Physical Address
304 North Cardinal St.
Dorchester Center, MA 02124
The Systemic Autoinflammatory Diseases
Definition
The systemic autoinflammatory diseases ( Table 240-1 ) are a group of disorders that are characterized by seemingly unprovoked inflammation, without evidence of high-titer pathogenic autoantibodies or antigen-specific T cells, thereby distinguishing them from the more classic autoimmune diseases. The first conditions recognized as autoinflammatory were the hereditary recurrent fevers, which are a group of mendelian disorders characterized by episodic or fluctuating degrees of fever and localized inflammation. The scope of autoinflammatory disease has broadened to include other heritable illnesses, including disorders in which purulent or granulomatous inflammation predominates, as well as inherited disorders of the complement system ( Chapter 37 ). In numerous autoinflammatory conditions, some of which manifest in childhood and others that occur later in life, a complex interaction of germline genetic susceptibilities, somatic mutations, and environmental factors contributes to the manifestation of the disease. Autoinflammatory illnesses include systemic-onset juvenile idiopathic arthritis (Still disease), Behçet disease, and even the crystalline arthritides. Many of the monogenic inherited autoinflammatory diseases are now considered inborn errors of innate immunity ( Chapter 35 ), the phylogenetically more primitive part of the immune system that uses germline membrane and intracellular receptors expressed in granulocytes and macrophages to mount the body’s first line of defense against pathogens.
TABLE 240-1
SYSTEMIC AUTOINFLAMMATORY DISEASES: A PARTIAL LISTING
| INHERITED AUTOINFLAMMATORY DISEASES | INHERITANCE | GENES OR RISK FACTORS | OMIM ∗ |
|---|---|---|---|
| INTERLEUKIN-1-BETA–RELATED DISORDERS | |||
| Familial Mediterranean fever (FMF) | Autosomal recessive | MEFV † | 249100 |
| Pyrin-associated autoinflammation with neutrophilic dermatosis | Autosomal dominant | MEFV † | 608068 |
| Tumor necrosis factor receptor–associated periodic syndrome (TRAPS) | Autosomal dominant | TNFRSF1A † | 142680 |
| Hyperimmunoglobulinemia D with periodic fever syndrome (HIDS)/Mevalonate kinase deficiency (MKD) | Autosomal recessive | MVK † | 260920 |
| Neonatal-onset multisystem inflammatory disease (NOMID)/Muckle-Wells syndrome (MWS)/familial cold autoinflammatory syndrome (FCAS) | Autosomal dominant/de novo | NLRP3 (formerly CIAS1 ) † | 607115 191900 120100 |
| Schnitzler syndrome | Sporadic | NLRP3 mosaic mutations (some) | |
| Multiple self-healing palmoplantar carcinoma Familial keratosis lichenoides chronica Autoinflammation with arthritis and dyskeratosis |
Autosomal dominant | NLRP1 † | 606636 615225 617388 |
| Deficiency of interleukin-1 receptor antagonist (DIRA) | Autosomal recessive | IL1RN † | 147679 |
| Deficiency of the IL-36R antagonist (DITRA) | Autosomal recessive | IL36RN † | 605507 |
| INTERFERON-RELATED AUTOINFLAMMATORY SYNDROMES (INTERFERONOPATHIES) | |||
| Aicardi-Goutières syndrome | Autosomal recessive or autosomal dominant | TREX1, RNASEH2A, 2B, 2C SAMHD1, ADAR (DRADA) IFIH1 (MDA5), LSM11, RNU7-1 |
225750 |
| STING-associated vasculopathy with onset in infancy (SAVI) | De novo | TMEM173 † | 612374 615934 |
| COPA (coatamer subunit α) syndrome | Autosomal dominant | COPA † | 601924 |
| Proteasome-associated autoinflammatory diseases (PRAAS)/Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) | Autosomal recessive, autosomal dominant, or digenic | PSMA3, † PSMB4, † PSMB8, † PSMB9, † PSMB10, † POMP, † PSMG2 † |
