Rheumatology

Autoinflammatory disorder

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Does this patient have an autoinflammatory disorder?

IL-1 family-mediated autoinflammatory disorders

IL-1 mediated disorders are characterized by systemic inflammation, elevated acute phase reactants, skin lesions, frequently bone lesions and often a dramatic response to IL-1 blockade. Organ manifestations may vary considerably based on the disease, mutation and between patients.

Deficiency of the IL-1 receptor antagonist (DIRA)

DIRA is an autosomal recessive disorder due to the genetic deletion IL1RN, the gene encoding the IL-1 receptor antagonist. 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 a 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 this would be expected to be lower in areas with no relation to the founder population.

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. Patients present with generalized pustular psoriasis, high fevers, malaise and elevated inflammatory markers.

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.

TNF receptor associated periodic syndrome (TRAPS)

Also known as familial Hibernian fever, TRAPS is due to autosomal dominant mutations in TNFRSF1A, the gene encoding the TNF receptor. 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 inflammatory markers.

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 very rare with an estimated incidence of 5.6 per 10,000,000 person-years.

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). Mutations in PSTPIP1 lead to increased pyrin binding and resultant activation of the NLRP3 inflammasome through decreased pyrin binding. Patients typically present in the first decade of life however may present in adulthood.

Clinical manifestations include pyoderma gangrenosum, cystic scarring acne, and pyogenic sterile arthritis. Arthritis and pyoderma gangrenosum lesions may occur after minor trauma. Pyoderma gangrenosum 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.

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. 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.

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 is a very rare disorder.

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. This is a component of the immunoproteasome.

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.

Differential diagnoses

DIRA

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.

DITRA

The differential diagnosis for DITRA includes pustular psoriasis and 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.

TRAPS

TRAPS is often confused with other autoinflammatory diseases including FMF and 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.

PAPA

The differential diagnosis for PAPA 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.

HIDS

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.

PGA

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.

CANDLE

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.

What tests to perform?

DIRA / DITRA

Laboratories

DIRA and DITRA are characterized by unopposed IL-1ß signaling with laboratory abnormalities being a consequence of IL-1 production and result and inflammation. Acute phase reactants (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

Genetic testing for deletions of ILRN and IL36RN 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. These disorders are autosomal recessive, therefore two deletions are necessary for disease manifestations.

Imaging

Joint radiographs

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. Patients with DITRA do not have classic radiographic findings.

Biopsy

A skin biopsy may be helpful in distinguishing the skin lesions of CAPS from those of other forms of urticaria. Histologically, the epidermal changes in DIRA are characterized by the presence of intra-epidermal neutrophils and neutrophilic pustules with marked papillary dermal edema.

An intense neutrophilic inflammatory infiltrate is present throughout the dermis and may extend to involve the superficial subcutis. DITRA is characterized by intra-epidermal neutrophilic spongiform pustules, acanthosis with elongation of rete ridges, and parakeratosis in the stratum corneum.

TRAPS

Laboratories

Acute phase reactants 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

Genetic testing for mutations in TNFRSF1A is commercially available and may be covered by insurance companies. 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.

Imaging

Joint radiographs

Patients with TRAPS do not typically show erosions on joint radiographs. MRI may reveal intramuscular and septal edema during flares. Synovial and tenosynovial enhancement may also be present.

Biopsy

Biopsies are not typically performed. However, skin biopsies may show mixed lymphocytic and monocytic perivascular and interstitial infiltrate.

PAPA

Laboratories

Acute phase reactants 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

Genetic testing for mutations in CD2BP1 is commercially available and may be covered by insurance companies. 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.

Imaging

Joint radiographs

Joint radiographs may be normal or may show erosions and deformities in patients with PAPA.

Biopsy

Biopsies are not typically performed due to concern for exacerbating the underlying condition. Pyoderma gangrenosum biopsies show neutrophilic inflammation of the dermis with superficial ulceration. Acne biopsies show burrowing and interconnecting abscesses and scars.

HIDS

Laboratories

Acute phase reactants 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

Genetic testing for mutations in MVK is commercially available and may be covered by insurance companies. Patients should have two mutations as this disorder is autosomally recessive.

Imaging

Joint radiographs

Patients with HIDS do not typically show erosions on joint radiographs.

Biopsy

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.

PGA

Laboratories

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

Genetic testing

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

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.

Biopsy

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

CANDLE

Laboratories

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

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

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.

Biopsy

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

How should patients with autoinflammatory disorders be managed?

DIRA

Patients with DIRA universally respond to IL-1 blocking therapies. As the IL-1 receptor antagonist has been deleted, patients are usually treated with anakinra (Kineret®), the recombinant IL-1 receptor antagonist. The other two commercially available IL-1 antagonists, canakinumab (Ilaris®) and rilonacept (Arcalyst™) have not been fully studied.

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 higher doses of medication than have been FDA approved for rheumatoid arthritis, similarly 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. In these cases, therapies other than anakinra could be efficacious. Patients with DIRA may benefit from referral to a tertiary care center with experience in the treatment of this disorder.

DITRA

DITRA was recently described in August 2011 and limited experience exists regarding the efficacy of treatment. 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.

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. IL-1 blocking therapies may be reasonable in patients unresponsive to conventional therapies

TRAPS

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 efficaceous than infliximab. 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 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 case series.

Case reports also exist for effective treatment with tocilizumab (Actrema®), the IL-6 monoclonal blocking antibody. Given the risk for development of amyloidosis, the goal of therapy should be the resolution of inflammation.

PAPA

Pyoderma gangrenosum in PAPA can be very difficult to treat, 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.

HIDS

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.

PGA

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.

CANDLE

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.

What happens to patients with autoinflammatory disorders?

