Monogenic and Multifactorial Autoinflammatory Diseases
AGS
Aicardi-Goutières syndrome (AGS) is a rare inherited disease referred to as type I interferonopathy, which usually manifests during infancy, and primarily affects the brain, immune system, and the skin. It is also characterized by the presence of cerebrospinal fluid with chronic lymphocytosis, elevated levels of interferon-alpha and by cardinal neuroradiological features such as cerebral calcification, leukoencephalopathy, and cerebral atrophy. The immune system in AGS patients activates destructive pathways targeting the white matter (myelin), which is responsible for the brain issues seen in these patients. Thus, most children have mild to severe intellectual and/or physical impairments. Rarely the disease may present in adults, who are genetic carriers for the disease.
Genetics & Epidemiology
AGS is a genetic disease usually inherited in an autosomal recessive manner (both parents each carry a genetic mutation). It is currently known to be caused by mutations in the following genes: ADAR1, TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, IFIH1, LSM11 and RNU7-1. In rare cases, AGS may be caused by a single mutation inherited from an unaffected parent or a somatic presentation may be observed.
Aicardi-Goutières Syndrome affects less than 200,000 people in the US population. This neurological disease occurs in all populations worldwide, and it is likely under-diagnosed. As of 2014, roughly 400 cases of AGS were known, and just over 120 cases had been reported in medical literature.
Symptoms, Flares & Triggers
There are two forms of AGS: an early onset form and a later-onset form. Symptoms for both begin in infancy, but at different times.
Early-Onset is the more severe form and occurs at birth. As a result, it causes permanent damage of the brain functions and inducing lifelong intellectual and physical disabilities. Over time, symptoms may be more severe, including seizures, liver inflammation, smaller head size (microcephaly), skin rashes, abnormal behavior, and poor feeding ability from birth.
Later-Onset is the less severe form and occurs within the first few weeks to months of infancy. Over time, symptoms may lessen or stabilize but may result in persistent neurologic issues. Immune dysregulation is also associated and may impact other organs in a mild to life-threatening manner. AGS may impact many of the organs including the heart, liver, lungs, skin, and kidneys; with symptoms such as weak or stiffened muscles (spasticity), intermittent fevers, declining head circumference, developmental delays, skin problems/chilblains (rash, lesions, or swelling on fingers, toes, and ears impacted by cold temperatures), and emotional irritability.
Diagnosis & Diagnostic Criteria
Diagnosis of Aicardi-Goutières syndrome is made based upon clinical symptoms, imaging of the brain, cerebrospinal fluid testing, and the results of genetic sequencing.
Magnetic resonance imaging (MRI) is a critical diagnostic tool for brain abnormalities, as it may detect patterns in tissue that are characteristic to AGS. It is key for the physician to evaluate calcium buildup (calcifications) as well as shrinking or atrophy of the brain. Cerebral spinal fluid (CSF) evaluation (analyzing fluid from the spinal cord) may reveal immune abnormalities and/or elevations of interferon-gamma, which may be a sign of AGS.
Treatments
There is no cure for AGS, and treatments for symptoms are based on each patient’s unique needs. Therapies may include chest physiotherapy for respiratory complication, feeding support with special diet, seizure control with anticonvulsant medications, endocrine issues with thyroid medication, hematological issues with platelet transfusion, and empirical therapy as needed, with immunosuppressant drugs. Many children with AGS benefit from physical and speech therapy to combat weaknesses caused by neurological damage.
New therapies considered include: JAK inhibitors (for non-neurological signs of type I interferonopathies), reverse transcriptase inhibitors, antiretrovirals (for CNS involvement), anti-IFN-α antibodies, anti-interleukin drugs (IL-6), antimalarials and other cGAS inhibitors. Altered DNA methylation and ISG expression may be considered as biomarkers and potential future treatment targets in AGS.
Laboratory Tests & Findings
Blood tests may not confirm the disease, whereas CNS from a spinal tap may reveal elevations in interferon, lymphocytes, and neopterin.
Children with AGS should be monitored for:
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glaucoma symptoms especially in the first few months of life with yearly examination after age one
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endocrine issues including diabetes and thyroid dysregulation
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development of pulmonary hypertension and inflammatory cardiomyopathy
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platelet levels and associated markers for any increased risk of bleeding
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neurologic blood vessel testing
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bones and possible joint dislocations as related to AGS motor and spinal issues
AOSD
Adult-Onset Still Disease (AOSD) is a systemic inflammatory disease that primarily presents at two age intervals (16 to 25 and 36 to 46 years of age), and predominantly affects more females than males. In certain patients, AOSD is the continuation of childhood sJIA. The clinical features of AOSD and Systemic Juvenile Idiopathic Arthritis (sJIA) suggest both clinical phenotypes represent the same disease with different ages of onset. The cause of AOSD is unknown, but it is characterized by daily fevers, arthritis, and a salmon-pink rash.
Genetics & Epidemiology
Adult-Onset Still's Disease (AOSD) has not been linked to any specific gene at this time. Thus, diagnostic criteria are clinical and not verified by genetic testing.
It has an estimated prevalence (independent of ethnicity) of 0.62 per 100,000 individuals worldwide. The number of cases in Japan and Turkey may be slightly higher based on recent research.
Symptoms, Flares & Triggers
Symptoms are systemic and include: fevers, rash, splenomegaly, lymphadenopathy, myalgia, arthritis, hepatomegaly, pericarditis, pleuritis, severe anaemia, abdominal pain, renal dysfunction, fatigue, headache, sore throat, and weight loss (may be rapid).
High daily fevers (≥39 °C/102.2 °F) usually spike during the evening at approximately the same time each day and return to normal in the morning. These fevers may be accompanied by a feeling of extreme fatigue with a rash.
The cutaneous/skin manifestations include a salmon-pink rash (small, non-itchy spots or patches up to 5 cm in diameter) that disappears quickly and usually presents on the trunk, neck, and extremities, which appears in 95% of patients. Urticaria (hives) may also present and can be raised and itchy. Fever and skin symptoms may present months or even years before developing chronic arthritis. Muscles and joints, typically impacting the knees and wrists, may swell and cause limited mobility due to stiffening and aching. Arthritis may also affect the fingers, shoulders, elbows, and ankles.
The disease onset may be triggered by a variety of genetic, environmental, and infectious (bacterial and viral) factors. However, it is uncertain, and research of causation is ongoing.
Diagnosis & Diagnostic Criteria
AOSD is typically considered as a diagnosis of exclusion and a definitive diagnosis should be made based on the Yamaguchi or Fautrel criteria only after excluding infectious, malignant, and other connective tissue diseases. Timely diagnosis and treatment of the disease with corticosteroids, followed by maintenance therapy with disease modifying antirheumatic drugs (DMARDs) or biologics such as TNF-alpha agents or interleukin (IL-1) inhibitors.
Patients with AOSD may experience macrophage activation syndrome (MAS), a severe and potentially life-threatening complication. Timely diagnosis and treatment of the disease may prevent symptoms, alleviate pain, and lead to a more favorable prognosis with improved quality of life.
The Fautrel criteria are:
Major criteria:
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Spiking fever > 39 °C
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Arthralgias
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Transient erythematous rash
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Sore throat
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PMN > 80% (polymorphonuclear)
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Glycosylated ferritin < 20%
Minor criteria:
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Maculopapular rash
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Leucocytosis > 10,000/mm3
Diagnosis requires at least 4 or more major criteria or 3 major + 2 minor criteria.
Treatments
NSAIDs and corticosteroids (prednisolone is the preferred choice for steroid use) represent the first line therapy, when there is limited systemic impact from the disease.
DMARDs such as Methotrexate, Cyclosporine, Azathioprine or Leflunomide, also may be used.
Patients who do not respond to these therapies, may benefit by taking biologics such as: IL-1 inhibitors anakinra, canakinumab and rilonacept, IL-6 inhibitor tocilizumab, anti-TNF agents such as infliximab, etanercept, and adalimumab. Research is ongoing in regard to using other types of biologics for AOSD patients.
Laboratory Tests & Findings
Laboratory tests should include acute phase reactants (CRP, ESR, SAA), ferritin, liver enzymes, albumin, complete blood count (CBC), ANA & rheumatoid factor (to rule out other rheumatic diseases).
Abnormalities may include extremely elevated neutrophils (leukocytosis within 15,000–30,000), high ferritin or liver enzymes, elevated erythrocyte sedimentation rate (ESR) & C-reactive protein (CRP), anemia, low albumin (hypoalbuminemia), and thrombocytopenia (> 400,000).
Inflammatory cytokines such as interleukin IL-1, IL-6, IL-18, TNF, and S100 proteins may also be elevated.
Pregnancy
AOSD female patients may have higher risk factors for successful pregnancy. Comorbidities may include hypertension, diabetes, and thyroid problems. Obstetrical complications may include: spontaneous abortion, prematurity, intrauterine growth restriction, premature rupture of membranes, and other issues, thus requiring a highly trained multidisciplinary team (rheumatologist and an obstetrician) before, during and post pregnancy.
Behçet's Disease
Behçet disease is a rare form of vasculitis, which may affect all size vessels, organs, and systems including the brain. It is characterized by complex symptoms including recurrent oral aphthous ulcers, genital ulcers, uveitis, and skin lesions. The systemic manifestations can be variable and cause problems throughout the body. Diagnosis is based on clinical criteria, as diagnostic tests are lacking. The treatment approach depends on the individual patient, severity of disease, and major organ involvement. The disease originated along the Silk Road, the ancient network that connected Asia with the Middle East and southern Europe.
