Hyperimmunoglobulin D syndrome: Management

INTRODUCTION — Hyperimmunoglobulin D syndrome (HIDS; MIM #260920) is a rare genetic disorder characterized by recurrent febrile episodes typically associated with lymphadenopathy, abdominal pain, and an elevated serum polyclonal immunoglobulin D (IgD) level. Recurrent fever that is not due to infection is a clinical feature of several disorders that are collectively referred to as autoinflammatory diseases. HIDS is one of the major periodic fever syndromes, which is a subset of autoinflammatory diseases (table 1). An overview of periodic and recurrent fevers and other autoinflammatory diseases is presented separately. (See "The autoinflammatory diseases: An overview".)

The management of HIDS is reviewed here. The pathophysiology, clinical features, and diagnosis of HIDS are reviewed in detail separately. (See "Hyperimmunoglobulin D syndrome: Pathophysiology" and "Hyperimmunoglobulin D syndrome: Clinical manifestations and diagnosis".)

COURSE AND PROGNOSIS — In general, patients with HIDS have a normal lifespan and rarely suffer any serious physical complications of the disease, with the uncommon exception of AA amyloidosis [1,2] and growth delay due to chronic inflammation [3]. However, the attacks may have a significant negative impact on quality of life (QoL), particularly if the episodes are more frequent and severe [4]. Social functioning, general health perception, vitality, autonomy, and social development were the QoL areas most impacted in one study. The periodic fever attacks are usually lifelong, although the frequency of attacks appears to decrease with age. With directed treatment, attacks may be prevented or, rarely, remit completely. (See "Pathogenesis of AA amyloidosis" and "Causes and diagnosis of AA amyloidosis and relation to rheumatic diseases" and "Treatment of AA (secondary) amyloidosis".)

GOALS OF MANAGEMENT — The goal of treatment is to alleviate the immediate symptoms for the purpose of improving quality of life (QoL) and avoiding unnecessary therapies. Amyloidosis and growth delay, the two serious potential complications, are rare. The drugs used to control symptoms also ameliorate inflammation and may mitigate some of the long-term effects of inflammation, such as the development of amyloidosis. Curative treatments that are sufficiently low risk are lacking. Interventions that prevent the febrile episodes are available but are associated with a higher risk of adverse events and are therefore reserved for patients whose benefits outweigh the risks. (See "Hyperimmunoglobulin D syndrome: Clinical manifestations and diagnosis".)

Alleviate symptoms — Symptomatic treatment of the fever and associated symptoms is one of the main focuses of management since the disease primarily affects QoL and rarely leads to severe physical complications. (See 'Symptomatic treatment' below.)

Avoid unnecessary surgery — Patients who present with fever and severe abdominal pain prior to the diagnosis of HIDS may undergo exploratory laparotomy with or without appendectomy. Once the diagnosis of HIDS is established, a much higher threshold for exploratory surgery is appropriate. If the timing and nature of the symptoms are compatible with a recurrent episode, observation is appropriate. If, however, abdominal pain occurs at a shorter than usual interval or there are symptoms that are unusual for a particular patient, clinical judgment may favor laparotomy.

Avoid unnecessary antibiotics — Prior to diagnosis, patients are commonly given courses of antibiotics due to the symptoms of an attack mimicking an infection. A higher threshold for starting antibiotics is appropriate after diagnosis, particularly if the timing and nature of the symptoms are compatible with a recurrent episode. However, patients should be evaluated for an infectious etiology if the symptoms or course of an episode are atypical.

PATIENT EDUCATION — Successful management of children with HIDS requires cooperation and involvement of the parents/caregivers. The risks and benefits of the interventions must be weighed and compared with the disquiet that is required to simply observe a child who is having a febrile episode. Patients and parents/caregivers need to be informed about the benign prognosis in that HIDS does not impact life expectancy, although it can impact quality of life (QoL). Discussing the tradeoff between potential adverse effects and the variable effectiveness of available pharmacologic interventions also helps balance expectations.

