaccharide Mevalonate kinase deficiency Mevalonic aciduria Mevalonate kinase Nod-like receptor family, pyrin domaincontaining protein 3 Non-steroidal anti-inflammatory drugs Pathogen- or damage-associated molecular patterns, respectively
Eur J Pediatr
SAA TNFα WBC
Serum amyloid A Tumor necrosis factor alpha White blood cells
Introduction Mevalonate kinase deficiency (MKD) is an autoinflammatory disorder with autosomal recessive inheritance [22]. Hyperimmunoglobulinemia D syndrome (HIDS) is a milder form of MKD and manifests with recurrent febrile episodes with various combinations of lymphadenopathy, abdominal pain, vomiting, diarrhea, arthralgia/arthritis, headache, skin rashes, mouth ulcers, hepatomegaly, and splenomegaly [51]. The more severe mevalonic aciduria (MVA) has additional features of growth failure, mental retardation, dysmorphisms, and neurological symptoms [18]. Mevalonate kinase (MVK) activity in HIDS patients varies from 1.8 to 28 % [10] as opposed to virtually no active MVK in patients with MVA [21]. In recent years, knowledge on the pathogenesis and treatment options of HIDS has expanded, and an increasing number of children now receive biological medicines. These include the anti-tumor necrosis factor alpha (TNFα) agents infliximab [24, 27], etanercept [53, 54], and adalimumab [15], the anti-interleukin (IL)-1 agents anakinra [5, 7, 15, 27] and canakinumab [15], and the IL-6 antagonist tocilizumab [41]. This paper presents a review of the use of biological drugs in the treatment of pediatric HIDS and the case studies of three Finnish children with HIDS who were treated with anakinra.
Literature review Pathogenesis MKD results in insufficient mevalonate phosphorylation in the sterol biosynthesis pathway (Fig. 1). The excess mevalonate does not contribute to inflammatory attacks in HIDS, but the deficiency of isoprenoids downstream in the MVK pathway does [14, 29]. In particular, the lack of geranylgeranyl-phosphate leads to caspase-1 activation through Rac1 signaling [25]. Caspase-1 then processes the IL-1β precursor to an active IL-1β [9], which initiates cytokine secretion. The currently available biological medicines include anakinra and canakinumab, which are both anti-IL-1 agents. The events take place within the nod-like receptor family, pyrin domain-containing protein 3 (NLRP3) inflammasome, also known as cryopurin [38], a complex network of intracellular molecular signaling pathways that form the basis of innate immune responses [32]. Inflammasomes are activated by pathogen-associated molecular patterns (PAMPS) or damageassociated molecular patterns (DAMPS), such as lipopolysaccharides (LPS) or signals from injured cells [33], and this can explain why infections, vaccines, and stress trigger inflammatory attacks in HIDS. NLRP3 is overexpressed in MVKdeficient patients, and stimulation with LPS in a cellular model of MKD resulted in the induction of NLRP3 and caspase-1 [50]. The complex interplay of cytokines in HIDS is not yet fully understood. Experimental evidence suggests that IL-6 may have reciprocal interactions with IL-1 [45], and anti-IL-6-targeted treatment may be an option in some HIDS patients [41].