Genetics & Epidemiology
Genome-wide association studies (GWAS) have demonstrated that both genetic and environmental factors may contribute to the development of BD. Several genetic variants strongly associated with BD, including variants in (HLA) such as -B15, -B27, -B51. Other genes that may contribute to the disease include CIITA, ERAP1, MICA, IL1A-IL1B, IL10/IL10RA, IL12, IL23R, IL-23R/IL-12RB2, IL1RL1-IL18R1, STAT4, CCR1/CCR3, RIPK2, KLRC4, LACC1, MEFV, IRF8, FUT2, CEBPB-PTPN1, plus others. HLA-B51 remains the most important genetic factor in Behçet's disease, although it should be noted that at least half of all patients do not have a positive HLA-B51 result.
Epigenetic modifications are also reported to play essential roles in the development of BD, including DNA methylation and histone modification.
Turkey has a prevalence of 20–602 cases per 100,000 population. The disease usually appears between the second and fourth decades of the life and affects both genders equally. However, the gender distribution may differ among different regions.
The prevalence in Japan, Korea, China, Iran, and Saudi Arabia ranges from 13.5 to 22 cases per 100,000 population. The prevalence in North America and Europe is much less, with 1 case per 15,000-500,000 population.
In the United States, the estimated prevalence ranges from 0.33 to 5.2 people per 100,000 population. Findings from the largest BD dataset in the U.S. suggest that BD patients are predominantly female.
Symptoms, Flares & Triggers
Aphthous ulcers
Oral ulcers occur in 97% to 99% of patients with Behcet disease, often representing the initial clinical feature. Lesions are usually painful, recurrent, and may be multiple in number. Ulcers may appear on the soft palate, hard palate, buccal mucosa, tongue, gingiva, lips, and tonsils. More than 90% of oral ulcers heal without scarring and typically heal within one to two weeks. A high percent of patients develop similar ulcers on the genitals, which occur most frequently on the scrotum in men and on the labia in women.
Skin manifestations
Dermatological findings for Behçet disease are variable and may affect many parts of the body. Painful pus-filled bumps and sores known as papulopustular lesions (pseudofolliculitis) on the skin may appear and typically present on the extremities. This is the most common cutaneous sign in Behcet’s disease. Patients may also have erythema nodosum, which are red, tender nodules that usually develop on the legs but can also occur on the arms, face, and neck. Other manifestations may also include mild to severe acne.
Skin pathergy reaction
Pathergy results from a hypersensitivity reaction induced by an intradermal prick. Often patients will then have a pustule form at the puncture site, which is considered a positive result.
Ocular manifestations
Ocular manifestations of the disease mainly comprise uveitis in 60-80% of cases, followed by retinal vasculitis and retinal vein occlusion. Behcet’s may cause either anterior uveitis (inflammation in the front of the eye) or posterior uveitis (inflammation in the back of the eye), and sometimes causes both at the same time. Anterior uveitis causes pain, blurry vision, light sensitivity, tearing, or redness of the eye. Posterior uveitis may be more threatening to vision, as it often causes fewer symptoms while damaging a crucial part of the eye — the retina.
GI manifestations
Gastrointestinal clinical presentation varies by patient with the most common symptom of intestinal BD being abdominal pain with or without diarrhea. About 30% of patients present with emergency conditions such as hemorrhage, obstruction, and perforation. The clinical manifestations of upper gastrointestinal tract involvement may present with painful swallowing and substernal pain. Symptoms of BD gastrointestinal involvement are similar to those associated with IBD (Inflammatory bowel disease) and may include anorexia, nausea, vomiting, dyspepsia, diarrhea, constipation, GI bleeding, and abdominal pain. These symptoms are induced by inflammation and ulceration within any location of the GI tract.
GI manifestations differentiating Behçet disease and Crohn’s IBD can be difficult to diagnose. Crohn’s disease (CD) is a type of inflammatory bowel disease that may affect any part of the gastrointestinal tract from mouth to anus. Symptoms include both intestinal & abdominal pain, diarrhea, vomiting and weight loss. The terminal ileum and cecum are common sites affected.
Behcet’s Disease vs. Crohn’s Disease
Behçet’s is a chronic inflammatory disease with multisystem organ and vascular involvement, while Crohn’s disease is a chronic relapsing inflammatory disorder of the gastrointestinal tract. Differentiation is usually based on the involvement of different organs and dermatologic manifestations.
Neuro-Behcet's Disease (NBD)
Neurological symptoms are likely present in less than 10% of cases and develop, on average, 5-6 years after the first non-neurological symptom. This presentation is associated with a worse prognosis of BD. The lesions result from vasculitis-induced thrombosis and are seen in the spinal cord, brainstem, basal ganglia, thalamus, or periventricular white matter.
NBD is defined as a combination of neurologic symptoms and/or signs that include brainstem syndrome, multiple-sclerosis-like presentations, movement disorders, meningoencephalitic syndrome, myelopathic syndrome, cerebral venous sinus thrombosis (CVST), and intracranial hypertension.
MAGIC syndrome
Mouth and genital ulcers with inflamed cartilage (MAGIC) syndrome refers to a condition in which features of Behcet’s disease (BD) and relapsing polychondritis (RP) occur in the same individual. The existence of MAGIC syndrome (very rare) suggests a potential common etiology for BD and RP.
Diagnosis & Diagnostic Criteria
There are no genetic tests to determine whether a patient has Behçet's disease, and clinicians must rely on symptoms. It is common for Behcet’s patients to be positive for HLA-B51; however, it is not always a requirement for the diagnosis.
Patients with Behçet are diagnosed according to the criteria as follows:
Major criteria is oral ulcers small or big aphthous herpetiform, which last for a week are painful and appear at least 3 times in a period of 12 months.
Two of the following represent the Minor criteria:
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Genital ulcers
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Optic neuritis or uveitis
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Skin pustules and papules
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Positive pathergy test
The Major plus any two Minor equate to a Behcet’s diagnosis.
Treatments
There is no cure for Behcet's disease. The medications serve to control the pain and inflammation of the flares and symptoms.
The following are commonly prescribed for ulcerations:
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Mouth rinses. Using special mouthwashes that contain corticosteroids and other agents might help to reduce the pain of mouth sores.
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Skin creams, gels, and ointments. Topical corticosteroid medicines are applied directly to skin and genital sores to reduce inflammation and pain.
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Eyedrops. Eyedrops containing corticosteroids or other anti-inflammatory medicines can relieve pain and redness in the eyes.
If topical medications are ineffective, colchicine is typically prescribed, which is used to treat oral and genital sores, as well as joint swelling. If the drug is ineffective, other medications will be prescribed.
Other treatments include:
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Corticosteroids. Medications such as prednisone are used to reduce the inflammation and is often prescribed in conjunction with other drugs to suppress the activity of the immune system.
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Immune suppressive medications. Drugs may include azathioprine (Azasan, Imuran), cyclosporine (Gengraf, Neoral, Sandimmune), cyclophosphamide, thalidomide, sulfasalazine, and methotrexate. A newer medication Apremilast (Otezla) is also used to prevent inflammatory lesions.
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Biologics. These may be used alone or in combination with other drugs. TNF inhibitors including infliximab (Remicade), adalimumab (Humira) and etanercept (Enbrel). Other biologics targeting IL-1, IL-6, IL-12/23, and IL-17 have become off-label treatment choices. Interferon alpha may be used in refractory cases.
Laboratory Tests & Findings
It is recommended that potential Behcet patients seek rheumatological workup to rule out a variety of autoimmune, monogenic disorders (TNFAIP3/HA20), vascular and blistering diseases including Lupus, Pemphigus, Sarcoidosis, Hypercoagulable states (e.g., protein C and S deficiency, factor V Leiden, hyperhomocysteinemia, prothrombin deficiency), etc.
Behcet patients typically present with normal levels of acute-phase reactants such as erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and serum amyloid A (SAA). Levels of IgA, IgG, alpha-2 globulin, IgM, and immune complexes are occasionally elevated.
Pregnancy
Pregnancy appears to improve disease symptoms with remission often continuing after the birth of the baby. BD is not usually associated with a detrimental effect on the pregnancy. However, successive outcomes of symptom abatement, during multiple pregnancies, is not predictable.
Many of the drug therapies used to treat BD are safe to use in pregnancy and in a breastfeeding mother. These include corticosteroids, azathioprine, calcineurin inhibitors and colchicine. The use of biologics in pregnancy is increasing and may be helpful. Drugs used in the management of BD that should be avoided in women planning a pregnancy include methotrexate, mycophenolate mofetil, thalidomide, cyclophosphamide and chlorambucil. It is advised that the treating physician and obstetric team work together to ensure medication safety and efficacy for both the pregnant Behcet’s patient and unborn fetus.
Blau Syndrome
Blau Syndrome, or early-onset sarcoidosis (EOS), is a rare monogenic autoinflammatory granulomatous disease that primarily affects the skin (skin rash), joints (arthritis), and eyes (uveitis). Signs and symptoms begin in childhood, usually in patients younger than four years of age. A form of skin inflammation called granulomatous dermatitis is typically seen as the earliest sign of Blau syndrome. This skin condition causes a persistent rash that can be scaly or involve hard lumps (nodules) that can be felt under the skin. The rash is usually found on the torso, arms, and legs.
Genetics & Epidemiology
Blau Syndrome results from mutations in the NOD2 (nucleotide-binding oligomerization domain 2) gene and is an autosomal dominant disease caused by mutations in CARD15, the gene that encodes the NOD-like Receptor (NLR) protein, NOD2. One copy of the altered gene in each cell is sufficient to cause the disease. In some patients, mutations may occur spontaneously (de novo), meaning that they have a non-inherited version of the disease, which is referred to as early-onset sarcoidosis (EOS).
The protein produced from this gene helps defend the body from foreign invaders, such as viruses and bacteria, by playing several essential roles in the immune and inflammatory response. This mutation results in abnormal inflammatory reactions.
The exact incidence and prevalence of Blau Syndrome remains unknown, but available data suggests a prevalence of less than one in one million.