Parental/caregiver awareness of the general timing of episodes and of the child's symptoms can help assist clinicians in deciding when watchful waiting is appropriate versus pursuing additional diagnostic testing or even laparotomy, as discussed above. (See 'Avoid unnecessary surgery' above.)

OUR APPROACH — Our approach is based upon the limited available data and clinical experience. We first ask the patient and parents/caregivers if they are comfortable with just observation during episodes or whether they would prefer symptomatic treatment (algorithm 1). If symptomatic treatment is chosen, we treat each attack with a nonsteroidal antiinflammatory drug (NSAID), starting at the earliest sign of an attack and continuing for the predicted duration of the attack. Patients who do not respond to NSAIDs and who wish to continue treatment are switched to episodic oral glucocorticoids. For patients who do not respond to either NSAIDs or glucocorticoids or who would benefit from a steroid-sparing agent and still want to continue treating episodes, we use the biologic anakinra, a short-acting anti-interleukin (IL) 1 agent. We use canakinumab, a long-acting anti-IL-1 agent, prophylactically in patients who have frequent episodes. It is typically given monthly initially but can be tapered to every two months or even once every three months in some patients. In patients who require therapy but fail treatment with anti-IL-1 agents, anti-tumor necrosis factor (TNF) or anti-IL-6 biologic response modifiers may be beneficial [5]. There are no clearly effective treatments for the rare patients with HIDS who develop amyloidosis. Most often, continuous therapy with a biologic agent is attempted, with the goal of minimizing symptoms, preventing further complications, and improving quality of life (QoL). We opt for observation in patients who fail to respond to all of the above therapies.

SYMPTOMATIC TREATMENT — No universally reliable means of arresting or mitigating the symptoms of a febrile episode have yet been identified. Several pharmacologic agents have been used to treat febrile episodes and associated symptoms (eg, arthralgia/arthritis, abdominal pain), with varying results. Treatment options with the lowest risk of serious side effects are used first since there is minimal risk of long-term sequelae from the disease (algorithm 1). Symptomatic treatment is started at the first sign of prodromal symptoms that are typical for the patient. These may include nasal congestion, sore throat, backache, fatigue, vertigo, headache, and behavioral changes. Not treating episodes is also an option. The symptoms of an attack are markedly blunted if treatment is started early, with the onset of prodromal symptoms, rather than waiting until the onset of fever and associated symptoms. (See "Hyperimmunoglobulin D syndrome: Clinical manifestations and diagnosis", section on 'Clinical manifestations'.)

First-line therapy — Observational data from case reports have shown that nonsteroidal antiinflammatory drugs (NSAIDs) alleviate the height and duration of fevers and mitigate associated symptoms in some patients [6,7] but not in others [8]. NSAIDs are suggested as first-line therapy for fever and pain associated with HIDS episodes, rather than an oral glucocorticoid, if parents/caregivers and/or patients opt for symptomatic management during these febrile episodes. NSAIDs are used for the predicted duration of the attack, typically for four to seven days, based upon the particular child's pattern. Episodic treatment can continue indefinitely, as long as the patient/caregivers wish to prevent symptoms from episodes.

There is no role for NSAIDs between episodes.

Treatment should be tailored to individual patients. Any NSAID can be used: generally, one that the parents/caregivers and clinician are comfortable using and in doses appropriate for the child's age. The effectiveness of the NSAID should be evident with the treatment of each episode, often within the first dose or two. If there is a partial response to the initial dose, a higher dose, up to the manufacturer's recommended maximum, can be used and the effect observed. Some patients respond better to certain NSAIDs over others. Thus, if one NSAID is ineffective, another should be tried. Patients are considered refractory to NSAIDs only after several NSAIDs have been tried and failed. (See "Pain in children: Approach to pain assessment and overview of management principles", section on 'Nonsteroidal antiinflammatory drugs'.)

