Conditions Improved with IL-1β TT
Familial Mediterranean Fever
Familial Mediterranean fever (FMF) is the most common inherited recurrent fever disorder. Affected patients experience 2- to 3-day-long inflammatory episodes characterized by fever, abdominal pain, and joint symptoms. Rash and chest pain can also occur during episodes. However, the most significant morbidity in these patients is systemic AA amyloidosis that often results in end-stage renal disease. The standard treatment is maintenance colchicine, which has been shown to reduce the frequency and severity of episodes but also significantly reduces the risk of amyloidosis [19•]. Most FMF patients have homozygous mutations in the MEFV gene that codes for the protein pyrin. Pyrin has some structural similarities to the NLR proteins and may interact with NLR inflammasomes or form its own inflammasome, resulting in dysregulated caspase-1 activation and IL-1β release [19•]. In addition, mononuclear cells from FMF patients release higher levels of IL-1β [19•]. For this reason, some FMF patients who do not respond to or who cannot tolerate colchicine have been treated with IL-1β TT, with promising results; however, colchicine remains the treatment of choice in most patients .
Tumor Necrosis Factor Receptor-Associated Periodic Syndrome
This autosomal dominantly inherited recurrent fever disorder, originally known as familial Hibernian fever, is associated with 1- to 3-week-long episodes of fever, abdominal pain, and joint symptoms that are often associated with rash and periorbital swelling. As in FMF, some patients develop AA amyloidosis and kidney disease. Symptoms usually respond to high-dose corticosteroids [19•], but the discovery of heterozygous mutations in the TNFR1a gene prompted the use of tumor necrosis factor (TNF)-α TT (etanercept), with good results initially . However, incomplete abrogation of episodes and persistent chronic inflammation despite proper dosing and evidence suggesting that TNF-α-mediated inflammation is dependent on IL-1β provided the rationale for IL-1β TT, with superior results to TNF-α TT [22, 23].
Hyper IgD Syndrome
Patients with hyper IgD syndrome experience recurrent episodes of fever, lymphadenopathy, splenomegaly, and abdominal pain lasting 3–7 days. This autosomal recessive disorder is caused by homozygous mutations in the gene (MVK) resulting in decreased mevalonate kinase activity, with effects on the isoprenoid pathway of cholesterol biosynthesis [19•]. Mechanisms responsible for inflammation are believed to be due to the deficiency of isoprenylated proteins, which intersect with the IL-1 pathway. In support of this mechanism, mononuclear cells from hyper IgD patients release more IL-1β [19•], and patients have responded to IL-1 TT .
Pyogenic Arthritis, Pyoderma Gangrenosum, and Acne
This rare autosomal dominant disease is characterized by joint inflammation, cutaneous ulcers, and cystic acne. Neutrophils are the predominant cell involved in tissue inflammation. Mutations in the proline-serine-threonine phosphatase interacting protein-1 are responsible for disease and are believed to affect interactions with the pyrin protein, resulting in IL-1-mediated inflammation [19•]. Mononuclear cells from patients release increased IL-1β, and patients have responded to IL-1 TT .
Deficiency of IL-1RA
Deficiency of IL-1RA is a rare autosomal recessive disease presenting with multifocal osteomyelitis, periostitis, and pustulosis. Mutations in the gene that codes for IL-1RA result in loss of function and unregulated IL-1 receptor-mediated inflammation. Therapy with anakinra results in complete resolution of symptoms .
Systemic-Onset Juvenile Idiopathic Arthritis and Adult-Onset Still’s Disease
Significant amelioration of signs and symptoms of both of these systemic inflammatory diseases occurs with use of anakinra. Results from a three-center pediatric rheumatology study and others demonstrated a reduction in large joint inflammation, corticosteroid dosage, acute-phase reactants, fever, and rashes in systemic-onset juvenile idiopathic arthritis and systemic inflammation in adult-onset Still’s disease [27, 28]. The mechanism for IL-1β secretion in this disorder is unknown, and no studies are available implicating involvement of the NLRP3 inflammasome.
Schnitzler syndrome is a rare disease characterized by fever, bone and joint pain, nonpruritic rash often mistaken for urticaria, and lymphadenopathy. Associated abnormal laboratory tests include leukocytosis, elevated erythrocyte sedimentation rate and other acute phase reactants, neutrophilic infiltration involving skin lesions, and IgM monoclonal gammopathy. Striking improvement occurs following anakinra therapy, suggesting the pathogenesis is IL-1β mediated . The cause of IL-1β secretion is currently unknown, and no studies have implicated involvement of the NLRP3 inflammasome.
Conditions with IL-1β Involvement Considered for IL-1β TT
The commonality of the following diverse clinical disorders with evidence of IL-1β secretion and neutrophilic inflammation is the association of ischemia, hypoxia, and reperfusion with metabolic acidosis and catabolism of tissues. It has been hypothesized by one of the authors (Dr. Wanderer) that these pathophysiologic conditions cause an increase in byproducts (DAMPs) from breakdown of cellular nucleotides or proteins, which could stimulate innate receptors such as NLRP3 to cause secretion of IL-1β, and subsequent neutrophilic inflammation.
