Classical Autoinflammatory Disorder Definition.

The autoinflammatory disorders are a group of diseases that, in their purest forms, manifest as recurrent fevers, high acute phase responses and a proclivity for inflammation of skin, joints, serosal surfaces and other organ involvement including the nervous system. These disorders lack the classical characteristics of autoimmune diseases such as high-titer autoantibodies. The innate immune system plays the primary pathophysiologic role in autoinflammatory diseases and in fact, these diseases are synonymous with dysregulation of the cells and molecular cascades intrinsic to innate immunity. Had this been appreciated at the outset these diseases could well have been designated as “innate autoimmunity” in contradistinction to “adaptive autoimmunity”.

A wider spectrum of autoinflammation

It is recognized that the pure monogenic autoinflammatory disorders sit at the diametric opposite of the spectrum from monogenic autoimmune disorders and that the full spectrum of inflammation against self sits along an immunological disease continuum (McGonagle & McDermott). Therefore, many common inflammatory disorders including Crohns disease, Behcet’s disease, psoriasis, psoriatic arthritis and ankylosing spondylitis (AS) may have a strong innate immunopathology or autoinflammatory component. These monogenic and polygenic disorders do share the commonality of good or dramatic responses to various cytokine blockade strategies.

Somatic mutations and autoinflammation

Historically, the autoinflammatory conditions were defined by the strong family histories and characteristic clinical features with disease onset often in childhood. More recently, sporadic cases of autoinflammatory diseases with identical clinical features but negative genetic testing have been recognized in adults. These cases respond dramatically to therapy and may be linked to somatic mutations in cells of the myeloid lineage.

In the last two decades, great advances in understanding innate immunologic pathways and discoveries of genes involved in human autoinflammatory diseases have proceeded significantly.

Interestingly, since the identification of autoinflammation diseases, close to 20 years ago, a constant increase of new monogenic autoinflammation diseases has been observed. The increment of the amount of these diseases is attributed to both, a better understanding and significant advances in genomic techniques as well. This section gives a flavour of the “classical” autoinflammatory disorders.

Deficiency of the IL-1 receptor antagonist (DIRA)

DIRA is an autosomal recessive disorder due to a loss of function mutation in the gene encoding cytokine antagonist, IL1RN, leading to unchecked IL-1β and IL-1α activity. Patients present at birth or within the first few weeks of life with fetal distress, a pustular skin rash, joint swelling, malaise, oral vesicles or ulceration, pain with movement, and elevated inflammatory markers.

Skin lesions can range from discrete pustules to generalized pustulosis and ichthyosiform lesions. Nail changes may also be present including pitting and onychomadesis. Multifocal sterile osteomyelitis, periostitis, and widening of the anterior rib ends and clavicles are also classic. Long bone epiphyseal bony overgrowth may be present, similar to that seen in NOMID.

Interestingly, fever is usually not present. Vasculitis and a predisposition to thrombosis have also been described. Patients respond dramatically to IL-1 inhibition and a lack of response is a clue for an alternate diagnosis. DIRA is a very rare disorder. In Puerto Rico, the carrier rate for deletions in IL1RN is 1.3%, however a lower carrier rate would be expected in areas with no relation to the founder population.

DIRA was first discovered as atypical CAPS, given the skin lesions, elevated inflammatory markers and impressive response to IL-1 blockade. It may also be confused with pustular psoriasis or other pustuloses, infectious osteomyelitis, chronic recurrent multifocal osteomyelitis (CRMO) and DITRA. Notably, patients do not have CNS or ear findings that may be present in CAPS, and the skin lesions are pustular rather than urticaria-like.

DIRA is characterized by unopposed IL-1ß signaling with laboratory abnormalities being a consequence of IL-1 production and result in inflammation. APRs including the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and serum amyloid A (SAA) are elevated. Notably, SAA is not commercially available, however, may be measured in a research setting.