Patients refractory to NSAIDs — Episodic treatment with glucocorticoids is the preferred next step in patients who fail treatment with nonsteroidal antiinflammatory drugs (NSAIDs) due to accessibility and simplicity of use. Treatment with a biologic agent is reserved for patients who fail both NSAIDs and glucocorticoids or who respond to glucocorticoids but require frequent and/or higher doses and would benefit from a steroid-sparing agent. The shortest acting and least immunosuppressive biologic agent (eg, anakinra) is tried first.

Oral glucocorticoids — For those who have a weak or nonexistent response to an NSAID and are willing to accept the potential adverse effect of a short course of systemic glucocorticoids, we suggest prednisone or prednisolone (1 mg/kg per day orally; maximum dose 60 mg/day) for four to seven days, depending upon the typical duration of attacks in a patient. Dosing varies from a single pulse dose at the onset of prodromal symptoms [7], to 30 mg prednisone daily for three days followed by a one-week taper [8], to 1 mg/kg prednisone initial dose with a two-week taper [6]. The last dosing regimen listed was also shown to alleviate arthritic symptoms.

While no randomized, controlled trials are available, individual reports demonstrate good responses to oral glucocorticoids, usually given for one to two weeks [6-8]. Patients responded with normalized temperatures and markedly decreased symptoms. It usually takes a day or two for glucocorticoids to control the fever. One case report documented remission of febrile attacks after six courses of a single-dose hydrocortisone (7 mg/kg intravenously) given at the onset of an attack [9].

Glucocorticoids have well-known potential side effects, both short term, such as gastritis and mood disturbance, and long term, such as slowed growth, myopathy, bone demineralization, glaucoma, and elevated blood sugar. (See "Major adverse effects of systemic glucocorticoids".)

Anti-IL-1 therapy — Febrile episodes in HIDS, as well as other periodic fever syndromes, may be caused by elevated interleukin (IL) 1 levels [10]. IL-1 receptor antagonist (IL-1Ra), the physiologic inhibitor of IL-1, may also be elevated during HIDS attacks [11]. IL-1 inhibitors include anakinra and canakinumab. Anakinra is a short-acting IL-1Ra that is dosed once daily. Canakinumab, an IL-1 beta blocker, has a much slower onset of action and longer half-life (dosed every 4 to 12 weeks); therefore, it is used for prophylactic therapy but not episodic therapy. (See 'Preventive treatment' below.)

One prospective, observational study showed effective use of anakinra as on-demand therapy [12]. In this study of nine patients with HIDS who were offered the choice of treatment with anakinra prophylactically or on demand, eight out of nine selected on-demand therapy (1 mg/kg per day, maximum 100 mg/day, for five to seven days) [12]. Eight of 12 attacks treated showed >50 percent reduction in symptom duration and also decreased attack severity, but there was no change in attack frequency. Given the side-effect profile, as well as local injection-site reactions, symptomatic treatment with anakinra may be preferred over preventive treatment by clinicians and patients alike. Some experts switch patients who have responded to anakinra over to canakinumab due to a more favorable side-effect profile and dosing schedule. (See 'Preventive treatment' below.)

The most common, significant side effects of anakinra are hypersensitivity reactions and immune suppression leading to increased risk of severe infections and malignancy. Milder side effects include injection-site reactions and symptoms such as headache, nausea, diarrhea, vomiting, fever, rash, and arthralgia due to the immunomodulatory effects. (See "Overview of biologic agents in the rheumatic diseases", section on 'Anakinra' and "Systemic juvenile idiopathic arthritis: Treatment", section on 'Biologic disease-modifying antirheumatic drug (DMARD) therapy'.)

Rilonacept, a monoclonal antibody that binds IL-1 beta and also has some binding to IL-1Ra and IL-1 alpha, may work well for HIDS based upon its mechanisms of action, but there are no reports of its use for HIDS in the literature. Rilonacept has been used in patients with other types of periodic fever syndromes [13]. The effect of rilonacept lasts for a week or longer. Thus, a single dose could be used to treat attacks, although studies of this approach are needed.