Symptoms, Flares & Triggers
Arthritis is a common feature of Blau Syndrome and is characterized by inflammation of the lining of joints (the synovium) and known as synovitis, which is associated with swelling and pain. Synovitis usually begins in the joints of the hands, feet, wrists, and ankles and as the condition worsens, it may involve additional joints and restrict movement by decreasing the range of motion.
Most patients with Blau Syndrome also develop uveitis, which is swelling and inflammation of the middle layer of the eye (the uvea). Uveitis can cause eye irritation and pain, increased sensitivity to bright light (photophobia), and blurred vision. Other structures of the eye that may be affected including the conjunctiva, the lacrimal glands, and the retina. Inflammation of any of these structures can lead to severe vision impairment or blindness.
Blau Syndrome may also cause kidney disease (nephritis) due to the inflammation and the build-up of calcium deposits in the kidneys. This may result in chronic kidney failure. Additionally, the inflammation of the blood vessels (vasculitis) may impede blood flow to tissues and organs.
Less commonly, Blau Syndrome may affect other parts of the body, including the liver, spleen, salivary gland, brain, blood vessels, lungs, and heart. Inflammation impacting these organs can impair their function and cause life-threatening complications. Rarely, affected individuals have episodes of fever or high blood pressure causing pulmonary hypertension.
Common symptoms:
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Arthralgia (joint pain)
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Erythema
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Hyperpigmentation of the skin (patchy darkened skin)
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Iridocyclitis (inflammation of the iris)
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Keratitis (corneal inflammation)
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Joint swelling
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Limitation of joint mobility (decreased joint mobility)
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Papule
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Polyarticular arthritis
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Posterior uveitis
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Skin rash (popular with non-caseating
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Granuloma
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Synovitis
Other possible symptoms: Camptodactyly (permanently bent finger), cataracts, dry skin, erythema nodosum (a type of skin inflammation), fever, glaucoma (increased pressure within the eyeball), photophobia, anaemia, dyspnoea (trouble breathing), etc.
Diagnosis & Diagnostic Criteria
Diagnosis is made by reviewing the medical history, assessment of the clinical symptoms, bloodwork, physical exam, skin biopsies and genetic testing.
Skin biopsy may be performed to confirm noncaseating granulomatous dermatitis, which is a particular pattern of mixed inflammatory infiltrates that are found in the upper dermis, often around hair follicles. Non-caseating granulomas may also be seen in biopsies from the eye, joint synovium, and other involved sites.
X-rays or scans may be taken of the affected joints to monitor disease progression. Slit lamp examination of the eyes should be performed regularly as early eye disease can be asymptomatic. CARD15/NOD2 gene mutation testing should be done for disease confirmation.
Treatments
Topical and systemic corticosteroids are currently the mainstay of treatment for Blau Syndrome and may be combined with methotrexate, thalidomide, ciclosporin or mycophenolate mofetil for improved efficacy. Biologics including interleukin 1β inhibitors (anakinra and canakinumab), as well as TNF-alpha inhibitors (infliximab, etanercept, adalimumab) have been used with variable success. There are no specific treatments for this life-long disease, and it can be challenging to treat.
Laboratory Tests & Findings
Monitoring of inflammatory markers such as erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) should be performed, as well as other blood tests measuring affected organs function.
Pregnancy
Patients with Blau syndrome do not appear to have fertility problems due to the disease. Special attention is required for women on certain drugs such as methotrexate and wanting to get pregnant. Methotrexate, as well as some other drugs, cannot be used during pregnancy as it can cause miscarriages or birth defects.
CANDLE Syndrome
CANDLE is a rare genetic autoinflammatory disease caused by mutations in the proteasome which then dysregulates type-1 interferon signalling. It typically starts at birth or in the first weeks/months of life and is often referred to as PRAAS (Proteasome-Associated Autoinflammatory Syndrome) or ALDD syndrome (Autoinflammation, Lipodystrophy, and Dermatitis). These defects lead to damaged proteins accumulating in the cells, which then cause overproduction of interferons, inducing a cycle of persistent inflammation.
Genetics & Epidemiology
CANDLE syndrome and related conditions, Nakajo-Nishimura syndrome (NNS) and Joint Contractures, Muscle atrophy, microcytic anemia, & Panniculitis-induced lipodystrophy syndrome (JMP), occur due to mutations in the PSMB8, PSMB9, PSMB4, PSMA3, PSMG2, and POMP genes. It is usually inherited in an autosomal recessive pattern; however, when associated with variants in the POMP gene, the disease may be inherited in an autosomal dominant pattern.
There are approximately 80 cases reported in the literature.
Symptoms, Flares & Triggers
Symptoms include recurrent or daily fevers, purpuric skin lesions/plaques, swollen eyelids, unique facial features, muscle atrophy, progressive lipodystrophy (fat loss) usually beginning on the face, hypochromic or normocytic anemia, delayed physical development, contractures, disabling joint manifestations, and seizures. Arthralgia and arthritis are almost always present throughout the patient’s life. Other clinical features may include excessive hair growth, dark discoloration of the skin, and alopecia areata.
Diagnosis & Diagnostic Criteria
Due to the early-onset systemic inflammation, CANDLE may be confused with a neonatal infection, NOMID, DIRA or other autoinflammatory diseases. Diagnosis is confirmed with genetic testing.
Treatments
Patients have had variable treatment responses to corticosteroids, methotrexate, calcineurin inhibitors, TNF and IL-6 inhibitors. Recently, treatment with JAK inhibitors, in research studies, has been shown to be highly effective and safe. Long-term effectiveness and possible serious side effects are being studied.
Laboratory Tests & Findings
The laboratory findings in patients with CANDLE include increased inflammatory markers, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), complete blood count (CBC) with differential, cholesterol panel including triglycerides, antinuclear antibodies (ANA), antineutrophil cytoplasmic antibodies (ANCA), and marked leucocytosis. Hypertriglyceridemia is a common finding. Imaging including MRI may be used to determine arthritis severity and panniculitis (a group of conditions that cause painful bumps, or nodules under the skin).
CAPS: FCAS, MWS, NOMID/CINCA
Cryopyrin-Associated Periodic Syndromes (CAPS) is a group of rare hereditary inflammatory diseases caused by mutations in the NLRP3 gene and encompasses three phenotypes: mild, moderate, and severe. The mild phenotype is called Familial Cold Autoinflammatory Syndrome (FCAS), the moderate phenotype is known as Muckle–Wells syndrome (MWS), and the severe phenotype is referred to as Neonatal-Onset Multisystem Inflammatory Disease (NOMID)/Chronic Infantile Neurologic Cutaneous Articular Syndrome (CINCA). These three syndromes are considered separate entities; however, patients may experience overlapping symptoms and triggers, presenting with urticarial rash (hives, itchy bumps), musculoskeletal abnormalities, ocular conjunctivitis, neurosensorial hearing loss, and neurological issues (headaches), combined with chronic systemic inflammation.
Genetics & Epidemiology
CAPS disorders are related to defects in the protein cryopyrin gene NLRP3 (formerly known as CIAS1 or NALP3). There are more than 240 sequence known variants in the NLRP3 gene. A majority are found in exon 3, and of those, more than 100 are known to be pathogenic/ likely pathogenic.
These syndromes are caused by gain-of-function NLRP3 mutations that are inherited in an autosomal-dominant pattern and are readily apparent in approximately 75% of the MWS and FCAS cases, whereas spontaneous de novo variants account for neonates born with CINCA/NOMID, consistent with a mutation occurring during embryogenesis.
The NLRP3 gene is expressed in neutrophils and chondrocytes (cartilage cells). It codes for cryopyrin, which is involved in the formation of the inflammasomes, complexes found inside cells and critical to the functionality of the innate immune system. Dysregulated cryopyrin increases caspase-1 activation, leading to elevations of interleukin (IL)-1, a powerful stimulator of the inflammatory cascade. Expression of the NLRP3 gene in chondrocytes may be relevant to the joint pain/swelling in FCAS, MWS and bone deformation caused by overgrowth in NOMID/CINCA.
CAPS is an orphan disease found to be equally prevalent in both males and females. The prevalence is 2.5 to 5.5 per 1,000,000 and may be even higher due to undiagnosis.
Phenotypes
Familial Cold Autoinflammatory Syndrome (FCAS)
FCAS inflammatory episodes are characteristically triggered by cold exposure, such as air-conditioning, swimming, or exposure to cold temperatures. Additionally, other environmental triggers may cause the symptoms of FCAS including urticaria (hive-like rash), fever, chills, nausea, severe thirst, red eyes, headaches, and joint pain. Episodes usually last up to one day (24 hours) and tend to be brief.
Gastrointestinal symptoms may occur and can range from mild to more severe. It is recommended to seek help from a gastroenterologist, especially if you are experiencing abdominal pain, diarrhea, vomiting, nausea, and weight loss, to be evaluated via endoscopy and colonoscopy.
Muckle-Wells Syndrome (MWS)
MWS episodes may be frequent but are typically triggered by cold. Episodes can occur randomly. Most flares last fewer than 36 hours but can last up to 5 days. Urticarial rash and amyloidosis, together with progressive sensorineural hearing loss, are clinical findings supporting the diagnosis of MWS. Patients develop episodic fevers, chills, rash, red eyes, joint pain, and severe headaches (aseptic meningitis) with vomiting. Musculoskeletal manifestations may include arthralgia, arthritis, and significant myalgia. Deafness or partial hearing loss often develops by the teenage years. If untreated, MWS patients have close to a 25% risk of renal amyloidosis. Eye inflammation, such as uveitis, may be present in addition to conjunctivitis. Patients may have lymphadenopathy (swollen or enlarged lymph nodes) and/or hepatosplenomegaly (swelling or enlargement of the liver and spleen).
Gastrointestinal symptoms may occur and can range from mild to more severe. It is recommended to seek help from a gastroenterologist, especially if you are experiencing abdominal pain, diarrhea, vomiting, nausea, and weight loss, to be evaluated via endoscopy.