Fig. 1 Hypothetical pathogenesis of HIDS. Adapted from Normand et al. [35]. HMG-CoA 3′-hydroxy-3′-methylglutaryl coenzyme A; PP pyrophosphate, GDP guanosine diphosphate, GTP guanosine triphosphate, IL interleukin
Eur J Pediatr
New insights into the pathogenesis of HIDS pave the way for novel therapeutic options, such as inhibition of Rac-1 or administration of the deficient geranylgeraniol, which have both been shown to decrease IL-1β secretion in cellular models [25, 50]. These options result in an inhibition of the overactivation of innate immunity, whereas currently available drugs only suppress the influence of the storm of innate immunity mediators. Complications HIDS attacks are accompanied by acute phase responses, presenting with leukocytosis and elevated C-reactive protein (CRP) and serum amyloid A (SAA) [52]. Only five cases of amyloidosis have been reported in HIDS patients, presenting as nephrotic syndrome at 19 to 29 years of age [26, 28, 36, 43]. Recently, renal amyloidosis was found in a 7-year-old boy with HIDS [54], emphasizing the potential importance of early suppression of inflammatory responses. Other reported complications are abdominal adhesions, presumably caused by repeated peritonitis during inflammatory attacks, and joint symptoms, which range from arthralgia to erosive arthritis and may lead even to joint contractures [2, 51]. Whether these long-term consequences of HIDS can be prevented by early anti-inflammatory treatment is not known. Treatment A number of medicines have been used to treat HIDS but with no, or marginal, efficacy. These include azathioprine, colchicine, cyclosporine, dapsone, methotrexate, montelukast, salazopyrin, tacrolimus, thalidomide, ranitidine, and immunoglobulins [51]. Paracetamol, non-steroidal anti-inflammatory drugs (NSAID) and corticosteroids may relieve symptoms and shorten the duration of febrile attacks, but the effects are inconsistent [47] and, as is well-known, long-term corticosteroid treatment has many side effects. HMG-CoA reductase inhibitors (statins) have a theoretical potential therapeutic effect on HIDS, as they block the MVK pathway and decrease mevalonate production [37]. However, a pediatric trial that used lovastatin to treat MVA was stopped because of disease exacerbation in two children [21]. A placebo-controlled randomized cross-over trial with simvastatin resulted in a positive clinical effect in five out of six adult patients with HIDS [44]. However, statins did not prove sufficiently effective in later studies [2, 51]. There is an anecdotal report of disease resolution with oral alendronate, which was initially prescribed to treat osteoporosis in a 14-year-old boy with HIDS [8]. Bisphosphonates inhibit the already compromised MVK pathway [38] and are, therefore, considered as contraindicated in HIDS. The normalization of SAA levels and complete resolution of attacks
during alendronate treatment are a paradoxical finding, which deserves further research. Biological agents Our current knowledge on the use of biologic medicines to treat HIDS has been derived from published case reports. This is because the number of diagnosed and registered HIDS patients is very low, at around 200 [47]. We searched PubMed for the phrases “mevalonate kinase deficiency,” “mevalonic aciduria,” and “hyper-immunoglobulin D (IgD) syndrome.” This identified 21 publications in English that contained information on biological therapy in 31 children, ranging in age from birth to 18 years, with genetically confirmed HIDS. In order to avoid double inclusion of the cases, we checked for the ages/dates of birth of reported patients whenever publications were from the same country. We evaluated the cases and classified their responses to treatment using six categories: (1) none (no change in symptoms), (2) complete (resolution of inflammatory attacks), (3) partial (improvement of symptoms during inflammatory attacks), (4) positive (reported as effective, but detailed data are not provided), (5) negative (worsening of symptoms), and (6) not specified (ns). The results of the 33 HIDS patients, including the two Finnish patients not published earlier, are presented in Table 1. Anakinra is a recombinant IL-1 receptor antagonist that can be administered purely on-demand during fever attacks or as continuous regular injections, usually on a daily basis. The drug has been used in 21 children with HIDS, with a complete response in four patients (19 %), partial or positive responses in 15 patients (71 %), including the four supplied with the drug on-demand, and no response in one child (5 %) (Table 1). It is important to point out that patient 16 experienced worsening of symptoms after a single anakinra injection, and this patient was then successfully treated with tocilizumab [34]. Patient 1 was treated with a dose of 5 mg/kg/ day, with a partial response, and followed up for 13 months. In this patient, the combination of adalimumab with anakinra had no additional benefits, and the disease was partially controlled after switching from anakinra to canakinumab [15]. Side effects of anakinra have included pain at the injection site [5], neutropenia [24], bacterial pneumonia [15], and herpes zoster infection [7]. Etanercept is a TNFα receptor fusion protein, which has been used in 16 children with HIDS, with a complete response in three patients (19 %), partial response in five patients (31 %), and no response in four patients (25 %) (Table 1). According to the retrospective data from the international registry that includes both adults and children, more patients responded to anakinra (24/27, 89 %) than to etanercept (11/17, 65 %) [47]. Susceptibility to respiratory infections was interpreted as a side effect of etanercept in two HIDS patients