256040 |
| NF-KAPPA-B–RELATED AUTOINFLAMMATORY SYNDROMES | |||
| RELA haploinsufficiency | Autosomal dominant | RELA † | 618287 164014 |
| Haploinsufficiency of A20 (HA20) syndrome | Autosomal dominant | TNFAIP3 † | 191163 616744 |
| OTULIN deficiency (otulipenia) | Autosomal recessive | FAM105B (OTULIN) † | 615712 617099 |
| NEMO deleted exon 5 autoinflammatory syndrome (NDAS) |
X-linked (de novo) | IKBKG † | 300248 301081 |
| Immunodeficiency, autoinflammation, and amylopectinosis | Autosomal recessive | HOIL1/RBCK1, † HOIP/RNF31 | 610924 612487 |
| Early-onset sarcoidosis/Blau syndrome | Sporadic, autosomal dominant | NOD2/CARD15 † | 186580, 605956 |
| COMPLEMENT DISORDERS | |||
| Hereditary angioedema | Autosomal dominant | C1NH | 106100 |
| Early-onset protein-losing enteropathy, and thrombosis, intestinal lymphangiectasia, and intestinal inflammation | Autosomal recessive | CD55 | 125240 226300 |
| Hemolytic-uremic syndrome | Autosomal dominant, sporadic | CFH (complement factor H) | 235400 |
| Age-related macular degeneration | Complex inheritance | CFH (complement factor H) | 603075 |
| OTHER AUTOINFLAMMATORY SYNDROMES | |||
| Deficiency of ADA2 (DADA2) | Autosomal recessive | ADA2 † | 607575 615688 |
| Syndrome of periodic fever with aphthous stomatitis, pharyngitis, and cervical adenopathy (PFAPA) | Complex inheritance | IL12A, IL10, STAT4, CCR1-CCR3, HLA-B ∗ 15:01 HLA-DQB1 ∗ 06:03, HLA-DRB1 ∗ 13:01, HLA-DQA-01:03 |
— |
| Autoinflammatory disease associated with NLRC4 mutations | Autosomal dominant | NLRC4 † | 606831 616050 |
| Systemic-onset juvenile idiopathic arthritis (SOJIA)/adult-onset Still disease | Complex inheritance | HLA-DRB1 ∗ 11, LACC1, IL6 , MIF polymorphisms | 604302 |
| Behçet disease | Complex inheritance | HLA-B ∗ 51 , polymorphisms in IL10, IL23R, CCR1-CCR3, STAT4, KLRC4, ERAP1, MEFV, TLR4, IL1A-IL1B, IRF8, CEPB-PTPN1, ADO-EGR2, RIPK2, LACC1, FUT2, IL12A, NOD2 | 109650 |
| Syndrome of pyogenic arthritis with pyoderma gangrenosum and acne (PAPA) | Autosomal dominant | PSTPIP1 † | 604416 |
| Chronic recurrent multifocal osteomyelitis (CRMO) | Sporadic, autosomal recessive | LPIN2 , † when associated with congenital dyserythropoietic anemia (Majeed syndrome) | 259680 |
| Syndrome of periodic fever with immunodeficiency and thrombocytopenia (PFIT) | Autosomal recessive | WDR1 † | 150550 604734 |
| Neonatal onset pancytopenia, autoinflammation, rash, and hemophagocytic lymphohistiocytosis (NOCARH syndrome) | De novo | CDC42 † | |
| Cleavage resistant RIPK1 induced autoinflammatory syndrome (CRIA) | Autosomal dominant | RIPK1 † | 618852 603453 |
| TBK1 deficiency | Autosomal recessive | TBK1 | |
| Retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, migraine headache (ROSAH) syndrome | Autosomal dominant | ALPK1 † | 614979 607347 |
| Autoinflammation and PLCγ2-associated antibody deficiency and immune dysregulation (APLAID) | Autosomal dominant | PLCG2 † | 614878 600220 |
| Vacuoles, E1 ligase, X-linked, autoinflammatory, somatic (VEXAS) syndrome | Myeloid-restricted somatic | UBA1 † | 301054 314370 |
| Synovitis acne pustulosis hyperostosis osteitis syndrome (SAPHO) | Idiopathic | — | — |
| Crystalline arthropathies | Complex inheritance | SLC2A9/GLUT9, ABCG2 | — |
∗ Online Mendelian Inheritance in Man, an online catalogue of genetic disorders, available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM . Accessed June 6, 2022.