Neonatal Onset Multisystem Inflammatory Disease (NOMID) or Chronic Inflammatory Neurological Cutaneous Articular Syndrome (CINCA)
NOMID is the most severe phenotype and presents at birth with rash, fever, and inflammation affecting multiple organs; however, but no infection is found. Initially, infants have diffuse erythema (abnormal redness of the skin) prior to developing urticarial rash, which resembles hives but tends not to itch. NOMID causes persistent inflammation, which can lead to chronic meningitis (inflammation of the membrane surrounding the brain) resulting in high CNS pressure. These neurological issues also include headaches, blindness, hearing loss, mental or cognitive impairments, and possible seizures. Patients may develop osteopathy and long-bone overgrowth, clubbing, growth delay/short stature, lymphadenopathy, with/or without hepatosplenomegaly, and pericarditis.
Joint inflammation and bone deformities range in severity. Many may have nonspecific joint pain and enlargement of the bones affecting the knee. These patients are unable to walk or bear weight on their legs due to joint damage and/or pain. Other bone malformations may include abnormal facial features and dental abnormalities.
Eye issues may include papilledema, uveitis, iritis, conjunctivitis, corneal haze, vision loss and retinal scarring. It is recommended that these patients are seen by specialty eye physicians.
The severity of NOMID varies from child to child. Early diagnosis and prompt treatment with appropriate medications are key for preventing severe complications of the disease and improving life expectancy.
Diagnosis & Diagnostic Criteria
CAPS is suspected by clinical findings, family history, and physical examination during a flare. Bloodwork should be taken during and between flares as it may reveal patterns of elevated levels of inflammation. In most cases, the diagnosis may be confirmed by genetic testing; however, some patients may not have any known/classified identifiable mutations in NLRP3. Other tests to support the diagnosis may include skin biopsy (examining a small sample of the skin), eye examination, hearing tests, lumbar puncture (obtaining fluid from the spine), and imaging of the brain and inner ears by magnetic resonance imaging (MRI).
The diagnostic criteria for CAPS includes:
Mandatory: elevated inflammatory markers (C-reactive protein/serum amyloid A) plus ≥two of six CAPS-typical symptoms:
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Urticaria-like rash
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Cold-triggered episodes
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Sensorineural hearing loss
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Musculoskeletal symptoms
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Chronic aseptic meningitis
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Skeletal abnormalities
Treatments
CAPS is treated with medications that target interleukin-1 including anakinra (Kineret), canakinumab (Ilaris) and Rilonacept (Arcalyst – USA only). These medications are given by subcutaneous injection. CAPS patients often require higher doses of IL-1 medications to control the disease and it may be escalated up to 600 mg.
Laboratory Tests & Findings
CAPS patients present with elevated levels of acute-phase reactants such as erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and serum amyloid A (SAA) (even between flares), as well as leukocytosis (elevated WBC). Elevated levels of serum amyloid A (SAA) are seen frequently in Muckle-Wells syndrome (MWS) and CSF leukocytosis in NOMID due to aseptic meningitis. Moreover, complete blood count (CBC) may show slightly decreased hematocrit levels and mild neutrophilia. Anaemia of chronic disease and elevated white blood cells count, especially neutrophils, may be detected.
Pregnancy
CAPS patients have successfully taken IL-1 biologics, as directed, before, during, and after their pregnancy. These medications have been deemed beneficial per clinical data, with no major obstetrical complications reported. It is important for patients not to discontinue any treatment during pregnancy without medical oversight.
CRIA Syndrome
CRIA (Cleavage-resistant RIPK1-Induced Autoinflammatory) syndrome, is a recently discovered autoinflammatory disease caused by mutations in the RIPK1 (Receptor-Interacting serine/threonine-Protein Kinase 1) gene. RIPK1 is a regulator of cell death, influencing a pathway responsible for cleaning up damaged, infected (pathogen), or inflamed cells. The gene may also be responsible for immune deficiency. However, when excessive inflammation occurs, it presents as an autoinflammatory syndrome.
Genetics & Epidemiology
RIPK1 issues have been found when mutations prevent the molecule from being cleaved into two sections, resulting in CRIA. The prevalence of CRIA syndrome is still undetermined, since it has only recently been identified in a few patients from a small group of families.
Symptoms, Flares & Triggers
Patients with CRIA syndrome present with a history of recurring high fevers, painful swollen lymph nodes, abdominal pain, headaches, gastrointestinal problems and enlarged liver & spleen. Patients present with inflammatory symptoms from childhood into adulthood. The fevers are persistent and episodic, occurring every 3–5 days from birth onward, and every 2-4 weeks into later years. These fevers are accompanied by lymphadenopathy.
Severe abdominal pains and gastrointestinal problems may be accompanied with diarrhea. Headaches, mouth ulcers, and tonsillitis have been reported. Genital ulcers and rashes have not yet been observed. Issues with enlarged liver and spleen (hepatomegaly & splenomegaly) have also been observed. Patients may suffer from arthralgia (joint pain) but without the swelling typically seen in various forms of arthritis.
Diagnosis & Diagnostic Criteria
Diagnosis currently requires genetic sequencing.
Treatments
Patients diagnosed with CRIA Syndrome have been treated with a variety of anti-inflammatory medications, including high doses of corticosteroids and biologics. Patients showed improvement on tocilizumab (interleukin-6 inhibitor), while others did not respond or had side effects. There are several RIPK1 inhibitors, that are being investigated as potential treatments. Research is ongoing, and none of the medications are available to the public.
Laboratory Tests & Findings
CRIA syndrome is characterized by chronic increased levels of inflammatory markers, even between flares.
CRMO Syndrome
Chronic Recurrent multifocal osteomyelitis (CRMO) is a rare autoinflammatory bone disease without a currently known genetic component and shares common features with its less severe form Chronic non-bacterial osteomyelitis (CNO). It usually presents early in life and is believed to be the pediatric presentation of SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome. CNO may be sporadic and has a broad clinical spectrum ranging from mild, time-limited, and monofocal bone inflammation to a severely chronic presentation. Sterile bone lesions resembling osteomyelitis are the hallmark of CRMO.
This disease causes the immune system to attack normal bone without the presence of infection or injury. Common features include pain, redness and inflammation primarily affecting the long bones. Other bone sites may be impacted, thus making it a multifocal disease. Fever may be present during flares and may last a few weeks or months. CRMO is often seen as a comorbidity in other autoinflammatory bone diseases: DIRA and Majeed.
Genetics & Epidemiology
There is currently no gene identified responsible for CRMO. However, it is suspected that the FBLIM1 gene and its STAT3 gene regulator, may be associated with the disease pathway. It is more commonly seen in girls than in boys and affecting children and adolescents between the ages of 7 and 12.
All ethnicities from all geographic regions can be affected. While highest disease incidences appear to exist in Western countries, particularly Central and Northern Europe. Its prevalence is 0.4 out of 100,000 people per year.
Symptoms, Flares & Triggers
Symptoms of CRMO may range from mild unspecific bone pain to severe presentation, commonly impacting the knee, ankle, wrist, back, pelvis or collarbone. Local swelling, redness and warmth accompanied by fevers and malaise are often seen during a flare. Mobility may be affected or limited. The inflammation and pain may be worse at night and should not be dismissed as a growing pain. Fractures, bone deformities (due to vertebral compression resulting in scoliosis and discrepancy in leg length) may also occur.
A strong association with other inflammatory diseases such as inflammatory bowel diseases, palmoplantar pustulosis, psoriasis vulgaris, Sweet’s syndrome, sclerosing cholangitis, arthritis, sacroiliac joint involvement, Still’s disease, Takayasu arteritis, ANCA-positive vasculitis, parenchymal lung disease and dermatomyositis have been described. The clinical signs and symptoms are nonspecific, hindering and delaying proper diagnosis.
Diagnosis & Diagnostic Criteria
CRMO is a diagnosis of exclusion and often requires a variety of tests including blood tests, X-rays, bone scans, MRI (Magnetic resonance imaging), and occasionally a bone biopsy.
Imaging techniques are key to diagnosing CNO/CRMO, especially in the early stages of the disease. MRI scans may detect bone edema (excess fluids in the bone marrow) prior to bone erosions/lesions and sclerosis developing, thus providing a more complete assessment for targeted diagnosis. It is recommended to use whole body imaging using MRI to identify clinically silent lesions, particularly in the vertebral column. MRI imaging techniques are also essential to assess disease activity and tissue damage and fractures. Bone biopsies may be required in some cases to exclude chronic infection, malignancies, or other systemic disease. X-rays may also reveal osteolytic lesions with surrounding sclerosis (abnormal hardening of body tissue).
Treatments
CRMO can be treated with a variety of medications and the goals are to reduce the pain, increase mobility and to improve the patient’s quality of life.
CRMO flares can be managed with nonsteroidal anti-inflammatory drugs (NSAIDs) such as Naproxen, Advil, Motrin (Ibuprofen), which are the first line of treatment. Should NSAIDs not be effective, other drugs used include: bisphosphonates (pamidronate), corticosteroids (low dose prednisone), DMARDs (methotrexate and sulfasalazine), and biological medications including TNF blockers (i.e. etanercept, infliximab, adalimumab) & IL-1 blockers (i.e. anakinra and canakinumab).
Limited surgical interventions or orthopedic procedures may be helpful or necessary in severe cases. Physiotherapeutic treatment may also aid in symptom reduction to strengthen muscles and improve joint mobility.
Laboratory Tests & Findings
Routine inflammatory markers including white blood cell count (WBC), liver and kidney chemistries, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) may range from normal to elevated. Bacterial and fungal cultures from blood or bone biopsies maybe taken to further confirm disease status based on negative findings. Granulocytic infiltrate is seen on histology of affected lesions and is nonspecific.