PREVENTIVE TREATMENT — Elevated acute-phase reactants and serum levels of inflammatory cytokines including tumor necrosis factor (TNF) alpha, interleukin (IL) 1 beta, and IL-6 suggest that a systemic inflammatory process causes the symptoms during febrile attacks [11,14]. Canakinumab, a long-acting anti-IL-1 agent that is given prophylactically every one to three months, is an alternative option to episodic treatment with anakinra for patients who fail symptomatic therapy with nonsteroidal antiinflammatory drugs (NSAIDs) and glucocorticoids and who still prefer treatment over observation due to more frequent and/or severe attacks or symptoms that have a significant negative impact on quality of life (QoL) (algorithm 1). It is also an option in patients who have tried episodic anakinra but are refractory or have intolerable side effects. Etanercept, anakinra, and tocilizumab are other anticytokine therapies that have also shown benefit at reducing attack frequency and duration when given prophylactically, with newer agents showing better efficacy than the older ones in the limited data available. Continuous therapy with a biologic agent is also used in those rare patients with HIDS who develop amyloidosis or in those who have ongoing intolerable symptoms of the disease. Local side effects may limit a patient's tolerance of these therapies. In addition, these agents are associated with an increased risk of serious infections. Febrile episodes may be due to an infection rather than HIDS in patients on these therapies. Thus, clinicians should monitor patients accordingly. (See "Hyperimmunoglobulin D syndrome: Pathophysiology" and "Overview of amyloidosis", section on 'Clinical manifestations' and "Causes and diagnosis of AA amyloidosis and relation to rheumatic diseases", section on 'Diagnosis' and "Overview of amyloidosis", section on 'Treatment'.)

There are two important points to remember with respect to the treatment of patients with such biologics:

●The preponderance of HIDS febrile attacks does not lead to long-term sequelae.

●Most biologics carry the risk of severe infections; other common adverse events include local injection-site reactions that impact the tolerability of the therapy. Fever is an expected symptom of periodic attacks in patients with HIDS. However, every new episode of fever that is not typical of the patient's HIDS attacks must be evaluated for the possibility of an infectious origin in patients treated with biologics.

If prophylactic therapy is chosen and is successful, a reasonable approach is to wait at least 6 to 12 months before doing a trial off of prophylaxis. However, patients successfully treated with prophylaxis may never want to stop for fear of returning symptoms, particularly if they have not experienced any significant adverse events from therapy. Thus, the decision is individualized.

TNF inhibition — Etanercept, a tumor necrosis factor (TNF) alpha receptor-immunoglobulin fusion protein, has been administered to some patients with HIDS with mixed results [15-20]. As an example, one case series reported that 4 of 13 patients treated had no response, five had some response, and four had a good response [4].

Case reports suggest that there may be a specific role for etanercept in the treatment of HIDS patients with overlap syndromes, such as those with homozygous mevalonate kinase (MVK) mutations who also carry the E148Q familial Mediterranean fever gene (FMF) [19,20] or the very rare patient with both HIDS and TNF receptor-1 associated periodic syndrome (TRAPS) [15]. (See "Autoinflammatory diseases mediated by inflammasomes and related IL-1 family cytokines (inflammasomopathies)", section on 'Familial Mediterranean fever' and "Autoinflammatory diseases mediated by NFkB and/or aberrant TNF activity", section on 'TNF receptor 1-associated periodic syndrome (TRAPS)' and "Hyperimmunoglobulin D syndrome: Clinical manifestations and diagnosis", section on 'Overlap syndromes'.)

Etanercept was effective in three case reports of HIDS with amyloidosis [2].

IL-1 inhibition — Monoclonal interleukin (IL) 1 inhibitors include short-acting anakinra and long-acting canakinumab. Canakinumab binds exclusively to IL-1 beta, blocking the interaction with cell surface receptors. It is not suitable for episodic therapy, because of its slower onset of action and longer half-life. However, it can be given prophylactically. Canakinumab has been used successfully in an increasing number of cases of HIDS [21-25]. It is more effective than anakinra in IL-1 blockade [24].