Peripheral white blood cell (WBC) counts may be elevated with a neutrophilic predominance and ferritin may also be increased as markers of acute inflammation. Unlike NOMID, CSF should not show evidence of pleocytosis. Genetic testing for deletions of ILRN is available in the research setting only. Referral to, or collaboration with, a subspecialty center with experience in the management of these disorders may be necessary for confirmation of a genetic diagnosis.

Multifocal sterile osteomyelitis, periostitis and widening of the anterior rib ends and clavicles may be visualized on plain films in DIRA. Bone MRI may be more sensitive in visualizing these lesions. A skeletal survey with possible bone scan is indicated to evaluate for lesions in suspected cases. In skin biopsy, epidermal changes in DIRA are characterized by the presence of intra-epidermal neutrophils and neutrophilic pustules with marked papillary dermal edema.

As the IL-1 receptor antagonist has been deleted, patients are usually treated with anakinra, the recombinant IL-1 receptor antagonist. The other two commercially available IL-1 antagonists, canakinumab and rilonacept have also been implicated and found to be effective. Most patients have a rapid and complete clinical response, with resolution of fevers, skin findings, bone lesions and elevated acute phase reactants. Patients may require doses of medication that are higher than those FDA-approved for rheumatoid arthritis, similar to doses necessary in NOMID. A smaller subset of patients do not show a complete response. This may be due to the fact that deletions often involve larger segments of the genome including areas beyond the IL-1 receptor antagonist. The impact of long-term therapy is yet to be determined.

Deficiency of IL-36R antagonist (DITRA)

IL-36 is a member of the IL-1 cytokine superfamily. DITRA is an autosomal recessive disorder due to the genetic deletion of IL36RN, the gene encoding the IL-36 receptor antagonist. IL-36 has proinflammatory effects in keratinocytes78; loss of the IL-36-receptor antagonist potentiates IL-36-mediated inflammation in keratinocytes. DITRA was firstly described in subjects with severe pustular psoriasis and fever. Patients also present with malaise and elevated inflammatory markers. The IL-36 subfamily consists of three ligands-IL-36α, IL-36β, and IL-36γ-and the natural antagonist IL-36Ra. These cytokines are expressed predominantly by epithelial cells and act on a number of cells including immune cells, epithelial cells, and fibroblasts.

The age of onset is variable with some patients presenting within a week of life and others in adulthood. In contrast to DIRA, bone involvement has not been reported. DITRA is a very rare disorder, with the exact prevalence unknown. Mutations of IL36RN differ among different ethnicities leading to various clinical features of pustular psoriasis. Homozygous or compound heterozygous IL36RN gene mutations are the cause of different clinical features of psoriasis including generalized pustular psoriasis, palmoplantar pustular psoriasis, acrodermatitis continua Hallopeau and acute generalized exanthematous pustular eruption.

The differential diagnosis for DITRA includes pustular psoriasis, other pustuloses, and DIRA. Clues to the diagnosis include an earlier age of onset than classic pustular psoriasis and a lack of bone findings that may be present in DIRA. Genetic testing for deletions of ILRN is available in the research setting only.

Histologically, DITRA is characterized by intra-epidermal neutrophilic spongiform pustules, acanthosis with elongation of rete ridges, and parakeratosis in the stratum corneum. In contrast to DIRA, it is not directly IL-1 mediated and therefore IL-1 inhibitors may not be efficacious. The ideal therapy would be to target IL-36 or a downstream pathway. However, these pathways are yet to be fully understood and clinical confirmation is needed. Given the lack of IL-36 inhibitors, patients should be managed similarly to other patients with pustular psoriasis, with the understanding that they may be more resistant to conventional therapies. As no effective therapies have been described for DITRA, it is anticipated that patients will have persistent skin and systemic inflammatory disease. Whether uncontrolled inflammation in DITRA leads to organ damage, including amyloidosis, remains to be determined. However, this was not observed in the initial cohort of patients.