† An updated list of disease-associated mutations is available online at https://infevers.umai-montpellier.fr/web/ . Accessed November 27, 2022.
Autoinflammatory syndromes can be grouped by key pathogenic cytokines and inflammatory pathways that are dysregulated and may be targets for effective therapies. These molecular targets include interleukin-1 (IL-1), type I interferons, and the NF-κB inflammatory signaling pathway.
Interleukin-1–Related Periodic Fever Syndromes
The IL-1–associated autoinflammatory diseases are linked by markedly increased expression of or cellular responsiveness to this cytokine, and resolution of symptoms with IL-1 blockade. Interleukin-1α and interleukin-1β (IL-1α and IL-1β) are structurally related cytokines released from cells in response to a number of inflammatory stimuli, such as lipopolysaccharide. These cytokines mediate inflammatory responses by binding to a common receptor that is present on the surface of a wide variety of cell types and that signals to activate inflammatory genes through the nuclear factor-kappa B (NF-κB) transcription factor complex. One example is idiopathic recurrent pericarditis ( Chapter 62 ). IL-1 is part of a larger family of cytokines (including IL-18, IL-33, and IL-36) that bind to related receptors and share the property of not having a characteristic signal peptide that normally targets cytokines to secretory vesicles. As a result, the IL-1 family cytokines may be secreted only by dead or dying cells, which function as molecular markers of cellular stress, and can trigger beneficial inflammatory responses to infection and injury. IL-1β and IL-18 are unique in that they are not biologically active until cleaved by the protease caspase-1, which also cleaves intracellular gasdermin D to induce an inflammatory form of cell death known as pyroptosis. Caspase-1 is itself activated in cytoplasmic protein complexes that contain various sensor proteins, such as NLRP3 and the adapter protein ASC. These complexes are referred to as inflammasomes because of their ability to trigger IL-1–mediated inflammation. IL-1–related autoinflammatory diseases (described later) are caused by mutations in genes encoding proteins that are directly or indirectly involved in the activation of IL-1 and the resulting inflammatory cascade.
Familial Mediterranean Fever
Definition
Familial Mediterranean fever (FMF) is a recessively inherited disease that typically manifests with 12- to 72-hour episodes of fever and localized serosal, synovial, or cutaneous inflammation. Between attacks, patients usually feel completely well, although biochemical evidence of inflammation may remain, and some patients eventually develop systemic amyloidosis ( Chapter 174 ).
Epidemiology
Familial Mediterranean fever is most common in individuals of Jewish, Arab, Armenian, Turkish, and Italian ancestry. The frequency of asymptomatic carriers of a single MEFV mutation in these populations is as high as 1 in 10, likely because heterozygosity is associated with protection against Yersinia pestis infection ( Chapter 288 ). With genetic testing, familial Mediterranean fever is now frequently recognized in both Ashkenazi (eastern European) and non-Ashkenazi Jewish populations, as well as in Mediterranean populations previously thought not to be at risk. Mutation-positive individuals with typical symptoms have been documented worldwide.