DIRA / DITRA

As these are newly described diseases, the natural history of disease is unknown. Most patients with DIRA respond well to anakinra with complete or near-complete resolution of symptoms. The impact of long-term therapy is yet to be determined. 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.

TRAPS

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. Therapy should be targeted at aggressively controlling systemic inflammation in an attempt to prevent this complication.

PAPA

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 pyoderma gangrenosum 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.

HIDS

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.

PGA

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. Cataracts develop in about half of patients and cataracts in a third. Arthritis and skin disease may also be chronic in nature, although arthritis rarely leads to joint destruction.

CANDLE

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

How to utilize team care?

DIRA

Rheumatology

Patients should be under the care of a rheumatologist, who is responsible for monitoring systemic inflammation and organ damage, as well as for guiding therapeutic dose escalations. Given the rarity of disease and potentially severe manifestations, referral to a tertiary care center with experience in the care of patients with DIRA may be indicated.

Dermatology

Co-management with a dermatologist experienced in the treatment of pustular skin disease is helpful in managing patients.

DITRA

Dermatology

Patients are often primarily under the care of a dermatologist who monitors the extent of skin involvement and guides therapeutic decisions.

Rheumatology

Patients should be co-managed with a rheumatologist to monitor systemic inflammation and to assist with immunosuppressant therapies.

TRAPS

Rheumatology

Patients should be under the care of a rheumatologist who is responsible for monitoring systemic inflammation and organ damage, as well as for guiding therapeutic dose escalations.

Ophthalmology

Patients with eye disease, particularly uveitis, should be co-managed with an ophthalmologist.

Nephrology

Referral to a nephrologist is urgently indicated in the setting of proteinuria given the concern for renal amyloidosis. A decision can then be made regarding the best location for biopsy to establish the diagnosis and to develop a treatment plan.

PAPA

Rheumatology

Patients should be under the care of a rheumatologist who is responsible for monitoring systemic inflammation and organ damage, as well as for guiding therapeutic decisions.

Dermatology

Co-management with a dermatologist experienced in the treatment of pyoderma gangrenosum and wound care is helpful in managing patients.

Therapists

Patients with joint deformities will benefit from a physical therapy evaluation and treatment plan to improve physical limitations. Shoe inserts, braces, stretching and exercise therapy may all be helpful in improving patient function.

Nurses

Wound care nurses can be helpful in assisting with the implementation of wound care regimens and monitoring the response to therapy.

HIDS

Rheumatology

Patients should be under the care of a rheumatologist who is responsible for monitoring systemic inflammation and organ damage, as well as for guiding therapeutic decision.

PGA

Rheumatology

Patients should be under the care of a rheumatologist who is responsible for monitoring systemic inflammation and organ damage, as well as for guiding therapeutic decision.

Ophthalmology

Given the risk for visual impairment and the development of cataracts and glaucoma, patients with eye disease should be co-managed with an ophthalmologist.

CANDLE

Rheumatology

Patients should be under the care of a rheumatologist who is responsible for monitoring systemic inflammation and organ damage, as well as for guiding therapeutic decision.

Endocrinology

Patients with lipodystrophy or lipid abnormalities may benefit from co-management with an endocrinologist.

Nurses

Autoinflammatory disorders are chronic conditions and the involvement of clinic nurses knowledgeable in this condition and with the individual patient is crucial for patient education and optimal care.

Pharmacists

Pharmacists can be helpful in evaluating for multiple drug interactions and in guiding changes in therapeutic doses when indicated due to renal insufficiency or other co-morbidities. They may also be helpful in guiding dose escalation decisions.

Are there clinical practice guidelines to inform decision making?

As these are all rare disorders, no clinical practice guidelines have been established. Treatment and management recommendations are based on small case series and expert opinion.

Other considerations

DRG codes

  • 240 Connective tissue disorders with complications, comorbidities.

  • 241 Connective tissue disorders without complications, comorbidities.

  • 256 Other musculoskeletal and connective tissue diagnosis.

Typical lengths of stay

Patients with autoinflammatory disorders are managed in the outpatient setting, with inpatient admissions required only in the event of complications.

What is the evidence?

Masters, SL, Simon, A, Aksentijevich, I, Kastner, DL. "Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease". Annu Rev Immunol. vol. 27. 2009. pp. 621-68..

Almeida de Jesus, A, Goldbach-Mansky, R. "Monogenic autoinflammatory diseases: concept and clinical manifestations". Clin Immunol. vol. 147. 2013. pp. 155-74..

Ter Haar, N, Lachmann, H, Ozen, S, Woo, P, Uziel, Y, Modesto, C. "Treatment of autoinflammatory diseases: results from the Eurofever Registry and a literature review". Ann Rheum Dis. vol. 72. 2013. pp. 678-8..

Aksentijevich, I, Masters, SL, Ferguson, PJ, Dancey, P, Frenkel, J, van Royen-Kerkhoff, A. "An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist". N Engl J Med. vol. 360. 2009. pp. 2426-37..

Marrakchi, S, Guigue, P, Renshaw, BR, Puel, A, Pei, XY, Fraitag, S. "Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis". N Engl J Med. vol. 365. 2011. pp. 620-8..

Liu, Y, Ramot, Y, Torrelo, A, Paller, AS, Si, N, Babay, S. "Mutations in proteasome subunit beta type 8 cause chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature with evidence of genetic and phenotypic heterogeneity". Arthritis Rheum. vol. 64. 2012. pp. 895-907..

Rose, CD, Arostegui, JI, Martin, TM, Espada, G, Scalzi, L, Yague, J. "NOD2-associated pediatric granulomatous arthritis, an expanding phenotype: study of an international registry and a national cohort in Spain". Arthritis Rheum. vol. 60. 2009. pp. 1797-803..

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