TNF receptor associated periodic syndrome (TRAPS)

Formerly known as familial Hibernian fever, TRAPS is due to autosomal dominant mutations in TNFRSF1A, the gene encoding the TNF receptor, affecting cysteine residues in the extracellular portion of the receptor that are important for protein folding. However, the pathogenesis of TRAPS remains unclear. The age of first presentation is variable, ranging from 3 years to adulthood. Patients present with fevers, severe myalgia, a characteristic rash, periorbital edema, serositis (peritonitis and pleuritis), arthritis, eye involvement and elevated APRs.

Rashes appear as migratory, centrifugal erythematous patches. Macules and generalized erythema may also be present. The skin is often warm and tender. The lesions typically start peripherally and migrate to more central locations on the body. The arthritis is nonerosive and often monoarticular, affecting large joints including hips, knees, or ankles. Tenosynovitis may also be present.

Conjunctivitis is common. However, more severe ocular manifestations including uveitis and iritis may also be present. Peritonitis is present in 90% of patients and may be severe enough to mimic an acute abdomen, resulting in an exploratory laparotomy.

Adhesions and inflammation may be present. Fever and myalgia are often the first signs of a flare. Attacks tend to be longer lasting than other fever syndromes, with a typical length of 21 days and occurring every 5-6 weeks, although considerable variability exists.

TRAPS is often confused with other autoinflammatory diseases including familiar Mediterranean fever (FMF) and hyperimmunoglobulinemia D with periodic fever syndrome (HIDS). The longer duration of flares (21 days) and associated myalgia and ocular edema may be clues to the correct diagnosis. It may also be confused with systemic-onset juvenile idiopathic arthritis (SoJIA), adult-onset Still’s disease (AOSD), or chronic infections.

APRs including ESR, CRP and SAA are elevated during flares and may remain elevated between flares. Peripheral WBC counts may be elevated with a neutrophilic predominance, and ferritin may also be increased as markers of acute inflammation. Many patients have a polyclonal gammopathy.

Genetic testing for mutations in TNFRSF1A is available and the presence of a single mutation confirms the genetic diagnosis as this disorder is autosomally dominant. Phenotype genotype associations show that patients with cysteine substitutions have a more severe disease course with a higher risk of secondary amyloidosis. Patients with TRAPS do not typically show erosions on joint radiographs. MRI may reveal intramuscular and septal oedema during flares. Synovial and tenosynovial enhancement may also be present. Although infrequently performed, skin biopsies may show mixed lymphocytic and monocytic perivascular and interstitial infiltrate.

Patients with mild attacks may be treated with nonsteroidal anti-inflammatory medications. Corticosteroids may alleviate symptoms, however, are not ideal for long-term management and the dosage requirement may increase with time. Given that TRAPS is TNF-mediated, TNF inhibitors are widely used. Etanercept is more efficacious than infliximab and indeed the latter can be dangerous and precipitate attacks. The reason for this is unclear, however, may be due to binding of monoclonal antibodies to the mutated receptor paradoxically, leading to increased signaling through the receptor. Interestingly, many patients with TRAPS show an inadequate response to TNF blockade. Increasing evidence shows that the mutated receptor may become misfolded and sequestered in the endoplasmic reticulum, resulting in inflammatory signals that may be augmented by the normal receptor. In this case, TNF inhibitors may be only partially effective. Anakinra is typically the next line therapy and has been effective in TRAPS. Another IL-1 antagonist, canakinumab produced a rapid clinical and serological benefit which was maintained with continued monthly dosing. Case reports also exist for effective treatment with tocilizumab, the IL-6 monoclonal blocking antibody.

The response to therapy is variable and therefore, some patients have chronic relapsing disease. Similarly to FMF, the most feared complication is amyloidosis, particularly renal amyloidosis, which may lead to death. Patients should be closely monitored for the development of proteinuria as a sign of kidney involvement secondary to amylodosis.

Pyogenic arthritis, pyoderma gangrenosum, and acne syndrome (PAPA)

PAPA is due to autosomal dominant mutations in CD2BP1, the gene encoding proline-serine-threonine-phosphate-interacting protein 1 (PSTPIP1), an adaptor protein that interacts with pyrin. Mutations in PSTPIP1 lead to increased pyrin binding and resultant activation of the NLRP3 inflammasome through decreased pyrin binding, leading to increased levels of IL-1β.