Eur J Pediatr Table 1 Case reports of biological medicines in pediatric patients with HIDS
a
Supplemented with additional data provided by Caroline Galeotti ns not specified
Patient number
Country and reference
Age (years)
Treatment
Regimen
Response
Follow-up (months)
1
France [15]
8
2 3
France [15] France [15]
3 4
4 5
France [15] France [15]
17 18
Adalimumab Anakinra Canakinumab Etanercept Anakinra Anakinra Canakinumab Anakinra Anakinra Canakinumab
ns Continuous Continuous ns Continuous Continuous Continuous On-demand Continuous Continuous
None Partiala Partial ns Partiala Completea Completea Partial Partiala Completea
ns 13 21 ns 19 2 12 2 39 18
6
France [27]
1
7 8
France [27] Italy [39]
0.25 7
9 10 11 12
Italy [34] Netherlands [5] Netherlands [5] Netherlands [48]
1.5 12 17 ns
13 14 15
Portugal [7] Portugal [7] Turkey [16]
3 5 2
16
UK [42]
13
17
USA [4]
ns
Etanercept Anakinra Infliximab Anakinra Anakinra Etanercept Anakinra Anakinra Anakinra Anakinra Etanercept Anakinra Anakinra Anakinra Etanercept Anakinra Etanercept Anakinra
ns Continuous Continuous Continuous Continuous Continuous Continuous Continuous On-demand Continuous Continuous Continuous Continuous Continuous Continuous Continuous Continuous ns
ns Complete Partial Positive Partial None Partial Complete Partial None None Partial Partial Positive None Negative Negative Positive
ns 6 2 7 18 ns 12 8 ns 3 6 7 17 ns 6 5 days 9 weeks ns
18 19 20 21 22 23
Portugal [40] Finland [23] Finland Finland France [15] France [15]
3 1.5 10 1 3 5
Anakinra Anakinra Anakinra Anakinra Canakinumab Canakinumab
Continuous Continuous On-demand On-demand Continuous Continuous
Partial Complete Partial Partial Partial Partiala
36 48 36 24 11
6 4 12 3 6 1.5 7 10 ns 14
Etanercept Etanercept Etanercept Etanercept Etanercept Etanercept Etanercept Etanercept Etanercept Etanercept Infliximab
ns Continuous Continuous Continuous Continuous Continuous Continuous Continuous Continuous Continuous Continuous
ns Partial None Complete Partial Complete Partial Complete Partial Partial Positive
24 25 26 27 28 29 30 31 32 33
Denmark [53] Italy [31] Italy [6] Turkey [1] Turkey [11] Turkey [49] Turkey [54] USA [46] USA [46] USA [24]
[46]. When etanercept therapy fails, anakinra may be effective and vice versa [51]. In the pediatric HIDS cases reviewed
16 ns 6 3 24 12 12 17 ns 24 36 12
here, anakinra also performed better than etanercept, with complete or partial responses in 90 and 50 %, respectively.
Eur J Pediatr
Infliximab treatment led to the resolution of keratopathy in patient 33 and had a partial effect on the gastrointestinal symptoms of patient 6 but did not have an impact on their other symptoms. An alternative to anakinra, which is rapidly eliminated with a serum half-time of 4 to 6 h, is canakinumab, a monoclonal anti-IL-1β receptor antagonist. The half-time of canakinumab is 22 to 25 days, meaning that it only needs to be administered once every 8 weeks [12, 13]. Canakinumab showed promising results in five pediatric patients followed up for 11 to 21 months, with complete responses in three children and partial responses in the remaining two (Table 1). The reported side effects were inflammatory reactions at the injection site, recurrent pharyngitis, and transient hepatitis [15]. Other anti-IL-1 agents not yet been trialed in patients with HIDS are rilonacept and gevokizumab. Rilonacept, a soluble receptor fusion protein binding both IL-1α and IL-1β, has been used successfully in cryopurin-associated periodic syndromes [20] and familial Mediterranean fever [19]. Gevokizumab, a monoclonal recombinant anti-IL-1β antibody, has shown promising results in Bechcet’s disease [17] and generalized pustular psoriasis [30].
Finnish cases Patient A (number 20, Table 1) was born in 2000 and is the second child of healthy unrelated parents. From the age of 2 days, she presented with repeated episodes of fever every 1 to 6 weeks, and these were accompanied by elevated CRP, white blood cells (WBC), and various symptoms, including skin rashes, mouth ulcers, febrile seizures, loose stools, abdominal pain, and a distended abdomen. The fever usually continued for 1 to 7 days, and the other symptoms disappeared more slowly and gradually. Extensive investigations, including immunological and autoimmune studies, could not establish any diagnosis in infancy. Intravenous antibiotics did not shorten the duration of the fever or other symptoms, and intravenous immunoglobulins did not prevent the symptomatic episodes. A single dose of oral prednisolone stopped the fever episode on one occasion but was ineffective after that. A tonsillectomy at 10 months of age had no effect on the febrile attacks. A diagnosis of HIDS was considered at 15 months of age. Serum IgD concentrations were 24–79 mg/l (normal
![[Hyperimmunoglobulinemia D and periodic fever syndrome].](/assets/img/hold.png)
