The continuous advance in the search for the cause and pathogenesis of the autoinflammatory syndromes, as well as reports of the efficacy of specific inflammation-mediator suppressors, has changed the way these syndromes are approached and treated; both the acute and long-term treatment of these diseases has improved significantly. Etiologic and pathophysiologic manipulation is and will be the future for controlling, even curing, this new and rare set of diseases.
Key points
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The initial therapy for all of the autoinflammatory syndromes is the control of fever, pain, or the symptoms derived from the inflammatory reaction.
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The initial effort should focus on making the precise diagnosis. This strategy facilitates the choice of appropriate initial therapy, which has been defined for many of these syndromes and diseases.
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Accurate diagnosis is often difficult; rendering symptom management the mainstay of initial therapy while the definitive diagnosis remains elusive.
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Steroids are not considered useful in the autoinflammatory syndromes, yet they still play an important role in the early treatment of these diseases.
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Colchicine has been approved for the treatment of familial Mediterranean fever and its late complications.
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Antitumor necrosis factor therapy has been used and proved useful in several autoinflammatory diseases.
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The most recent acquisition for the treatment of autoinflammatory syndromes is anti-interleukin 1, anakinra, rilonacept, and canakinumab, with good results in many of the autoinflammatory syndromes.
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New molecules and pathways of disease will facilitate the development of effective therapies.
Introduction
The autoinflammatory disorders are an expanding group of diseases characterized by recurrent systemic inflammation in the absence of infection, autoantibodies, or antigen-specific T cells; they are thus probably related to a primary dysfunction of the innate immune system, with no adaptive immune deregulation. Dysfunction of the innate immune system includes abnormal responses to pathogens associated with the lipopolysaccharide and peptidoglycan of myeloid cells, such as neutrophils and monocytes in blood and tissues, in addition to the dysregulation of inflammatory cytokines and their receptors, like interleukin 1β (IL-1β), tumor necrosis factor α (TNF-α), and others ; thus, these substances and molecules have become the targets for present and future therapies.
The autoinflammatory diseases include hereditary disorders like: familial Mediterranean fever (FMF), mevalonate kinase (MK) deficiency, tumor necrosis factor receptor–associated periodic syndrome (TRAPS), cryopyrin-associated periodic syndrome (CAPS), familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurologic, cutaneous, and articular (CINCA) syndrome, Blau syndrome, hyperimmunoglobulin D syndrome (HIDS), pyogenic sterile arthritis, pyoderma gangrenosum and acne (PAPA) syndrome, chronic recurrent multifocal osteomyelitis; some multifactorial disorders like Crohn and Behçet disease, juvenile idiopathic arthritis (JIA), adult Still disease, and macrophage activation syndrome (MAS) are considered autoinflammatory diseases; so are periodic fever, aphthous stomatitis, and adenopathy (PFAPA) syndrome and Majeed syndrome.
Introduction
The autoinflammatory disorders are an expanding group of diseases characterized by recurrent systemic inflammation in the absence of infection, autoantibodies, or antigen-specific T cells; they are thus probably related to a primary dysfunction of the innate immune system, with no adaptive immune deregulation. Dysfunction of the innate immune system includes abnormal responses to pathogens associated with the lipopolysaccharide and peptidoglycan of myeloid cells, such as neutrophils and monocytes in blood and tissues, in addition to the dysregulation of inflammatory cytokines and their receptors, like interleukin 1β (IL-1β), tumor necrosis factor α (TNF-α), and others ; thus, these substances and molecules have become the targets for present and future therapies.
The autoinflammatory diseases include hereditary disorders like: familial Mediterranean fever (FMF), mevalonate kinase (MK) deficiency, tumor necrosis factor receptor–associated periodic syndrome (TRAPS), cryopyrin-associated periodic syndrome (CAPS), familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurologic, cutaneous, and articular (CINCA) syndrome, Blau syndrome, hyperimmunoglobulin D syndrome (HIDS), pyogenic sterile arthritis, pyoderma gangrenosum and acne (PAPA) syndrome, chronic recurrent multifocal osteomyelitis; some multifactorial disorders like Crohn and Behçet disease, juvenile idiopathic arthritis (JIA), adult Still disease, and macrophage activation syndrome (MAS) are considered autoinflammatory diseases; so are periodic fever, aphthous stomatitis, and adenopathy (PFAPA) syndrome and Majeed syndrome.