DIRA
Deficiency of interleukin one receptor antagonist - DIRA is an early onset autoinflammatory disease with systemic inflammation that affects the skin and the bone. DIRA is caused by loss-of-function mutations in IL1RN. The disease presents at birth or in the first few days of life and may be fatal if untreated. DIRA presents with aseptic multifocal osteomyelitis, variable skin pustulosis, periostitis, and elevated inflammatory markers.
Genetics & Epidemiology
DIRA is an autosomal recessive disease caused by a mutation in the gene IL1RN, responsible for the production of the natural antagonist receptor of IL1.
Cases have been identified in Puerto Rico, Newfoundland (Canada), the Netherlands, Lebanon, and India. It is estimated that the disease may occur as frequently as 1: 6,300 patients in Puerto Rico.
Symptoms, Flares & Triggers
Children with DIRA present with: systemic inflammation at/or within days of birth, bone pain, multifocal sterile osteolytic bone lesions (as seen on radiographs), widening of multiple anterior ribs, periostitis, pustular skin lesions/rash (prominent in the back and upper forehead), skin pathergy, and elevated acute phase reactants. Affected individuals show symptoms such as fetal distress, enlargement of liver and spleen, joint swelling, oral lesions, and pain with movement. Fever is typically absent.
Without treatment the disease progression leads to a cytokine storm, which is due to these proteins including interleukins, lymphokines and cell signal molecules, triggering inflammation. Often these untreated patients will develop acute respiratory distress that is often misdiagnosed as sepsis (life-threatening response to infection).
Diagnosis & Diagnostic Criteria
Genetic analysis is essential to establish the diagnosis.
Treatments
Treatments for DIRA are based on high doses of corticosteroids and anti-IL blockers such as anakinra and rilonacept.
Laboratory Tests & Findings
The inflammatory markers such as ESR (erythrocyte sedimentation rate) and CRP (C-reactive protein) are typically elevated.
DADA2
Deficiency of Adenosine Deaminase 2 (DADA2) is a rare genetic disease that is comprised of systemic inflammation, immunodeficiency, vasculitis, early onset stroke, and bone marrow dysregulation. DADA2 may present as chronic, mild, or severe, and can damage vital organs and several body systems.
DADA2 may begin at any time, but typically presents in early childhood before age one and up to age 10 years old. Early onset (infancy) cases may present with bone marrow failure. The abnormal inflammation may affect the skin, gastrointestinal tract, liver, kidneys, vessels, and nervous system. The disease can be disabling or even life-threatening, depending on the patient’s unique presentation and location of the inflammation. The clinical presentation is categorized by inflammatory/vasculitis, immune dysregulation, and haematological issues. However, patients may have an overlap and express with a variety of symptoms.
Genetics & Epidemiology
DADA2 is caused by variants in the CECR1 gene, and it is recessively inherited, thus correct encoding for the enzyme Adenosine Deaminase 2 or ADA2 is insufficient.
The identified population is approximately 600 patients based on the medical literature and it is estimated there are likely 35,000+ individuals globally undiagnosed.
Symptoms, Flares & Triggers
Disease presentation may vary in frequency and severity among patients, even within the same family. Dermatological symptoms include the appearance of livedo reticularis, livedo racemosa, and cutaneous vasculitis, which are often initially diagnosed as polyarteritis nodosa (PAN). Patients may also experience peripheral neuropathy and muscle problems. Bone marrow failure and pure red cell aplasia may also present in severe cases.
Early onset neurological symptoms including ischemic stroke, intracranial hemorrhage, and neuropathy are key features of DADA2. Additionally, recurrent fevers, anemia, cytopenia, neutropenia, joint pain, enlarged lymph nodes, fatigue, and others, may impact the patient. Repeated infections related to Primary immune deficiency (PID) may also be present.
The disease may also cause blood vessel abnormalities in a variety of organs resulting in enlargement or dysregulation (liver, spleen, kidneys, heart) due to aneurysm, infraction, stenosis, amyloidosis, and myopathy. The gastrointestinal tract may also be affected with hemorrhage, ischemia, necrosis, bowel perforation, colitis, diarrhea, abdominal pain, and constipation.
Diagnosis & Diagnostic Criteria
Genetic testing is used to diagnose DADA2.
Treatments
Treatment for patients with vasculitis or systemic inflammation includes TNF inhibitors such as etanercept, adalimumab, infliximab, and golimumab, as well as biosimilars. DMARDs, steroids, and other biologics such as IL-6 inhibitors may also reduce symptoms.
Treatment for patients with bone marrow failure and immune deficiency may include gamma globulin replacement and hematopoietic stem cell transplantation (HCT).
Laboratory Tests & Findings
Laboratory tests include ESR, CRP, SAA, serum immunoglobulin levels, CBC, iron and ferritin values, ANA autoantibodies, anti-neutrophil cytoplasmic antibodies (ANCA), and antiphospholipid antibodies. Additionally, an enzymatic test for determining Adenosine Deaminase levels is now available.
Autoinflammatory Diseases
Autoinflammatory diseases are a group of rare disorders caused by genetic or acquired defects due to abnormal activation of the innate immune system. Faulty inflammasome, elevated interleukins (1 α /β, IL-6, TNF-α, etc) and caspase pathways are triggers for systemic and localized inflammation.
This abnormal activation causes recurrent episodes of fever, abdominal pain, joint inflammation & swelling, urticaria/rashes, headaches, mouth/genital ulcers, etc, and if left untreated, the inflammation can damage vital organs. Inflammatory markers in blood work (CRP, ESR, SAA) may or may not be elevated during flares. Additionally, these diseases can range from mild to severe presentation, and may be substantially debilitating causing pain and fatigue. People of all ages, ethnicities, and genders can be affected by autoinflammatory diseases.
A patient’s quality of life may be severely impacted due to a diagnosis delay, as these diseases are not well known to the medical community. Additionally, they are difficult to diagnose and treat due to their complexity and rare nature. If a potential patient has recurrent symptoms, it is important to advocate for an autoinflammatory investigation. Physicians who typically recognize these diseases are expert rheumatologists or immunologists and may work for specialized centers. Therefore, travel may be necessary to obtain a correct diagnosis.
DITRA is an autosomal recessive (hereditary) autoinflammatory disease caused by mutations in the IL36RN gene. It is a rare, potentially life-threatening autoinflammatory disease characterized by repeated episodes of high fever, the sudden onset of generalized pustular psoriasis (GPP), asthenia, and systemic inflammation. In most cases, symptoms are present in neonates or develop during early childhood or adolescence. However, the age of onset may vary considerably and even presenting in adulthood.
Genetics & Epidemiology
DITRA is often used to describe rare cases of generalized pustular psoriasis (GPP) originating from the IL36RN mutation. The scope of the disease has widened to now include other gene mutations that enhance the inflammatory cascade and the recruitment of neutrophils and macrophages in a subgroup of GPP patients. These include mutations in the CARD14 gene that encodes caspase-activating recruitment domain member 14 and in the AP1S3 gene that encodes adaptor protein complex 1 subunit sigma 3. These associated variants in CARD14 and/or AP1S3 were identified in 15% of IL36RN mutation carriers, indicating an oligogenic (few) instead of monogenic inheritance pattern. Worldwide, approximately 200 cases have been reported.
Symptoms, Flares & Triggers
Patients suffering from this syndrome often present with the following symptoms:
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Flares of acute generalised skin pustulation (raised bumps filled with pus)
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Fever
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Systemic inflammation
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General malaise
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Elevated leukocytosis (increased number of white cells) during flares
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Geographic tongue
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Nail dystrophy
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Failure to thrive
Other phenotypes of the IL36RN mutation may include:
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Related pustular disorders
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Palmoplantar pustulosis (of palms and soles)
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Acrodermatitis continua of Hallopeau (abbr. ACH, a rare inflammatory disease characterized by pustular eruptions beginning in the tips of fingers and toes)
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Acute generalized exanthematous pustulosis (a sudden skin eruption, also known as pustular drug eruption)
Flare ups may present at irregular intervals and may last days to weeks, with some chronic symptoms lingering in between.
Flares may be triggered by viral and bacterial infections (e.g., urinary tract; gastroenteritis; upper respiratory tract; bronchitis, common cold, and sinusitis), stress, medication use (penicillin, sulfonamides, codeine, paracetamol, metamizole, acetylsalicylic acid, verapamil), withdrawal of drug use (retinoid, methotrexate, corticosteroids), menstruation, pregnancy, red wine, and surgical interventions.
Diagnosis & Diagnostic Criteria
If DITRA is suspected based on the symptom presentation of the patient, genetic testing should be performed.
Treatments
DITRA may be treated with a variety of biological inhibiting medications including TNF-alpha (adalimumab), IL-12/23 (ustekinumab), and IL- 17 (secukinumab), and IL-1 (anakinra). Topical and oral steroids, vitamin D3, and acitretin may also be used.
Other treatments have included:
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Intravenous methylprednisolone (steroids)
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Cefotaxime and co-trimoxazole (antibiotics)
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Methotrexate (DMARD)
Laboratory Tests & Findings
Blood tests should be done, looking for elevations in C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). A complete blood count (CBC) should be done to measure white blood cell (WBC) counts to identify leukocytosis with neutrophilia. Asthenia or muscle weakness may be identified with nerve testing and imaging. Skin biopsies may be used to determine infection or clarify further diagnosis.
DITRA
FMF
HA20 (A20 haploinsufficiency) is an early onset autoinflammatory disease resembling Behçet disease. The major phenotype of HA20 is Behçet disease–like symptoms, including a recurrent aphthous stomatitis (mouth ulcers), genital ulcers, and intestinal symptoms. Some patients present with not only the symptoms of autoinflammatory disorders but also several autoimmune-like symptoms. HA20 might be difficult to differentiate from other autoinflammatory disorders.