Patients typically present in the first decade of life however may present in adulthood. Clinical manifestations include pyoderma gangrenosum (PG), cystic scarring acne, and pyogenic sterile arthritis. Arthritis and PG lesions may occur after minor trauma. PG typically occurs on the legs and is characterized by poor healing and rolled edges. Arthritis may be severe, leading to joint erosion, destruction and deformities.

PAPA is a very rare disorder. However, its differential diagnosis includes idiopathic PG, as well as PG secondary to other etiologies including inflammatory bowel disease or malignancy. Other neutrophilic dermatoses should be considered including Sweet’s syndrome (a pathologic diagnosis) and infectious causes of abscesses.

The APR including ESR, CRP and SAA are elevated during flares and may remain elevated between flares. Peripheral WBC counts may be elevated with a neutrophilic predominance and ferritin may also be increased as markers of acute inflammation. Skin and joint fluid cultures should be sterile unless a superinfection is present.

Genetic testing for mutations in CD2BP1 is commercially available. The presence of a single mutation confirms the genetic diagnosis as this disorder is autosomally dominant. Phenotype genotype associations show that patients with cysteine substitutions have a more severe disease course with a higher risk of secondary amyloidosis. Joint radiographs may be normal or may show erosions and deformities in patients with PAPA. Biopsies are not typically performed due to concern for exacerbating the underlying condition. PG biopsies show neutrophilic inflammation of the dermis with superficial ulceration. Acne biopsies show burrowing and interconnecting abscesses and scars.

The treatment of PG in PAPA can be very difficult, requiring multiple high dose immunosuppressants. Corticosteroids may be helpful in some cases, however, high doses are often required and this is not ideal long term. Patients may show only a partial response to immunosuppressives. Unlike some other autoinflammatory syndromes, patients do not respond to colchicine. Case reports exist for successful treatment with anakinra and etanercept, however, long term or controlled studies are lacking. The efficacy and safety of combinations of immunosuppressives and biologics in resistant disease remains to be reported.

The natural history of PAPA is quite variable with some patients developing minor flares and others with a more chronic, severe course. It is often difficult to treat PG and cystic acne lesions with patients developing disfiguring, scarring skin disease. Arthritis can be destructive leading to joint deformities. A single case report exists for renal amyloidosis in PAPA, with the exact risk of developing this complication unknown.

Hyperimmunoglobulinemia D with periodic fever syndrome (HIDS)

HIDS is due to autosomal recessive mutations in MVK, the gene encoding mevalonate kinase, an enzyme involved in cholesterol synthesis, and has also been linked to pyrin-inflammasome activation. The resulting deficiency in mevalonate kinase leads to induction of IL-1β pro-inflammatory cytokine.

Patients present within the first few weeks to decade of life. Clinical manifestations include fevers, malaise, chills, rashes and headache. Lymphadenopathy is common and occurs in about 90% of patients. Episodes last 3-7 days and occur once or twice per month. Gastrointestinal symptoms are common including abdominal pain, diarrhea and vomiting.

Peritonitis is present in 90% of patients and may be severe enough to mimic an acute abdomen, resulting in an exploratory laparotomy. Adhesions and inflammation may be present. An (erosive /nonerosive) arthritis is observed in over 80% of patients and may affect large joints as well as smaller joints including metacarpophalangeal and proximal interphalangeal joints.

While a rash is common, its presentation is variable in nature including erythematous macules, papules, nodules, petechiae and purpura. Oral and/or genital ulcers may be present. Mevalonate aciduria can exist in the event of a complete lack of enzyme activity. This presents with the findings of HIDS in addition to failure to thrive, developmental delay, hepatosplenomegaly, and cataracts. HIDS is a very rare disorder. Approximately 50% of patients have a Dutch ancestry.