Treatment
The initial therapy for all the autoinflammatory syndromes is the control of fever, pain, or the symptoms derived from the inflammatory reaction. Antiinflammatory medications are the initial choice; nonsteroidal antiinflammatory drugs (NSAIDs) have been used with variable success for decades; so have systemic steroids.
The initial effort should focus on making the precise diagnosis. This goal facilitates the choice of appropriate initial therapy, which has been defined for many of these syndromes and diseases. Accurate diagnosis is often difficult, rendering symptom management the mainstay of initial therapy while the definitive diagnosis remains elusive.
Chronic management includes symptom management and prevention of complications of long-term disease and treatment, including amyloidosis and premature coronary artery disease ( Table 1 ).
| Feature | FMF | HIDS | TRAPS | MWS | FCU | CINCA |
|---|---|---|---|---|---|---|
| Treatment | Colchicine to prevent attacks and for long-term prevention of amyloidosis | Supportive NSAIDs, prednisone, simvastatin | NSAIDs and steroids, anti-TNF, anti-IL-1 | NSAIDs and steroids, anti-IL1 | Anti-IL-1 | Anti-IL-1 |
Nonspecific Medications
The initial drug management includes corticosteroids or nonsteroidal medications, as well as others with antiinflammatory effects, as follows.
Cimetidine
Cimetidine is a histamine 2 (H 2 ) receptor antagonist that inhibits stomach acid production. Used to treat and reduce the symptoms of gastritis and peptic ulcer disease, it has been shown debatably useful in the treatment of herpes simplex 1 and 2, herpes zoster virus, common warts, some inflammatory conditions associated with calcifications, and so forth. It has also been used to modify epidermal growth factor, vascular endothelial growth factor, and E-selectin, for the treatment of several cancers and their metastasis. Cimetidine was shown to be of some benefit in the pain of interstitial cystitis. Cimetidine has been used in PFAPA syndrome, with resolution of the fever and some of the other manifestations of the syndrome; at a dose of 20 mg/kg/d, cimetidine has a response greater than 50%; the mechanism of action is not known, but has been linked to inhibition of T-suppressor cells by blocking H 2 -receptors, with minimal side effects.
Statins
The involvement of MK in the cholesterol synthesis pathway encouraged the introduction of statins in the management of MK deficiency and HIDS; good results were obtained in a small group of patients. MK plays an essential role in the cholesterol synthesis pathway; during cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (the enzyme inhibited by statins) converts HMG-CoA to mevalonate. This conversion is blocked when a mutation in the MVK gene exists and mevalonate is not converted to mevalonate phosphate, causing an increase in mevalonic acid in serum, tissues, and urine. The absence of a negative feedback loop, naturally provided by the presence of the end products of synthesis, leads to increased HMG-CoA reductase activity, consequently increasing serum, tissue, and urine levels of mevalonic acid. The inhibition of MK also activates caspase 1 and decreases isoprenoids, which increase IL-1β. The blockade of these mediators may soon help to clarify the pathophysiology of these diseases.
NSAIDs
NSAIDs are nonselective inhibitors of cyclooxygenase, acting on both isoenzymes Cox1 and Cox2, causing a reversible inhibition, which is in contrast with that produced by aspirin, which is irreversible, with no formation of prostaglandins and thromboxane (mediators of inflammation). In crystal-induced arthritis, NSAIDs have been shown to inhibit urate crystal phagocytosis. The mechanism of action of NSAIDs is to block the formation of prostaglandin E 2 , which regulates neurons within the hypothalamus responsible for the generation of temperature increase or fever.