Pathobiology
MEFV, which is the gene mutated in familial Mediterranean fever, encodes a 781–amino acid protein denoted pyrin (or marenostrin) that is expressed in granulocytes, monocytes, and dendritic cells, as well as in peritoneal, synovial, and dermal fibroblasts. The N-terminal 92 amino acids of pyrin are the prototype for a motif, the PYRIN domain, that is involved in cognate interactions between proteins; this domain defines a family of more than 20 human proteins, including pyrin itself, that are involved in the regulation of cytokine production (particularly the IL-1 family), NF-κB activation, and cell death. Most of the pathogenic familial Mediterranean fever–associated mutations in pyrin reside in the C-terminal domain encoded by exon 10 of MEFV . An even larger number of variants of unknown significance have been described in individual patients with a spectrum of inflammatory phenotypes, and some patients with clinical presentations similar to that of familial Mediterranean fever have been found to have pyrin mutations on only one allele. The assembly of pyrin-containing inflammasomes is activated by bacterial toxins that inactivate the GTPase RhoA, including toxins derived from Clostridia, Yersinia, and Vibrio species. RhoA inactivates pyrin by inducing phosphorylation of pyrin on N-terminal serine residues, which leads to sequestration of pyrin by 14-3-3 proteins and inhibition of pyrin’s ability to promote processing of the cytokine IL-1β. Familial Mediterranean fever–associated mutations in MEFV render pyrin resistant to RhoA-mediated inactivation, thereby providing a mechanism for the heightened secretion of IL-1β by cells harboring familial Mediterranean fever–associated pyrin mutations. These mutations also confer resistance to an important virulence factor produced by Yersinia pestis (the agent of plague in humans). Additional evidence for the importance of pyrin phosphorylation in the regulation of IL-1β production is that mutations in one of the phosphorylation sites of pyrin are associated with a severe early-onset syndrome of autoinflammation and neutrophilic dermatosis (PAAND).
As a consequence of its ability to depolymerize microtubules, colchicine activates RhoA, probably through the release of the RhoA guanine-nucleotide-exchange factor GEF-H1 from microtubules. Activated RhoA leads to increased phosphorylation of pyrin, thereby inactivating its pro-inflammatory function, even in cells harboring familial Mediterranean fever–associated pyrin mutations. Microtubule inhibitors also block pyrin inflammasome assembly in a phosphorylation-independent fashion.
Clinical Manifestations
Familial Mediterranean fever usually manifests in childhood, sometimes even in infancy, although approximately 10% of patients experience their first attack as adults. Infrequently, symptoms first appear in persons older than age 40 years.
Episodes of familial Mediterranean fever are more properly termed recurrent rather than periodic, and some patients associate attacks with psychological stress or physical exertion. Women of childbearing age sometimes experience their attacks with menses, with remissions during pregnancy. Some patients are unaware of fever during the attacks, but fever is almost always observed when sought. Serosal involvement is usually peritoneal or pleural. Abdominal attacks are the most frequent, and they may vary from mild discomfort to frank peritonitis, with boardlike rigidity, direct and rebound tenderness, and air-fluid levels on upright films of the abdomen. Regardless of the severity of the abdominal attack, constipation is much more common than diarrhea. If a laparotomy or laparoscopy is performed during an attack, a small amount of sterile exudate rich in polymorphonuclear leukocytes may be found. Except for serosal inflammation, the appendix is normal. Repeated abdominal attacks may cause peritoneal adhesions, but ascites is rare. Pleurisy, usually unilateral, may accompany abdominal pain, or it may occur independently. Physical findings, if present, may include diminished breath sounds and a pleural friction rub, whereas chest radiograms may show a small effusion or atelectasis. With multiple attacks, pleural thickening may develop. Symptomatic nonuremic pericardial involvement has been reported but is unusual.
In adults, the arthritis of familial Mediterranean fever typically manifests as monoarticular involvement of the knee, hip, or ankle, and attacks of arthritis may persist for up to 1 week at a time. In children, oligoarticular or polyarticular joint involvement may occur. Large joint effusions are sometimes present, and the synovial fluid may have as many as 100,000 leukocytes/μL. In approximately 5% of patients who are not treated with prophylactic colchicine, chronic arthritis (usually of the hip or knee) may develop, often necessitating joint replacement surgery. Regardless of colchicine treatment or a particular human leukocyte antigen (HLA-B27) status, some patients with familial Mediterranean fever develop sacroiliitis. Arthralgia without frank arthritis is common in familial Mediterranean fever. The MEFV M694V mutation is a risk factor for both ankylosing spondylitis ( Chapter 244 ) and Behçet disease ( Chapter 249 ).