In one trial, 72 patients with refractory HIDS were randomly assigned to canakinumab 150 mg (or 2 mg/kg if body weight ≤40 kg) subcutaneously or placebo every four weeks [26]. A second dose could be given if the baseline flare persisted between days 8 and 14 or had not resolved by day 15. Canakinumab every four weeks led to a higher rate of complete response (resolution of baseline flare by day 15 and no additional flares by week 16) than the control group (35 versus 6 percent, respectively). This resolution rate increased to 57 percent when those receiving a second dose of canakinumab for the initial flare were included. Among patients who had a complete initial response and were randomly assigned to canakinumab or placebo given every eight weeks, 82 percent remained flare free from weeks 16 to 40 on a reduced frequency of canakinumab compared with 27 percent of patients in the placebo group. Of note, patients on placebo were eligible to receive the second dose of canakinumab for the initial flare and were also able to receive up to 300 mg of canakinumab every four weeks for flares after the first 29 days of the study.

There are an increasing number of case reports of successful treatment with anakinra [4,17,23,24,27-29], although there is also one case report of increased febrile episode duration with this therapy [18]. In one review of case reports in the literature, 19 of 21 patients treated with anakinra had a complete or partial response [3]. Anakinra was effective in one patient who did not respond to etanercept [17]. It was not effective in one patient with amyloidosis [2]. (See 'Anti-IL-1 therapy' above.)

IL-6 inhibition — Interleukin (IL) 6 is often elevated during febrile attacks. Case reports have shown successful prevention or reduction of febrile episodes in HIDS patients using the humanized monoclonal antibody inhibitor of the IL-6 receptor, tocilizumab [14,30,31]. Successful treatment of febrile attacks was documented in one patient refractory to anti-IL-1 therapy with anakinra [31].

THERAPIES THAT ARE NOT RECOMMENDED — A number of therapies have been tried for HIDS based upon the pathophysiology of the disease or successful use in patients with other periodic fever syndromes. However, none of these have shown sufficient efficacy to outweigh the associated risks of the therapy.

Colchicine — Although a therapeutic trial of colchicine may have a role in excluding familial Mediterranean fever, clinical experiences with colchicine in HIDS suggest a minimal effect, if any. Colchicine slightly increased duration of symptom-free intervals and had little or no effect on symptoms during febrile episodes [6-8,32]. In the absence of even anecdotal documentation to support efficacy, and, given the availability of more efficacious biologic agents, we would not use colchicine for patients with HIDS.

Cyclosporine — There is a paucity of data on the use of cyclosporine in this disease. Two patients in one family were treated with cyclosporine; one remained attack free for six years, while her brother had no benefit [6].

Intravenous immune globulin — Data are sparse on the use of intravenous immune globulin (IVIG). Among five patients treated with IVIG, one had a diminished number and severity of episodes while the other four showed no response [6]. We are unaware of any other reports of successful use. In view of the expense and risk of adverse effects for IVIG, we would not use IVIG to treat HIDS.

Statins — Mevalonate kinase (MVK) is one enzymatic step downstream of the 3-hydroxy-3-methly-glutaryl-coenzyme A (HMG-CoA) reductase enzyme in the cholesterol synthetic pathway. Thus, use of an HMG-CoA reductase enzyme inhibitor (statin) seemed a logical choice for treatment of HIDS episodes. However, clinical experience has provided mixed results. These results, and an evolving understanding of the pathogenesis of disease symptoms, suggest that statins are unlikely to be efficacious and may instead increase the risk of exacerbating symptoms. Thus, we would not use statins to treat patients with HIDS.

In two cases of mevalonic aciduria (due to near or complete absence of MVK enzyme activity and resulting in a more severe phenotype than HIDS), treatment with lovastatin resulted in worse crises [33].

