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Treatment of Autoinflammatory Conditions:
Current Options and Future Directions

Steven Spalding, MD


Introduction to the autoinflammatory conditions

The autoinflammatory conditions represent a fascinating, emerging, and ever-expanding series of diseases unified by perturbations in the control of the innate immune response. Research has recently provided a better understanding of the immunologic alterations causing these conditions, leading to the creation of novel immunomodulatory agents designed to disrupt specific targeted proinflammatory pathways. Early recognition and treatment with immunoregulatory agents has the potential to improve quality of life and reduce the risk of disease sequelae.

Understanding treatment options for patients with autoinflammatory conditions first requires an overview of the innate immune system and how genetic mutations deregulation its response. The innate response represents our immune system’s “first-response.” White blood cells (neutrophils, dendritic cells, macrophages, natural killer cells), proinflammatory signaling proteins (cytokines), and the complement system constitute the effector arm of the innate system. Interleukin 1 (IL-1), IL-6, and tumor necrosis factor (TNF) alpha represent the critical proinflammatory cytokines. Almost all autoinflammatory conditions are linked to mutations that disrupt regulation of inflammatory signaling within the innate immune system. Loss of this inherent control system leads to a proinflammatory state and the symptoms observed in patients with autoinflammatory conditions.

The following provides a brief review of these conditions.

Familial Mediterranean fever (FMF)

This syndrome, initially described in 1949, is the most common and well-characterized autoinflammatory syndrome. In FMF, a genetic mutation in theMediterranean fever gene —MEFV— results in altered function of the protein pyrin, which plays an important role in the regulation of the proinflammatory cytokine Interleukin-1 (IL-1). FMF is usually described as an autosomal recessive condition, although many patients have only one abnormal allele. Most patients with FMF suffer their first inflammatory attack between ages 5 to 15 years, with roughly 20% having their first attack after age 20.1 These attacks are characterized by brief episodes of intense fever (>39°C) lasting fewer than 72 hours and associated with serositis. Abdominal serositis may mimic appendicitis and result in exploratory surgery. Most patients have symptoms of arthritis, and less than 50% will develop and erysipelas-like rash. Without treatment, ongoing, unchecked inflammation may result in amyloidosis of the kidneys or liver.

Hyperimmunoglobulin D syndrome (HIDS)

HIDS, also autosomal recessive, stems from a defect within the mevalonate kinase gene MVK.The resulting dysfunctional protein, mevalonate kinase, an enzyme that plays an importantrole in the cholesterol biosynthesis pathway, leads to decreased production of geranylgeranyl and increased release of IL-1 beta from peripheralblood mononuclear cells.

Attacks of HIDS begin early in life, with morethan 70% of patients suffering their firstattack before age 2 years.2 Febrile attacks typically last 4 days and are associated with cervicallymphadenopathy (90%), erythematousrash characteristically located onthe palms and soles (80%), in addition to headache, arthritis, and abdominalpain (70%).Although the frequency of attacks decreaseswith age, patients may still suffer from diminished quality of life, compared with healthy peers. Reports of amyloidosis are rare.

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS)

The TRAPS has a variable presentation owingto the numerous mutations in the gene encoding of the cell surface receptor for TNF, TNFRSF1A, resulting in abnormal receptor-ligand signaling. Attacks of TRAPS are much longer than FMF and HIDS, typically lasting 7 days or more.

Most patients develop symptoms as toddlers or during elementary school years, but disease onset has been reported to occur in almost any decade of life. During attacks, most patients experience intense myalgias in addition to abdominal and pleuritic chest pain. Patients can also develop an erythematous rash during attacks and travels proximal-to-distal directions. Periorbital edema and painful conjunctivitis also may occur during attacks. Patients with TRAPS occasionally develop amyloidosis, and attacks can persist throughout life.

Cryopyrin-associated periodic syndromes (CAPS)

The most phenotypically diverse group of autoinflammatory conditions, CAPS consists of three overlapping phenotypes: Familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystemic inflammatory disorder (CINCA/NOMID). Mutations within the NLRP3 gene (NOD-like receptor family, pyrin domain), which encodes the protein cryopyrin, cause the symptoms of CAPS. NLRP3 mutations result in an abnormal cryopyrin structure and increased IL-1 beta production. CAPS can be transmitted in an autosomal dominant fashion but spontaneous mutationsare also common.