Cutaneous manifestations of familial Mediterranean fever tend to be less common than serosal or synovial involvement. The characteristic skin lesion is erysipeloid erythema, which is a painful, demarcated erythematous area most often seen on the lower leg, ankle, or dorsum of the foot. This rash may occur independently, or it may accompany an episode of arthritis. Histologically, a mixed perivascular cellular infiltrate is seen. Other acute manifestations of familial Mediterranean fever include unilateral scrotal inflammation (the tunica vaginalis is an embryologic remnant of the peritoneal membrane) and myalgia, either with fever or, especially in children, without fever and induced by vigorous exercise. Henoch-Schönlein purpura may occur in children with familial Mediterranean fever, and polyarteritis nodosa is less frequently seen ( Chapter 249 ).
Diagnosis
Based on a simple recessive model of inheritance, two mutations in MEFV, in trans, should be identified to establish the genetic diagnosis of familial Mediterranean fever. Nevertheless, the interpretation of genetic testing is complicated by complex alleles that consist of various combinations of mutations in cis, as well as by the observations that as many as one third of patients with clinically typical familial Mediterranean fever have only one demonstrable mutation in MEFV, and a few patients with typical disease have no identifiable MEFV mutations. These latter two findings suggest that, under some circumstances, one MEFV mutation may be sufficient for symptoms or that additional disease-causing genes exist.
For these reasons, clinical data remain an essential part of the diagnosis of familial Mediterranean fever, and genetic testing plays an adjunctive role in settings in which clinical experience is limited. Clinical criteria emphasize the duration of the attack (12 to 72 hours); recurrence of symptoms (three or more episodes); documented fever (rectal temperature >38° C); painful manifestations in the abdomen, chest, joints, or skin; and the absence of other causative factors. The differential diagnosis includes the other hereditary recurrent fever syndromes ( Table 240-2 ), as well as other conditions specific to the clinical setting. For patients with recurrent abdominal pain, considerations include gynecologic disorders, porphyria ( Chapter 194 ; which can be distinguished by hypertension during attacks, dominant inheritance, and urine porphyrins), and hereditary angioedema ( Chapter 232 ; which usually does not cause fever). The syndrome of periodic fever with aphthous stomatitis, pharyngitis, and cervical adenopathy is probably the most common cause of unexplained recurrent fever in children and is also included in the differential diagnosis. In patients who present primarily with recurrent monoarthritis, joint aspiration for cultures and crystals may aid in excluding bacterial and crystalline arthritis.
TABLE 240-2
CLINICAL CHARACTERISTICS OF SELECTED AUTOINFLAMMATORY DISEASES
| CLINICAL FEATURE | FAMILIAL MEDITERRANEAN FEVER (FMF) | TUMOR NECROSIS FACTOR RECEPTOR–ASSOCIATED PERIODIC SYNDROME (TRAPS) | HYPERIMMUNOGLOBULINEMIA D WITH PERIODIC FEVER SYNDROME (HIDS) | FAMILIAL COLD AUTOINFLAMMATORY SYNDROME/MUCKLE-WELLS SYNDROME/NEONATAL-ONSET MULTISYSTEM INFLAMMATORY DISEASE (FCAS/MWS/NOMID) | DEFICIENCY OF ADENOSINE DEAMINASE-2 (DADA2) |
|---|---|---|---|---|---|
| Typical ethnicity | Arab, Armenian, Italian, Jewish, Turkish | Any ethnicity | Dutch, other North European | European | Georgian Jewish origin for PAN-like disease |
| Age of onset | Childhood or adult | Childhood or adult | Early childhood, especially tied to immunizations | Childhood or adult (FCAS) Childhood (MWS) Infancy (NOMID) |
Usually childhood |
| Attack duration | 12-72 hr | Days to weeks | 3-7 days | 12-24 hr (FCAS) 1-2 days (MWS) Continuous, with flares (NOMID) |
Occasional fevers Can have long asymptomatic periods |
| Abdominal involvement | Sterile peritonitis, constipation > diarrhea | Severe pain, vomiting, peritonitis | Sterile peritonitis, diarrhea, rarely constipation | Nausea (FCAS) Abdominal pain (MWS) Uncommon (NOMID) |