HIDS may be a difficult diagnosis to make with a median delay to diagnosis of 9.9 years. It may be confused with FMF or TRAPS. The presence of lymphadenopathy can be a helpful clue and the lack of a response to colchicine helps differentiate HIDS from FMF. Other differential diagnoses include SoJIA, AOSD, Behcet’s disease when mucocutaneous ulceration is present, and chronic infections.

The APRs including ESR, CRP and SAA are elevated during flares and may remain elevated between flares. Peripheral WBC counts may be elevated with a neutrophilic predominance and ferritin may also be increased as markers of acute inflammation. IgD (and often IgA) levels are elevated in the majority of patients. However, it is important to note that this is not specific for the diagnosis of HIDS and some patients with this disorder will have normal IgD levels.

Genetic testing for mutations in MVK is commercially available and patients should have two mutations as this disorder is autosomal recessive.

Skin biopsies may show a perivascular mixed neutrophilic and lymphocytic infiltrate with fibrinoid vessel wall changes consistent with a leukocytoclastic vasculitis. IgD and C3 granular perivascular deposits may be observed on direct immunofluorescence. Sweet syndrome, cellulitic changes and deep vasculitis may also be observed.

Patients with mild disease may respond to nonsteroidal anti-inflammatory medications and intermittent steroids. Unlike some other autoinflammatory syndromes, patients do not respond to colchicine. TNF inhibitors and anakinra may be helpful in some patients. Anakinra may be effective on an intermittent basis in decreasing the length of febrile episodes and may also prevent flares occurring after vaccinations. Given the involvement of mevalonate kinase in cholesterol synthesis, statins have been studied, however, whether they are effective remains unclear as patients showed only a nonsignificant reduction in the number of febrile days. A successful allogeneic bone marrow transplant was performed in a patient with severely affected mevalonate aciduria resulting in complete remission.

Patients may have variably relapsing and remitting disease. Abdominal adhesions may occur in the setting of peritonitis. Amyloidosis is quite rare but has been reported. Clinical symptoms may improve with age.

Pediatric granulomatous arthritis (PGA)

Also known as Blau syndrome, PGA is due to autosomal dominant genetic mutations in NOD2, encoding a protein belonging to a group of intracellular sensing proteins composed of NACHT-leucine-rich repeat (LRR) receptors. Patients present in childhood with granulomatous arthritis, uveitis and dermatitis. Arthritis is symmetric, polyarticular and described as “boggy”, with many patients also developing tenosynovitis.

Ocular findings can include bilateral uveitis, conjunctivitis, cataracts and glaucoma. The rash is pink, red or tan, with a scaly ichthyosiform character. Fevers, lymphadenopathy, and hepatosplenomegaly may be present.

PGA may be confused with sarcoidosis when non-caseating granulomas are observed on biopsy. The typical lack of lung findings and earlier age at presentation are clues to the correct diagnosis. Other diagnoses to consider include oligoarticular JIA and chronic granulomatous infections.

Patients may have elevations of APRs, WBC and/or thrombocytosis as a result of chronic inflammation.

Genetic testing for mutations in NOD2 should be performed in the research setting. Referral to, or collaboration with a subspecialty center with experience in the management of these disorders may be necessary for confirmation of a genetic diagnosis. As PGA is autosomal dominant, only one mutation is necessary to confirm the genetic diagnosis.

Imaging is not a routine aspect of clinical care and should be conducted in response to patient symptoms. Arthritis is not typically erosive. In contrast to adult pattern sarcoidosis, patients with PGA do not usually have lung findings. However, interstitial lung disease has been reported.

Skin biopsies show non-caseating granulomas and are indistinguishable from sarcoidosis. Granulomas are composed of multinucleated histiocytes mixed with scattered inflammatory cells.

PGA has no effective treatment beyond corticosteroids. Biologics, including TNF and IL-1 inhibitors have been tried, but results have been disappointing, with no consistent efficacy demonstrated. No therapeutic clinical trials have been performed in this group of patients because, in part, of the rarity of the disorder.