Patients with HA20 are juvenile-onset and partially resemble those with Behçet disease, but their phenotypes (phenotype is the observable characteristics of an organism that result from the interaction of its genotype [total genetic inheritance]) are distinct from those of classical Behçet disease. The patients with HA20 showed an excess production of proinflammatory cytokines. Proinflammatory cytokines are increased during flares. The disorder results from inappropriate activation of inflammatory cytokines; treatment with tumor necrosis factor (TNF) inhibitors may be beneficial.
Genetics & Epidemiology
Mutations in the TNFAIP3 gene have been found to cause haploinsufficiency of A20 (HA20).
Symptoms, Flares & Triggers
Early-onset systemic inflammation, recurrent fevers, arthralgia/arthritis, skin lesions musculoskeletal disorders, autoimmune thyroid disorder/psoriasis/atopic dermatitis, recurrent oral, genital and/or gastrointestinal ulcers are the hallmark features of HA20. The frequency and intensity of other clinical manifestations including eye issues, vascular problems and CNS symptoms may vary. The duration of flares averages between 1 day and 2 weeks, and frequency is variable. Proinflammatory cytokines are increased during flares.
Diagnosis & diagnostic criteria
Due to the extensive heterogeneity of HA20, it makes it almost impossible to set clinical diagnostic criteria. Therefore, genetic sequencing is necessary for a definitive diagnosis of HA20.
Treatments
Treatment regimens may be based on disease severity, and location of mutation. Treatments may include colchicine, biologics IL-1 or TNFα inhibitors, sulfasalazine, and thalidomide. Corticosteroids and immunosuppressive agents are often effective treatments, and cytokine antagonists may be used in refractory cases.
Laboratory Tests & Findings
Laboratory tests include CBC with differential, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Other tests should include ferritin/storage, fibrinogen, platelets, albumin, and triglycerides.
Findings may include elevated white blood cells (WBC), C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR). Patients should be tested and may be positive for antinuclear antibodies, anti-Sjögren’s syndrome antigen A, dsDNA, rheumatoid factor, Coombs test, and thyroid antibodies.
HA20
Mevalonate Kinase Deficiency (MKD) is a rare autoinflammatory disease characterized by clinically recurrent fever episodes are accompanied with rash, abdominal pain, swollen lymph nodes, etc. Hyper-IgD-Syndrom (HIDS) is the less severe form and MA being less common and of more severe presentation. Amyloidosis and growth delay, although rare, are the two serious potential complications of this disease. The onset is typically in infancy.
Genetics & Epidemiology
HIDS is caused by mutations in the gene MVK, which produces the enzyme mevalonate kinase, and is inherited in an autosomal recessive manner. Most people with the disorder are individuals of western European heritage, with approximately 60% occurring in Dutch or French individuals, but it also affects other ethnic groups. A recent case demonstrated a HIDS-like presentation in a related gene PMVK (phosphomevalonate kinase) and in the future, it may be relevant to sequence this gene. HIDS has an incidence of 1:50,000 to 1:5,000.
Symptoms, Flares & Triggers
The recurrent symptoms during flares include:
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Fever
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Chills
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Headache
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Swelling of lymph nodes (lymphadenopathy) in the neck
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Abdominal pain
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Arthralgia(pain)
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Rash (non-migratory maculopapular)
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Arthritis (joint inflammation)
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Serositis
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Fatigue
Additional symptoms include:
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Nausea
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Oral/genital ulcers
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Diarrhea
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Hepatomegaly (enlargement of the liver)
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Splenomegaly (enlargement of the spleen)
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Vomiting
The skin lesions or rash may be described as urticarial (hive-like), reddish (erythematous), small flat spots (macules), raised bumps (papules or nodules), as well as measle-like (morbilliform). Less common rashes include petechiae and Henoch-Schönlein purpura. Some patients may have pharyngitis. Affected children often have a high, spiking fever that may cause febrile seizures. Children are also more likely to have an enlarged spleen.
The first flare usually occurs during infancy, before age 1. There is often an abrupt onset of fever with no associated infection. Most flares last from three to seven days and occur approximately every 1–2 months. The frequency of flare episodes and their severity vary greatly from person to person throughout their lifetime. Flares can occur spontaneously or be triggered by vaccinations, infections, physical and/or emotional stress and trauma (i.e. accidents, surgery).
Diagnosis & Diagnostic Criteria
A HIDS diagnosis is based upon a thorough clinical evaluation, identification of characteristic symptoms (e.g., lifelong recurrent fevers not due to infection), and a variety of blood and urine tests. High levels of immunoglobulin D (IgD) is indicative of mevalonate kinase deficiency, but does not confirm a diagnosis. There are patients who have normal IgD levels, while others may express with elevated IgA. Some patients do not express with either. Patients with mevalonic aciduria (MA) may suffer from developmental delay, failure to thrive, retinal dystrophy, cataracts & uveitis, mild facial deformities, liver/spleen enlargement, anemia, and myopathy (muscle weakness). Growth and development are usually not affected in HIDS, unlike in MA.
Treatments
Targeted biologic treatment that blocks interleukin-1 such as canakinumab and anakinra are standard treatment for HIDS. Other medications may include: corticosteroids (in particular during flares), colchicine and NSAIDs. IL-6 inhibitor (tocilizumab) may also be used.
Laboratory Tests & Findings
HIDS patients present with elevated inflammatory markers during flares: white cell count (leukocytosis), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and serum amyloid A (SAA).
A urine test may reveal high levels of mevalonate acid, which is indicative of mevalonate kinase deficiency. However, many people with this disorder have normal levels of mevalonate acid outside their flares. Patients with amyloidosis, however, have permanently elevated protein concentrations in the urine.
Pregnancy
HIDS is not associated with complications during pregnancy, and the frequency of flares are diminished. Since HIDS is of autosomal recessive inheritance, it is not transmitted to the fetus in utero.
Hidradenitis Suppurativa
Hidradenitis Suppurativa (HS), also called acne inversa, is a painful, long-term inflammatory skin disease that forms under the skin. It is characterized by persistent or recurrent boil-like nodules, abscesses and scarring on air follicles where there are sweat glands, affecting the groin, buttocks, breasts and armpits.
It often starts after puberty and may persist for many years and worsen over time. It is three times more common in females than in males. However, in women, it may resolve at menopause. HS has serious effects on the patient’s daily life and emotional well-being. Combined medical and surgical therapy can help manage the disease and prevent complications.
Genetics & Epidemiology
While the exact cause of HS is unknown, evidence suggests that genetic factors in PSTPIP1, NCSTN, PSEN1, PSENEN, and AIM2 can play a role in developing this condition due to family history, which is reported in about one-third of patients. Variations in the γ-secretase genes are found mainly in familial cases with an autosomal dominant pattern of inheritance. HS incidence in different countries ranges from 6 per 100.000 people.
Symptoms, Flares & Triggers
Hidradenitis suppurativa can affect one or several areas of the body. Signs and symptoms of this disease include:
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Blackheads – Blackheads appear in small, pitted areas of skin, often appearing in pairs.
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Pea-sized lumps – The condition usually starts with a single, painful lump under the skin that persists for weeks or months. More bumps may form later, usually in areas where you have more sweat and oil glands or where the skin rubs together, such as the armpits, groin, buttocks and breasts.
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Bumps or sores – Bumps or sores may enlarge, break open, and drain pus with an infection and odor.
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Tunnels – Over time, tunnels form under the skin, connecting these glandular lumps and cause painful wounds that usually do not heal very quickly. Additionally, they may drain blood and pus causing an infection to form.
HS flares vary from person to person and may be triggered by heat, stress, and exercise. A flare-up may last 1-2 weeks. Obesity and smoking are strongly associated with HS and are potential triggers.
Diagnosis & Diagnostic Criteria
Diagnosis of HS is made based on the clinical symptoms. Three diagnostic criteria must be met for hidradenitis suppurativa: typical lesions, occurrence in one or more of the predilection areas, and that it is chronic and/or recurrent. Several outcome measures are used, including patient-reported pain and itch scales, Dermatology Life Quality Index, and Hurley Staging.
Treatments
There is no cure for HS, but it can be treated. It is important to have a treatment plan in place for controlling the disease and reducing the symptoms.
There are several treatments available:
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Antibiotics for bacterial infections
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Oral treatments such as hormonal therapies, immunomodulatory and steroids
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Other systemic medical treatments used off-label: acitretin, dapsone, colchicine or Metformin
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Biologics such as TNF blockers, IL-17/23 blockers, IL-1
Other medications are under investigation.
Laboratory Tests & Findings
HS patients may present with increased inflammatory markers C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR), and cytokine levels. Serum IL-6, CRP, and ESR are effective biomarkers for evaluating the severity of HS.
Pregnancy
HS may worsen during pregnancy, as a study demonstrated that half of the women enrolled with HS experienced worsening of symptoms during pregnancy and in the months after giving birth. Pregnant women are more likely to have a C-section, as well as pregnancy-related high blood pressure (hypertension). It is important to be monitored during pregnancy by a dermatologist.
Idiopathic Recurrent Pericarditis
Recurrent pericarditis is a relatively common complication of acute pericarditis. However, in approximately 20% of patients, no specific cause is identified, and the disease is referred to as Idiopathic recurrent pericarditis (IRP). Recurrent pericarditis occurs when symptoms of acute pericarditis return after a symptom-free interval of least four to six weeks. IRP is currently considered a rare autoinflammatory disease characterized by recurrent episodes of sterile inflammation. Recurrent pericarditis may also occur as a symptom in monogenic autoinflammatory diseases such as FMF and TRAPS.
Pericarditis is the swelling and irritation of the pericardium, a sac-like organ with two thin layers of tissue that surround the heart to hold it in place and help it work. A small amount of fluid keeps the layers separate and decreases the friction as the heart beats. For unknown reasons, some patients with this condition have sharp chest pain as the tissues become swollen and irritated. Additionally, they are at risk for fluid build-up around the heart that may lead to other medical problems.