NSAIDS are used initially in the antiinflammatory syndromes to relieve constitutional symptoms or inflammatory signs like fever and arthritis, but in most instances, they are not the mainstay of therapy. Nonsteroidal and steroidal drugs have been used in Majeed syndrome for the control of symptoms, but the long-term management of the hematologic manifestations is accomplished by splenectomy and transfusions.
Corticosteroids
Prednisone is a glucocorticoid converted in the liver to prednisolone, its active form. Isolated in 1950 and introduced for usage in 1955, it has been the mainstay of therapy for many autoimmune and inflammatory diseases in which steroids are helpful. Steroids are not considered useful in the autoinflammatory syndromes, yet they still play an important role in their early treatment.
Steroids are the main treatment option in acute attacks of HIDS. Patients with PFAPA syndrome are treated with prednisone for their fever. In some situations, PAPA syndrome responds well to oral glucocorticoids. Steroids are used in the febrile crisis of TRAPS, but their use in the chronic setting is best avoided. Low-dose steroids are recommended in JIA and in adult Still disease; prednisone 1 to 5 mg per day is used, although some patients may require 1 to 2 mg/kg/d, usually in divided doses.
In MAS, the usual starting dosage is pulse methylprednisolone at 30 mg/kg/d for 3 to 5 days or prednisone 1 to 2 mg/kg/d, usually in divided doses, 2 or 3 times a day.
Colchicine
Historically, colchicine has been used for nearly all the rheumatic diseases. It was described for the treatment of rheumatism and swelling in the Egyptian Ebers Papyrus (ca 1500 bc ). Extracted from the meadow saffron ( Colchicum autumnale ) in the early 1970s, colchicine was found useful in the acute management of FMF, as well as in the prevention of its long-term complications like amyloidosis. Colchicine was only approved by the US Food and Drug Administration (FDA) in August, 2009 for use in gout and FMF. The mechanism of action of colchicine is believed to be inhibition of microtubule polymerization by tubulin binding, which blocks cell mitosis in neutrophils, and by antiinflammatory mechanisms involving altered expression of adhesion molecules and chemotactic factors, coming from the generation of reactive oxygen species occurring in crystal-induced arthritis.
Amyloidosis is a feared long-term complication of FMF; it results from accumulation of serum amyloid A (SAA) protein, deposited mainly in the kidney. A major manifestation of amyloidosis is renal injury, which may lead to proteinuria renal failure. Patients are normotensive, with no hematuria. Since the adoption of colchicine for FMF, the prevalence of amyloidosis among patients with FMF has decreased significantly. For adults, the dose of colchicine is 0.5 to 1 mg/d; for children, the starting dose should be 0.5 mg/d or less if younger than 5 years, 1 mg/d for children 5 to 10 years, and 1.5 mg/d for those older than 10 years; dosage can be increased in a stepwise fashion up to a maximum of 2 mg/d. A few patients do not respond to colchicine, usually because of poor treatment adherence; at the suggested dosage, it is a safe drug; side effects, including gastrointestinal, hematologic, and neuromuscular symptoms, are rare.
Bisphosphonates
These medications are being used and positive outcomes obtained with pamidronate and zolendronic acid in the treatment of SAPHO (synovitis, acne, palmoplantar pustulosis, hyperostosis, and osteitis) syndrome, via their antiosteoclastic effect and supposed antiinflammatory action, may be related to the suppression of TNF-α.
Immunosuppressive Drugs
Methotrexate and cyclosporine have been tried in autoinflammatory disorders but proved ineffective in many, both as disease modifiers and steroid-sparing drugs. In TRAPS, they do not reduce the frequency or intensity of flares and have no effect in secondary amyloidosis. In Blau syndrome, they have been used with limited success. Cyclosporine has been used in the treatment of MAS in association with steroids and is used for disease control, with good results ; anakinra in MAS has been shown to be effective.