Ultraviolet-Induced Skin Damage
There is evidence using in vitro keratinocytes that the inflammasome can be activated by UVB radiation and cause IL-1β secretion . The UVB band is similar to exposure to sunlight, and release of IL-1β may explain the fever, leukocytosis, and acute-phase responses seen with severe sunburns.
Chronic Neutrophilic Pulmonary Disorders
Examples include severe corticosteroid-resistant neutrophilic asthma and chronic obstructive pulmonary disease. It has been posited that hypoventilation with hypoperfusion and reoxygenation exhibit similarities to biphasic pathobiology of classic ischemia reperfusion injury. Low pH in exhaled breath condensates in these disorders provides evidence for the existence of acidotic milieu in affected tissues and cells, which in turn can cause DAMPs formation, IL-1β secretion, and neutrophilic inflammation. This ongoing process may explain steroid unresponsiveness . Efforts are in progress to test this hypothesis by treating these diseases with IL-1β TT.
Sickle Cell Anemia
Neutrophilic inflammation is prominent in sickle cell disease and in transgenic sickle cell disease mice subjected to hypoxia and reperfusion. In addition, transgenic sickle cell disease mice compared with wild mice exhibit a heightened proinflammatory state to microbial molecules, as marked by elevated neutrophil counts, increased secretion of soluble vascular adhesion molecules, and increased secretion of proinflammatory cytokines (IL-1β and TNF-α). A similar observation of heightened inflammatory responses to microbial infections is manifested as chest injury in sickle cell disease patients. There is also evidence of DAMPs formation in sickle cell disease, as uric acid elevations are frequently observed and thought to be caused by a combination of hemolysis and nucleotide breakdown in tissues induced by ischemia and reperfusion. Ischemia reperfusion is a consequence of vasoocclusion from sequestration of sickle erythrocytes, polymerized free sickle hemoglobin, activated monocytes, neutrophils adherent to activated endothelial cells, and embolized fat from bone marrow. It is now known that PAMPs and DAMPs added to normal monocytes in vitro can cause synergistic secretion of IL-1β, which could explain the amplified inflammatory responses in these patients . A trial involving sickle cell disease mice challenged by hypoxia and treated with IL-1 TT is in progress.
It has been posited that intrapartum hypoxia-ischemia through stimulation of the NALP3 inflammasome by DAMPs has a significant role in causing inflammation associated with hypoxic-ischemic encephalopathy. The following is presented as evidence for this hypothesis:
Metabolic acidosis (pH <7.0 and base deficit) in fetal umbilical arterial blood samples obtained at delivery is one of the International Cerebral Palsy Task Force putative criteria to diagnose an acute intrapartum hypoxic event sufficient to cause cerebral palsy. This indicator of metabolic stress could enhance DAMPs formation;
A newborn pig model subjected to sustained hypoxic injury exhibited a rapid decrease in phosphocreatine/inorganic phosphorus ratios, pH, and adenosine triphosphate, all metabolic events that could lead to DAMPs formation. A perinatal hypoxia-ischemia rodent model (rat) with carotid arterial occlusion showed progressive decreases in phosphocreatine and adenosine triphosphate to values of less than 10% of the control ipsilateral cerebral hemisphere during the course of hypoxia-ischemia over a 3-hour duration. They also demonstrated decreased intracellular pH in areas affected by arterial occlusion.
A study of premature infants with elevated uric acid concentration, noted on the first postnatal day, subsequently developed hypoxic-ischemic-induced injury (ie, intravascular hemorrhage and/or leukomalacia).
The observation of elevated IL-1β levels in spinal fluid samples obtained from hypoxic-ischemic human newborns as compared with control newborns evaluated for possible sepsis/meningitis that was subsequently ruled out .
To date, there are no known ongoing studies involving animal studies comparing hypoxic-ischemic stress between wild type and Nlrp3 knockout mice or in mice with and without pretreatment using monoclonal IL-1β TT, and there are no human trials with IL-1β TT to determine if hypoxic-ischemic encephalopathy can be reduced with this adjunct therapy.
Organ Ischemia Reperfusion Injury Disorders (Renal, Myocardial, Central Nervous System, and Transplantation Organ Injury)
Increased secretion of IL-1β has been observed in many models of ischemia reperfusion, including models of transplantation. It also has been demonstrated in animal models that IL-1β TT can prevent and/or minimize the neutrophilic inflammation associated with these models. Although PAMPs can induce IL-1β secretion, in many of the animal and transplantation models, PAMPS are not detected, suggesting that other mechanisms may cause induction of IL-1β secretion. One such paradigm is the production of DAMPs formation from the pathobiological effects of ischemia reperfusion injury, which in turn could stimulate NLRP3 and cause IL-1β secretion with subsequent neutrophilic inflammation . There are no known trials of IL-1β TT in these conditions.