This disease causes the immune system to attack normal bone without the presence of infection or injury. Common features include pain, redness and inflammation primarily affecting the long bones. Other bone sites may be impacted, thus making it a multifocal disease. Fever may be present during flares and may last a few weeks or months. CRMO is often seen as a comorbidity in other autoinflammatory bone diseases: DIRA and Majeed.
Genetics & Epidemiology
Genetic screening is recommended for patients with a family history of pericarditis, autoimmune, vasculitis, connected tissue or autoinflammatory diseases.
Symptoms, Flares & Triggers
Chest pain is the most common symptom of pericarditis and usually presents as a sharp or stabbing pain. However, others may experience a dull, achy or pressure-like pain in the chest.
Pericarditis pain usually occurs behind the breastbone or on the left side of the chest that may spread to the left shoulder and neck. It tends to get worse when coughing, lying down or taking a deep breath. Sitting up or leaning forward may help alleviate symptoms and pain.
Other signs and symptoms of pericarditis include:
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Cough
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Fatigue
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Leg swelling
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Low-grade fever
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Heart palpitations (pounding or racing)
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Shortness of breath
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Swelling of the abdomen
Diagnosis & Diagnostic Criteria
Idiopathic recurrent pericarditis is considered an autoinflammatory disease when distinctive features such as relapsing episodes accompanied by fever and high acute phase reactants [C-reactive protein (CRP), erythrocyte sedimentation rate (ESR)] in the absence of specific autoantibodies or autoreactive T cells.
The diagnosis of acute pericarditis should be based on the presence of at least two of the following four criteria:
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Characteristic chest pain
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Pericardial friction rub
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Characteristic electrocardiographic changes
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New or worsening pericardial effusion
Treatments
According to the most recent Guidelines from the European Society of Cardiology (ESC), there are three levels of treatment for recurrent pericarditis.
NSAID + Colchicine
First or initial line of treatment consists of a combination of aspirin (ASA) or non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, indomethacin, and colchicine.
Corticosteroids + Colchicine
The second line of treatment consists of corticosteroids (prednisone or equivalent) and colchicine for patients who do NOT respond or tolerate aspirin or NSAIDs. Despite this treatment approach, a number of patients either do not respond or cannot tolerate the above therapies.
IL-1 biologics or Azathioprine or Intravenous Immunoglobulins (IVIG)
Approximately 5% of recurrent pericarditis patients who fail to achieve remission with the second level approach. The third line of treatment addresses this small subgroup of patients with refractory pericarditis. Treatment options include IL-1 biologics, azathioprine, and IVIG replacement. For patients who display a complete response (absence of symptoms and with normal CRP), NSAIDs and corticosteroids are gradually tapered and discontinued followed by tapering and discontinuation of colchicine (given at least for 6 months).
Laboratory Tests & Findings
Laboratory workup, including assessment for inflammation and myocardial damage, is also recommended. Cardiac magnetic resonance (CMR) may be helpful when the diagnosis is uncertain, echocardiographic imaging is challenging, or myocardial involvement is suspected.
Majeed syndrome is an autoinflammatory disease presenting in early infancy to age 2, causing recurring fevers, anemia, GI symptoms, enlarged spleen/liver, and neutrophilic dermatosis/Sweet syndrome. CRMO (Chronic Recurrent Multifocal Osteomyelitis) and bone pain are also present and may contribute to joint swelling and contractures.
Genetics & Epidemiology
Majeed syndrome is caused by mutations in the LPIN2 gene, and it is inherited in an autosomal recessive pattern, which means that two copies of the mutated gene are required. Although parent carriers typically do not show signs and symptoms of the condition, some may have psoriasis.
The incidence of Majeed syndrome is rare (1/1,000,000 children). To date, only a few families have been identified with Majeed syndrome, and have been predominantly Middle Eastern.
Symptoms, Flares & Triggers
The disease is characterized by episodes of fevers and painful joint swelling that may lead to complications impacting bone growth and cause joint deformities. Growth patterns may be affected. Additional manifestations may include weakness, shortness of breath, and fatigue due to the red blood cell shortage from congenital dyserythropoietic anemia. Patients may also develop skin issues such as painful blisters or raised bump lesions (Sweet’s syndrome) that may express on the face, neck, and arms. Liver enlargement (hepatomegaly), spleen enlargement (splenomegaly) and diarrhea with abdominal pain are common features.
Multiple flare episodes usually occur monthly presenting with fever, pain and joint swelling, and lasting for several days.
Diagnosis & Diagnostic Criteria
The diagnosis is based on genetic testing.
Treatments
Treatments include non-steroidal anti-inflammatory medications (NSAIDs), corticosteroids, colchicine, TNF-α blockers and IL-1 inhibitors. Physical therapy may be ordered to support bone or joint issues, and blood transfusions may be helpful for the anemia.
Laboratory Tests & Findings
Laboratory tests include erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum amyloid A (SAA), and complete blood count (CBC) for anaemia issues. Imaging studies are recommended.
HIDS/MKD
NLRP12-Associated Autoinflammatory Disease, formerly known as Guadeloupe-type fever syndrome, is characterized by episodic fevers, recurrent urticaria rash, arthralgia, myalgia, and headache. The age at onset is variable, usually beginning in infancy. The clinical presentation of this condition overlaps with Cryopyrin-Associated Periodic Syndromes (CAPS).
Genetics & Epidemiology
NLRP12-associated autoinflammatory disease is referred to as FCAS2 (Familial Cold Autoinflammatory Syndrome type 2) and caused by autosomal dominant mutations in the NLRP12 gene, and is also known as Monarch-1, which is involved in the inhibition of the inflammatory response. One copy of the altered gene in each cell is sufficient to cause the disorder.
Prevalence: <1 / 1 000 000. NLRP12 was originally identified in two families from Guadeloupe (Antilles) and other cases have been reported in the USA, Armenia, France, Italy, and Martinique.
Symptoms, Flares & Triggers
FCAS2 presents with fever, joint pain, and urticarial rash, but may also have headaches, arthralgias (often affecting the hands, knees, and ankles), myalgias, abdominal pain, chills, joint swelling, adenopathy, mouth ulcers, and conjunctivitis. Usually, symptoms begin after exposure to cold temperatures. The most severely affected patients may suffer from sensorineural hearing loss. Rashes, may be described as itchy or burning, often begin on the face or extremities and may spread to the rest of the body. Occasional swelling in the extremities may occur.
Flares typically last 5–10 days with fevers 39–40 °C (102–104 °F), and often also accompanied by rash, pain, fatigue, and malaise. Patients often present more than one attack per month. Chills, sweating, drowsiness, headache, thirst, and nausea may also occur during flare episodes. Patients report that cold and physical exertion are major triggers for episodes.
Diagnosis & Diagnostic Criteria
Diagnosis may be made based on clinical symptoms (recurrent fever, rash, etc), family medical history, and genetic testing. Patients may or may not present with elevated acute phase reactants (CRP, etc) during a flare. Genetic testing will help rule out similar diseases such as Cryopyrin-Associated Periodic Syndromes (CAPS).
Treatments
The treatments for NLRP12 may include NSAIDs, corticosteroids (i.e. prednisone) and IL-1 blockade with anakinra and canakinumab. At this time, there are no medications that are uniformly effective for all patients.
Laboratory Tests & Findings
Laboratory findings including C-reactive protein (CRP), serum Amyloid A protein (SAA) and complete blood count (CBC) are all important to monitor during a flare. Labs are also recommended between flares.
Majeed Syndrome
PAAND is a rare disease that shares some clinical features with Familial Mediterranean Fever (FMF) and is differentiated by cytokine differences and activation of a binding pyrin motif. PAAND is characterized by chronic systemic inflammation with fever, arthralgia, myalgia, and neutrophilic dermatosis (e.g. acne, pyoderma gangrenosum). Gastrointestinal manifestations may also be present and debilitating.
Genetics & Epidemiology
Reported cases of PAAND have been associated with a dominant p.S242R mutation in the MEFV gene. The MEFV gene encodes for pyrin causing elevated IL-1β serum levels. PAAND is inherited in an autosomal-dominant pattern and clinically presents during childhood with longer fever episodes (several weeks) unlike Familial Mediterranean Fever. Only a single copy of the mutation is required to cause this disease and affects 50% of the children born to adult patients.
Symptoms, Flares & Triggers
PAAND is characterized by sterile skin abscesses, long episodes of high fever, myalgia, myositis, fatigue, and it is not characterized by serositis or amyloidosis. Skin manifestations closely resemblance patients with PAPA (pyogenic arthritis, pyoderma gangrenosum, and acne); however, patients lack the pyogenic arthritis. Other symptoms include maculo-papular and pustular skin rash on the perioral region and upper and lower extremities, perineal mucosal inflammatory lesions, abdominal pain, failure to thrive, developmental delay, episodic myalgias and arthralgias.
Treatments
Colchicine, IL-1β, and TNF-α blockers are used for the treatment of PAAND.
Laboratory Tests & Findings
Lab tests should include erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum amyloid A (SAA), HLA-B27, ferritin and related labs, as anemia may be present in these patients. Skin biopsies may be recommended as well.
PFAPA Syndrome
PFAPA syndrome (periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis) is the most common cause of periodic fever in children. It typically starts in early childhood (between ages 2 yrs and 5 yrs) and tends to be more common among males. Children usually grow out of PFAPA. However, there is evidence that in a few cases, it may persist into adulthood. PFAPA is not caused by an infection, nor is it contagious or treatable with antibiotics.
Genetics & Epidemiology
No genetic marker for PFAPA has been identified as of yet, and its etiology remains unknown. It is recommended that patients are screened clinically and genetically for other known periodic syndromes prior to receiving a PFAPA diagnosis. Positive family history may be relevant.