Attacks of CAPS consist of recurrent fevers accompanied by urticarial rash and inflammation of the central nervous system inflammation.

  • Patients with FCAS very frequently present in the neonatal period through early childhood. They experience brief episodes(<24 hours) of fever, joint pain, and urticarial rash when exposed to sudden drops in ambient temperature.
  • Attacks in patients with MWS typically last longer than FCAS and are inconsistently related to changes in ambient temperature. In addition to fever and urticarial rash, these patients may also develop arthritis and headaches fromaseptic meningitis.
  • The most severe phenotype, CINCA/NOMID, classically manifests with fever and persistent urticarial rash within the first few days of life. Patients with CINCA/NOMID have the most severe neurological and musculoskeletal involvement with increased risk of developmental delay, visual impairment, and decreased physical function.

Other autoinflammatory disorders

The pool of autoinflammatory conditions grows deeper every year. Conditions such as deficiency of interleukin 1 receptor antagonist (DIRA), demonstrate how lack of a naturally occurring IL-1 receptor antagonist can result in inflammatory symptoms including to severe pustular rash and osteitis.3,4 Patients with pyogenic arthritis, pyodermagangrenosum,and acne syndrome have increased IL-1 production due to amutation in the cytoplasmic adapter proteinproline-serine-threonine phosphatase-interactingprotein (PSTPIP1) gene.5 A mutation in the LPIN2 gene results in Majeed syndromes and causes early-onset chronic recurrent multifocal osteomyelitis, neutrophilic dermatosis, and dyserythropoietic anemia.6 Blau syndrome patients have a mutation in the NOD2/CARD15 gene that manifestations as recurrent or chronic episodes of granulomatous arthritis, colitis, and uveitis.

Treatment of Autoinflammatory Conditions

The primary goal of therapy should be to preserve the structure and function of the various affected body systems. In general, most autoinflammatory conditions become less severe and frequent over decades, so treatment is aimed at minimizing potential end-organ damage while improving or maintaining quality of life and avoiding unwanted adverse effects of medications. It is important to note that all medications used to treat autoinflammatory disease are designed to disrupt normal signaling pathways in the innate response, thus increasing the risk of infection. Other potential concerns regarding increased risk of malignancy due to perturbation of naturally occurring cancer surveillance processes, a risk observed in conditions such as rheumatoid arthritis but not in studied in great detail in the autoinflammatory conditions.

Monitoring treatment response can be a challenge. Changes in objective measures of disease activity such as acute-phase reactants (erythrocyte sedimentation rate, C-reactive protein) can occur quite quickly following initiation of therapy, and monitoring these levels consistently can help anticipate disease flares. Disease-specific activity indices have been recently developed and are gaining more consistent use as an everyday clinical tool.Lastly, health-related quality of life and functional scales can provide an important clue into patient’s perception of how their disease affects their health and function and may indicate the need for involvement of ancillary services to improve these domains.

Interleukin-1 inhibitors

Inhibition of the proinflammatory effects of IL-1 offers significant improvement in the symptoms of many of the autoinflammatory conditions.Since the approval of anakinra in 2001, two other IL-1 inhibitors have been brought to market — rilonacept and canakinumab.During the last 5 years, clinical trials have repeatedly demonstrated that this class of medications can effectively manage the symptoms and improve the quality of life for this patient population. All IL-1 inhibitors are administered as subcutaneous injections and have acceptable safety profiles. Infectious complications, although reported, are rare. With longer periods of observation, these medications may have the potential to reduce the possibility of complications associated with autoinflammatory diseases such as hearing loss and amyloidosis.

Originally developed in an attempt to quell the cytokine storm accompanying septic shock in critically ill patients, anakinra is an IL-1 receptor antagonist that prevents soluble IL-1 from interacting with its receptor on the cell membrane.Although anakinra failed to reduce mortality rates associated with sepsis, clinicians recognized the potential of this medication to treat other chronic inflammatory conditions, such as rheumatoid arthritis.The first report of anakinra’s efficacy in the autoinflammatory conditions was in MWS and CINCA/NOMID in 2004.7 Since then, multiple observational trials and retrospective case series have repeatedly demonstrated reduced disease activity and dramatic reductions in levels of acute-phase reactants in patients with CAPS treated with anakinra.Response is most vigorous in CAPS; however, additional studies have demonstrated the efficacy of anakinra in patients with HIDS, FMF, TRAPS, Blau syndrome, and DIRA syndromes.