As many patients respond poorly to therapy, clinical manifestations can be chronic and persistent. Particularly worrisome is the chronic eye disease observed in many patients. The majority of patients have bilateral disease with some degree of posterior involvement. Visual impairment is common and occurs in almost half of patients with eye disease. Arthritis and skin disease may also be chronic in nature, although arthritis rarely leads to joint destruction.

Pyrin associated autoinflammation with neutrophilic dermatosis (PAAND)

This form of an inflammatory disease is due to mutations in the MEFV gene (that codes for pyrin) which is also associated FMF, leading to high serum IL-1β levels during febrile episodes. Unlike FMF, it is an inherited autosomal-dominant gene mutation disease and clinically presents during childhood with longer fever episodes (several weeks).

The PAAND is characterized by sterile skin abscesses, long episodes of high fever, myalgia, myositis, fatigue and unlike FMF it is not characterized by serositis or amyloidosis. Clinical cutaneous manifestations evoked a closer resemblance to PAPA (pyogenic arthritis, pyoderma gangrenosum, and acne), with a lack of pyogenic arthritis. Elevated APRs and anemia are normally present among these patients. Muscle biopsy from this patient indicated inflammatory infiltrate mainly composed of macrophages. Limited data on interleukin-1 pathway as an therapy has been furnished.

Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE)

CANDLE (also known as joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced childhood-onset lipodystrophy (JMP) syndrome), is an autosomal recessive disorder due to mutations in PSMB8, the gene encoding the proteasome subunit ß type 8, a component of the immunoproteasome. The result is an accumulation of ubiquitinated proteins in the cytoplasm, ultimately leading to high levels of interferon-induced genes, considered now as targets of therapeutic trials of JAK inhibitors.

Most patients present within the first few weeks of life and all by one year of age. It is characterized by onset during the first year of life, recurrent fevers, purpuric skin lesions, violaceous swollen eyelids, arthralgias, progressive lipodystrophy, hypochromic or normocytic anemia, delayed physical development, and increased levels of acute-phase reactants.

Other clinical features include hypertrichosis, acanthosis nigricans, and alopecia areata. Patients with JMP syndrome have the same mutation but also have joint contractures and muscle atrophy. Mental retardation occurred in some patients. However, these patients were not reported to have fevers or consistently elevated inflammatory markers. Given the shared genetic mutation, these may be members of the same disease spectrum.

CANDLE and JMP are very rare disorders with the exact prevalence unknown. Due to the early-onset systemic inflammation, CANDLE may be confused with a neonatal infection, NOMID or DIRA. SoJIA is also a consideration, however, it does not usually present within the first weeks of life. In an older child, myositis, chronic infections or genetic lipodystrophy may be considered.

APRs and WBC counts are elevated frequently in association with anemia and thrombocytosis due to chronic inflammation. Triglycerides are usually elevated and may be a clue to the etiology of lipodystrophy. Aseptic meningitis and abnormal liver function tests may be present. Unlike other autoinflammatory diseases, antinuclear antibodies (ANA) and antineutrophil cytoplasmic antibodies (ANCAs) may be elevated.

Genetic testing for mutations in PSMB8 is available in the research setting only. Referral to, or collaboration with a subspecialty center with experience in the management of these disorders may be necessary for confirmation of a genetic diagnosis. CANDLE is autosomal recessive, however in some cases, only a single mutation has been detected.

Imaging should be conducted as relevant to an individual patient’s symptoms. MRI can show synovial enhancement in the setting of arthritis. Fat enhancement but not muscle enhancement, indicating panniculitis, may be observed.

Skin biopsies show a characteristic interstitial infiltrate of mononuclear cells with nuclear atypia and both mature and immature neutrophils, with areas of karyorrhexis.

CANDLE was only recently described and no therapeutic trials or series have been reported. Patients in the one series had a variable response to high doses of corticosteroids, methotrexate, calcineurin inhibitors, TNF and IL-6 inhibitors. Functional studies suggest an interferon-mediated pathway and therapies blocking interferon may be reasonable investigational targets in the future.

As no clearly effective therapies exist, lipodystrophy and inflammation may persist. The long-term consequences of persistent disease have yet to be described.

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