TNF Inhibitors
In 1999, the cloning of the gene for the TNF receptor defined the cause of TRAPS. Etanercept, a soluble antagonist of TNF, has proved useful in patients with TRAPS. Worsening of disease has been seen in some patients treated with anti-TNF ; this phenomenon resembles the contradictory responses observed in some patients with JIA treated with anti-TNF medication who go on to develop MAS, when the MAS is induced or favored by the use of the anti-TNF medication, suggesting that it should be used with caution. Infliximab, another TNF molecule and receptor antagonist, has been used in TRAPS and in Blau syndrome, with good responses, and in some cases, with reduced long-term complications; the response of amyloid deposition is controversial, and there is no definitive information on the effectiveness of anti-TNF in reducing long-term complications.
Anti-TNF medication has been described as useful in case reports for SAPHO syndrome.
Anti-IL-1
Short-acting
Anakinra, a receptor antagonist for IL-1, showed no efficacy in sepsis and rheumatoid arthritis. IL-1 inhibition also occurs in systemic idiopathic arthritis and recurrent pericarditis of noninfectious origin. Anakinra has been used in systemic-onset JIA, with excellent results, and it has been used to prevent attacks and reduce systemic inflammatory markers in patients with colchicine-resistant FMF, HIDS, and even etanercept-resistant TRAPS. Similarly, remarkable responses were also reported in patients with Blau syndrome, PAPA syndrome, and deficiency of IL-1-receptor antagonist. Anakinra is effective during episodes of acute gout.
Anakinra has been shown to prevent cold-induced symptoms when administered to patients with FCAS before a cold room challenge.
Excessive production of IL-1 is seen in diseases like MWS, CINCA syndrome, and neonatal onset multisystem inflammatory disease (NOMID), and excellent therapeutic responses have been described.
The dosage used of anakinra varies from 0.3 to 3 mg/kg/d, in divided doses.
Long-acting
Rilonacept is a recombinant fusion protein with a half-life of 8.6 days, it has a high affinity for IL-1β and also for IL-1α and IL-1 receptor accessory protein; it is used weekly at a dose of, for patients aged 12 years or older, 4.4 mg/kg, up to a maximum of 320 mg, delivered as 1 or 2 subcutaneous injections with a maximum single-injection volume of 2 mL. If the initial dose is of 2 injections, they should be given on the same day at 2 different sites; dosing should be continued with a once-weekly injection of 2.2 mg/kg, up to a maximum of 160 mg, administered as a single subcutaneous injection of up to 2 mL. Canakinumab is a humanized monoclonal antibody against IL-β; its half-life is 28 days and it may be dosed every 8 weeks; for body weights greater than 40 kg, the recommended dose is 150 mg as a single dose via subcutaneous injection; for body weights between 15 kg and 40 kg, the recommended dose is 2 mg/kg as single subcutaneous injections; for children 15 to 40 kg with inadequate response, the dose can be increased to 3 mg/kg as single subcutaneous injections.
Both rinolacept and canakinumab are useful in the treatment of NOMID, FCAS, MWS, HIDS, and, as recently reported, JIA and in CAPS, both are FDA approved for this use. Also, in crystal-induced arthritis, canakinumab was used with good results. Recently, results of the treatment of Blau syndrome with canakinumab showed good responses. Two randomized trials with canakinumab in JIA reported benefits. Also, tozilizumab an anti-IL-6, used in JIA, was recently described as effective.
Adverse Effects of Biological Therapies
Experiences with autoimmune disease have shown increases in the rates of mild to severe bacterial and viral infections, but the pathophysiology of these diseases is different and it is difficult to extrapolate. Nevertheless, at least a good history to exclude for tuberculosis, fungi, and viral diseases such as hepatitis C and B is mandatory; on the other hand, the use of immune-suppressive therapies might increase the risk of opportunistic infections in patients with autoimmune diseases. The situation is different for the autoinflammatory syndromes. Increased rates of meningitis and urosepsis have been described in small CAPS trials with both rilonacept and canakinumab. Injection-site reactions are common with all antileukins.
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