Anakinra is supplied as a prefilled syringe that patients self-administer on a daily basis.Doses start at 1 to 3 mg/kg with the recommended adult dose being 100 mg every 24 hours.Autoinflammatory disease experts have reported the need to increase dosing in children to 4 to 6 mg/kg due to more rapid metabolism of the drug.Response times to anakinra are dramatic with many patients reporting significant improvement in symptoms within hours of the first dose.

Adverse event rates are low, with serious infections or severe allergic reactions occurring in less than 5% of patients.The most common adverse event is skin reactions, which manifest as red, raised, pruritic and or painful plaques and develop at the injection site within 1 to 6 hours of administration.These cutaneous eruptions typically resolve over 6 to 36 hours and can be improved with use of ice or topical antihistamines.

Rilonacept is a dimeric fusion protein consisting of two different Fab fragments bound to the Fc chain of IgG1. These Fab fragments have the ability to scavenge IL-1 using two different targets. Rilonacept has been demonstrated to improve disease symptoms, inflammatory markers and patient functional status in both CAPS and FMF.

Rilonacept is prepared by reconstituting the lyophilized drug in sterile saline then administering through a subcutaneous injection. Similar to anakinra, the safety profile of rilonacept is quite attractive with a low rate of serious adverse events.Infectious complications are infrequent as are injection site reactions.

This is the most recent addition to the anti-IL-1 armamentarium, a humanized monoclonal antibody that specifically binds IL-1beta. This medication has a novel, long-acting profile, being administered every 4 weeks by subcutaneous injection after reconstitution of the drug.In the same manner as rilonacept and anakinra, canakinumab has proven to be effective in CAPS and FMF.Patients with CAPS typically report an almost complete improvement in symptoms when treated with canakinumab.8 Patients with FMF refractory to colchicine also receive symptom relief from use of canakinumab.9 Pediatric patients with CAPS may require higher doses of canakinumab than recommended by the manufacturer. Dosing frequency should be driven by clinical phenotype and disease severity and adjusted to deliver symptom relief and improved quality of life.


Most experience with TNF-inhibitors stems from the use of etanercept in patients with TRAPS. In these patients, etanerceptimproved symptom scores, symptom frequency, and laboratory markers of inflammation.10 Case reports also have documented etanercept efficacy in patients with FMF, CAPS, and HIDS. Scattered reports of adalimumab and infliximab efficacy have been reported in FMF patients as well.

For almost a half-century, colchicine has been the mainstay of therapy for patients with FMF.In up to 70% of patients, colchicine use results in cessation of febrile attacks while and an additional 25% have a reduction in the severity and frequency of attacks. A small number of FMF patients (5%-10%) have no response to colchicine; this may be partially due to difficulty with compliance related to common drug-associated gastrointestinal side effects.In patients unresponsive to colchicine or unable to tolerate it, IL-1 inhibitors offer a potential option. By far the most important benefit offered by colchicine is the reduced risk of amyloidosis.Historically, that risk has been close to 40%, but with consistent use of colchicine, the risk is reduced to less than 5%.

Drug pipeline

The future of therapeutic options for patients with autoinflammatory disorders is optimistic.There is a steady stream of agents in developmentthat target components of the proinflammatory pathway critical to driving the autoinflammatory phenotype.Examples include tocilizumab, an IL-6 inhibitor, and tofacitinib, a janus-associated kinase (JAK) inhibitor.These drugs offer novel options for additional blockade of inflammatory signaling.

Therapeutic protocols involving combination of medications, similar to the approach in patients with rheumatoid arthritis, may offer additional benefits, but the safety of these regimens will need to be closely monitored.Given the well-recognized role of stress on worsening symptoms of autoinflammatory conditions, studies examining the added benefit of stress-reducing complementary therapies such as antidepressants, anxiolytics, biofeedback, acupuncture, and yoga could provide novel insight and relief for individuals suffering from these symptoms.


The autoinflammatory conditions offer a novel opportunity to learn how alterations in molecular and cellular control mechanisms affect the inflammatory response. Several pharmacologic options exist that control disease activity and reduce the likelihood of serious disease sequela. As understanding of the molecular pathology that underlies autoinflammatory disorders continues to improve, so will the therapeutic options available to treat these conditions and, most importantly, patient quality of life.

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