Can be seen associated with abdominal vasculitis and infarctions, portal hypertension |
| Pleural attacks | Common | Common | Rare | Rare (MWS, NOMID) | Rare |
| Joint/bone involvement | Monoarthritis, rarely protracted arthritis in knee or hip | Arthritis in large joints, arthralgia | Arthralgia, symmetrical polyarthritis | Polyarthralgia (FCAS, MWS) Oligoarthritis (MWS) Clubbing (MWS, NOMID) Epiphyseal overgrowth, contractures, intermittent or chronic arthritis (NOMID) |
Uncommon |
| Skin rash | Erysipeloid erythema on lower leg, ankle, foot | Migratory rash, underlying myalgia | Diffuse maculopapular rash, urticaria | Urticaria-like rash (cold-induced in FCAS) | Livedo reticularis, cutaneous vasculitis, scarring lesions, and necrosis can occur |
| Hematologic | Splenomegaly, occasional lymphadenopathy | Splenomegaly, occasional lymphadenopathy | Cervical adenopathy in children | Hepatosplenomegaly, adenopathy (NOMID, rare in MWS) | Cytopenias including pure red-cell aplasia, hypo-Ig, hepatosplenomegaly |
| Neurologic involvement | Aseptic meningitis? | Controversial | Headache | Headache (FCAS) Sensorineural deafness (MWS, NOMID) Chronic aseptic meningitis, intellectual disability (NOMID) |
Recurrent ischemic strokes |
| Ophthalmologic involvement | Rare | Conjunctivitis, periorbital edema, rarely uveitis | Uncommon | Conjunctivitis (all) Uveitis (MWS, NOMID) Progressive vision loss (NOMID) |
Retinal artery occlusion |
| Vasculitis | Henoch-Schönlein purpura (HSP), polyarteritis nodosa | HSP, lymphocytic vasculitis | Cutaneous vasculitis common, rarely HSP | Not seen (FCAS, MWS) Occasional in NOMID |
Small and medium vessels, can present as polyarteritis nodosa |
| Systemic amyloidosis | Risk depends on MEFV and SAA genotypes; more common in Middle East | Occurs in ≈10%; risk increased with cysteine mutations | Uncommon, associated with V377I/I268T genotype | Rare (FCAS) 25% (MWS) May develop in adulthood (NOMID) |
Can occasionally develop |
| Autoantibodies | Not usually seen | Not usually seen | Not usually seen | Not usually seen | ANCA usually negative |
| Effective treatments | Colchicine, IL-1 blockade | IL-1 blockade | IL-1 blockade | IL-1 blockade | TNF blockade, hematopoietic stem cell transplant for severe cytopenias |
ANCA = antineutrophil cytoplasmic antibody; IL = interleukin; TNF = tumor necrosis factor.
Still disease in children (systemic-onset juvenile idiopathic arthritis) and adults (adult-onset Still disease) is also considered in the differential diagnosis. Adult-onset Still disease (see Table 240-1 ) is an uncommon autoinflammatory condition of unknown cause that is not considered to be hereditary. It is characterized by spiking fever, an evanescent salmon-pink maculopapular rash, arthritis, and neutrophilic leukocytosis. It can be clinically distinguished from familial Mediterranean fever by the pattern of fever (intermittent quotidian in Still disease as compared with discrete episodes in familial Mediterranean fever), the pattern of arthritis (chronic polyarthritis vs. intermittent monoarthritis), the characteristic skin involvement (evanescent rash vs. erysipeloid erythema), and the presence of lymphadenopathy (more common in Still disease).
Treatment
The mainstay of therapy is daily oral colchicine, which can prevent both acute attacks and the development of systemic amyloidosis. In adults, the therapeutic dose is 1.2 to 1.8 mg/day, and nearly 90% of patients note significant improvement at this dose. The major side effects are gastrointestinal, and they usually can be minimized by gradually increasing the dosage and avoiding milk products in patients who develop lactose intolerance. Most experts continue to prescribe colchicine to patients during pregnancy, with the recommendation that amniocentesis be performed to exclude trisomy 21, for which the risk may be slightly increased. Use of colchicine in lactating women is considered safe. Intravenous colchicine should be used with extreme caution, if at all, because fatal toxicity has been reported in patients who are already receiving oral colchicine.