A one-year study randomly assigned six adult patients with HIDS to statin therapy with a crossover design [34]. There was no statistically significant difference in febrile days or severity between the statin and placebo periods. No deleterious effects were noted. This study lacked statistical power to exclude a small difference.

Thalidomide — Thalidomide may reduce cytokine release but has no demonstrated efficacy for HIDS. This was illustrated in a study of six adults with HIDS who were randomly assigned to thalidomide or placebo and followed for 36 weeks [35]. No significant difference in the severity of symptoms and only a mild decrease in acute-phase reactant levels were noted in those treated with thalidomide [35]. No side effects were noted. In view of the frequent side effects of thalidomide, particularly somnolence and neuropathy, and the lack of supporting evidence of efficacy, we would not use thalidomide to treat HIDS.

Hematopoietic cell transplanation — Potentially curative therapy in the form of allogeneic hematopoietic cell transplantation (HCT) has been performed for the more severe disorder, mevalonic aciduria, although the risks of allogeneic HCT outweigh any potential benefit for patients with HIDS given that it is not a lethal disorder [1].

SUMMARY AND RECOMMENDATIONS

●Clinical manifestations – Hyperimmunoglobulin D syndrome (HIDS) is a genetically inherited periodic fever syndrome associated with sustained high fevers, lymphadenopathy, abdominal pain, arthritis, and skin rashes. Interval periods range from four to eight weeks on average, during which patients remain completely asymptomatic. (See "Hyperimmunoglobulin D syndrome: Clinical manifestations and diagnosis".)

●Management goals – The goals of management are to alleviate symptoms, improve quality of life (QoL), avoid unnecessary surgical intervention and antibiotic therapy, and minimize the risk of adverse effects of treatment. Side effects of pharmacologic agents and their cost must be weighed against the knowledge that HIDS usually does not cause premature death or serious, permanent complications with the rare exception of amyloidosis. (See 'Goals of management' above.)

●Clinical decision making – For children with HIDS, decisions regarding the management approach should involve the patient, when feasible, and the parents/caregivers. After appropriate education, they, in conjunction with the treating clinician, must weigh the risks and benefits to determine their choice of therapy, which may include no therapy at all (algorithm 1).

●Symptomatic management during febrile episodes – For patients who opt for symptomatic management during febrile episodes, we suggest use of a nonsteroidal antiinflammatory drug (NSAID) rather than an oral glucocorticoid as the initial agent (Grade 2B). For those who do not respond to an NSAID, we suggest a short course of an oral glucocorticoid for the predicted duration of an attack (Grade 2C). For patients who fail glucocorticoid therapy (or wish to avoid the potential side effects of glucocorticoids), we suggest episodic treatment with anakinra, a short-acting anti-interleukin (IL) 1 agent (Grade 2C). (See 'Symptomatic treatment' above.)

●Preventive treatment – An alternative to episodic anakinra, particularly in patients who have frequent episodes, is canakinumab, a long-acting anti-IL-1 agent that is give prophylactically every one to three months. Canakinumab is also an option in patients who have tried episodic anakinra but are refractory or have intolerable side effects and who still prefer treatment over observation due to more frequent and/or severe attacks or symptoms that have a significant negative impact on QoL. Etanercept, anakinra, and tocilizumab have also shown benefit at reducing attack frequency and duration, with newer agents showing better efficacy than the older ones in the limited data available. Continuous therapy with a biologic agent is also attempted in those rare patients with HIDS who develop amyloidosis or in those who have intolerable effects from their disease. (See 'Preventive treatment' above.)

●Adverse effects – Local side effects to biologic agents may limit a patient's tolerance of these therapies. In additional, these agents are associated with an increased risk of serious infections. Febrile episodes may be due to an infection rather than HIDS in patients on these therapies. Thus, clinicians should monitor patients accordingly. (See 'Anti-IL-1 therapy' above and 'Preventive treatment' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to earlier versions of this topic review.