In adult patients who are poorly responsive to colchicine or who cannot tolerate therapeutic doses, canakinumab, a recombinant human anti–human-IL-1β antibody (starting at 150 mg subcutaneously and increasing to 300 mg if needed), is usually safe and effective in preventing flares. ,
Prognosis
Effective control of flares with colchicine and/or IL-1 inhibition prevents the development of secondary amyloidosis and appears to result in a normal life expectancy. Before the widespread use of colchicine prophylaxis, however, systemic AA amyloidosis ( Chapter 174 ) was a frequent complication of familial Mediterranean fever, because of the ectopic deposition of a misfolded fragment of serum amyloid A, which is an acute phase reactant, in the gastrointestinal tract, kidneys, spleen, lung, testes, and adrenals. Malabsorption and nephrotic proteinuria leading to renal failure are the most common manifestations of AA amyloidosis. Cardiomyopathy is less common, and neuropathy and arthropathy are rare. Risk factors for amyloidosis include late diagnosis of familial Mediterranean fever, noncompliance with colchicine, male sex, and specific genotypes of the MEFV and SAA genes. Amyloidosis is less common with familial Mediterranean fever in the United States than in the Middle East. The diagnosis of amyloidosis in familial Mediterranean fever is best made by rectal or renal biopsy. With early diagnosis, aggressive suppression of the acute phase response with colchicine or IL-1 inhibitors may lead to improvement. For patients with renal failure, however, early renal transplantation is preferred.
Hyperimmunoglobulinemia D with Periodic Fever Syndrome (Mevalonate Kinase Deficiency)
Hyperimmunoglobulinemia D with periodic fever syndrome (HIDS) was first described in six patients of Dutch ancestry who had extremely high levels of immunoglobulin D (IgD) in their serum. Hyperimmunoglobulinemia D, though quite rare, is now recognized in a broader ethnic distribution, although northern Europeans still predominate. The elevated IgD levels appear to be an epiphenomenon and do not correlate with the severity of disease, either among patients or in a given patient over time. Because modestly increased IgD levels can be seen in other inflammatory conditions and up to 20% of patients (particularly young children) with typical recurrent fevers and MVK mutations can have normal serum IgD levels, IgD levels alone are an unreliable diagnostic tool. Consequently, some experts prefer the term mevalonate kinase deficiency (MKD) to denote this illness.
This autosomal recessive disease is caused by mutations in MVK, which encodes the mevalonate kinase enzyme involved in the biosynthesis of cholesterol and nonsterol isoprenes. Enzymatic activity in patients is markedly reduced but not absent. The isoprenoid deficiency resulting from MVK mutations is thought to be the basis for the clinical manifestations. Reduced prenylation inactivates the GTPase RhoA, thereby abrogating its negative regulation of the pyrin inflammasome and resulting in increased production of IL-1β. IL-1β and increased body temperature can further decrease mevalonate kinase enzymatic activity, thereby creating a vicious circle in which infection or immunization can precipitate clinical attacks.
Clinical Manifestations
One of the well-recognized clinical characteristics of hyperimmunoglobulinemia D is the provocation of attacks by immunizations. Other distinguishing clinical features include a very early age of onset (average age, 6 months), a 3- to 7-day duration of attacks (intermediate between familial Mediterranean fever and tumor necrosis factor [TNF] receptor-associated periodic syndrome), prominent cervical lymphadenopathy during attacks, polyarticular joint involvement, a diffuse maculopapular rash, the predominance of diarrhea over constipation with abdominal attacks, and the infrequency of pleuritic attacks or systemic amyloidosis.
The diagnosis can be established in a patient with recurrent episodes of fever and typical associated findings by documenting either two mutations in MVK or elevated levels of mevalonic acid, the substrate for mevalonate kinase, in the urine during attacks. Approximately 10% of patients with otherwise typical disease have only a single identifiable MVK mutation.
You're Reading a Preview
Become a Clinical Tree membership for Full access and enjoy Unlimited articles
If you are a member. Log in here