Negative genetics means that no identifiable variants for autoinflammatory syndrome have been found. However, this does NOT rule out having an autoinflammatory disease.
Many patients who have clinical autoinflammatory symptoms are often diagnosed as uSAID (undefined systemic autoinflammatory disease) if no genetic mutation is found. For example, approximately 25-30% of Familial Mediterranean Fever patients have no identifiable variants yet are treated with colchicine if symptomatic. In 40-60% of patients with SAIDs (systemic autoinflammatory diseases) are diagnosed as uSAID.
Symptoms, Flares & Triggers
PFAPA symptoms include recurrent episodes of fever ranging from 38.5–41 °C (101.3 to 105.8 °F) lasting approximately 4–5 days and recurring every 3–6 weeks. In between flares, patients are symptom free.
Other clinical features include:
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Sore throat (pharyngitis)
-
Tonsilitis
-
Mouth & canker sores
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Swollen lymph nodes (neck)
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Abdominal pain
-
Nausea/vomiting
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Diarrhea
-
Leg pain (arthralgias with no permanent joint or bone issues)
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Fatigue
-
Malaise
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Headaches
-
Febrile seizures
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Rashes (uncommon)
What PFAPA is NOT:
PFAPA may mimic other rheumatic, PIDs (primary immunodeficiencies), autoimmune, or autoinflammatory diseases. To ensure that a patient is not being misdiagnosed, the following should be a “red flag” for further medical investigation:
-
Urticaria/rashes
-
Respiratory/lung infections
-
Early onset (PFAPA does not occur in the first few months of life)
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Proteinuria
-
Symptoms presenting between flares
Diagnosis & Diagnostic Criteria
PFAPA diagnosis is based on clinical findings and diagnostic criteria:
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Regularly recurring fevers with an early age of onset (<5 years of age) (usually between 2-3 years of age)
-
Constitutional symptoms in the absence of upper respiratory infection and with at least 1 of the following clinical signs:
-
Mouth ulcers or aphthae (aphthous stomatitis)
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Lymph nodes in the neck (cervical lymphadenitis)
-
Sore throat (pharyngitis)
-
-
Completely asymptomatic intervals between episodes
-
Normal growth and development
When considering the diagnosis of PFAPA syndrome, the physician must have a clear knowledge and understanding of the differential diagnosis that includes syndromes such as cyclic neutropenia, hereditary fevers, and Behçet disease.
Febrile episodes, called flares, last 4–5 days and recur every 3–6 weeks. The syndrome causes fevers as well as sore throat, mouth ulcers, swollen lymph nodes, fatigue, chills, abdominal pain, and headache. Patients are symptom-free between episodes, and flares resolve spontaneously.
Treatments
There are several options for treating PFAPA and medications may be combined based upon the patient’s needs.
Symptomatic: NSAIDs (ie Ibuprofen: Advil, Motrin) and paracetamol (Tylenol) are used to manage the symptoms of fever and pain.
Abortive: Corticosteroids, usually a single dose, is given to stop the flare and associated inflammation.
Prophylaxis: Daily medications such as cimetidine (liquid form) and colchicine (pills/capsules) may also be given to prevent PFAPA from flaring.
Surgical: Patients flaring more often using corticosteroids or non-responsive to cimetidine or colchicine may elect to undergo both T&A (tonsillectomy and adenoidectomy).
There are no medications to cure PFAPA. However, corticosteroids are highly effective in aborting the flares. A single dose of prednisone (1– 2 mg/kg) given at the onset of an episode can dramatically abort fever attacks within a few hours (it may take up to 4 hours). Mouth ulcers, however, can take longer to resolve. If one dose is not effective, a second dose may be given the following day or as prescribed by the doctor. The administration of this medication does not prevent future flares, and in some cases, the use of corticosteroids may cause the patient to flare more often.
Laboratory Tests & Findings
Laboratory testing for PFAPA should include complete blood count (CBC), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and serum amyloid A (SAA – not available in USA), and should be checked during and between flares to ensure that the inflammation resolves.
NLRP12-AID
PLCG2 associated antibody deficiency and immune dysregulation (PLAID) is a complex dominantly inherited disease characterized almost universally by cold urticaria (hives), and variably by recurrent bacterial infection, autoimmunity and skin granuloma formation. Several striking phenotypes can emerge from this disease, and the pathophysiology leads to a complex mix of loss and gain of function in cellular signalling.
Symptoms, Flares & Triggers
Some individuals with PLAID can develop a burn-like rash at birth in areas more likely to get cold, such as the nose. People with PLAID may also have recurrent bacterial infections, autoimmune symptoms and an increased likelihood of developing an autoimmune disorder, and a burning sensation in the throat when eating cold foods.
Autoinflammation and PLCG2-associated antibody deficiency and immune dysregulation (APLAID) is an autosomal dominant systemic disorder characterized by recurrent blistering skin lesions with a dense inflammatory infiltrate and variable involvement of other tissues, including joints, eyes, and the gastrointestinal tract. Affected individuals have a mild humoral immune deficiency associated with recurrent sinopulmonary infections (involving, or affecting the paranasal sinuses and the airway of the lungs), but no evidence of circulating autoantibodies. The symptoms were partially responsive to an IL1 inhibitor and high-dose corticosteroids.
Treatments
No treatments that target the underlying cause of PLAID and PLAID-like diseases exist, so people with PLAID are advised to avoid allergic triggers by warming rapidly after showers, avoiding drafts, and towelling off sweat. Antihistamines are used to treat allergic reactions.
Watch a time-lapse video from the NIH. In this video, once can see infrared footage of the inflammatory response in a person with cold allergy, a condition known as cold urticaria.
PAAND
PAPA syndrome (pyogenic Arthritis, Pyoderma gangrenosum and Acne) is a rare genetic disease characterised by its effects on the skin and joints. It affects the skin and joints in children and adolescents. PAPA stands for the manifestations of this condition including pyogenic arthritis, pyoderma gangrenosum and acne, which may present differently in individual cases.
Genetics & Epidemiology
PAPA syndrome is caused by mutations in the PSTPIP1 gene, which causes increased pyrin binding, resulting in activation of the NLRP3 inflammasome and increased levels of IL-1β. A single mutation in this gene confirms the genetic diagnosis as this disorder is autosomally dominant (inherited disorder). Phenotype-genotype associations demonstrate that patients with cysteine substitutions have a more severe disease presentation and may have a higher risk of secondary amyloidosis.
The prevalence of PAPA syndrome is approximately 0.01 case per 100,000 individuals worldwide. According to a 2018 paper, there are 53 cases of PAPA syndrome reported in the literature. The disease commonly affects children, but may develop later in life for some adults, and affect men and women equally. PAPA syndrome cases have been reported in Europe, New Zealand, and the USA.
Symptoms, Flares & Triggers
PAPA syndrome presents with recurrent episodes of pyogenic arthritis and may present with fevers during flares. The joints at disease onset typically manifest with mono- or oligoarticular (affecting a few joints) but may become polyarticular (affecting many joints) over time. The arthritis is severe and may lead to joint destruction, deformities, stiffening and immobility due to fusion of the bones (ankylosis). Joint radiographs may be normal or may show erosions and deformities in patients with PAPA.
Cystic acne usually begins in early puberty and continues into adulthood. Acne is nodulocystic involving the face and the upper back and varies in severity. Pyoderma gangrenosum is also a feature of PAPA and causes large, deep cutaneous ulcerations, typically located on the lower extremities, and is characterised by poor healing and rolled edges. This is one of the most challenging symptoms to treat.
Diagnosis & Diagnostic Criteria
Diagnosis of PAPA syndrome is based on clinical findings, including imaging, skin presentation, family history, and genetics. The ulcers may be biopsied, and pathology may show superficial ulceration with neutrophilic infiltrate. Acne biopsies may show burrowing and interconnecting abscesses and scars. Other neutrophilic dermatoses such as Sweet’s syndrome should be ruled out.
Treatments
Corticosteroids are useful in management of both articular and cutaneous manifestations, although high doses are often required to control the disease. The skin lesions of PAPA have responded to TNF inhibitors (i.e. etanercept), as well as IL-1 inhibitors (anakinra, canakinumab). Acne may be treated with oral tetracycline or isotretinoin. The treatment of PG in PAPA can be challenging, requiring high doses of immunosuppressants, which may only have partial efficacy. Colchicine has been trialled but is not effective.
Laboratory Tests & Findings
Inflammatory markers such as erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and SAA may be elevated during and between flares. Peripheral WBC counts may be elevated with a neutrophilic predominance as well as ferritin, which may also be a marker of acute inflammation.
Pregnancy
There is limited data due to the rarity of the disease. However, the risk of cardiovascular events associated with pregnancy requires further investigation.
SAPHO Syndrome
SAPHO syndrome is an acronym name for symptoms of synovitis, acne, pustulosis, hyperostosis, and osteitis and is considered a rare autoinflammatory disorder of bone, joints, and skin, which currently has no identifiable genetic association. Neutrophilic cutaneous involvement presenting as skin lesions and chronic osteomyelitis (lesions and inflammation of the bones) are also disease manifestations.
Genetics & Epidemiology
The genetic of SAPHO syndrome remains unknown and is a rare disease with limited data available regarding its prevalence, which is estimated as 1 in 10,000. It may impact European Caucasian populations at a higher rate. However, cases have been found in other parts of the world, suggesting a worldwide distribution. Individuals between the ages of 30 and 50 appear more frequently affected with a female predominance, especially in patients less than 30 years of age.
Symptoms, Flares & Triggers
SAPHO syndrome is characterized by multiple bone and joint issues that may present with pain, swelling, and tenderness and may be chronic or episodic, relapsing, focal or multifocal. These clinical features include synovitis, osteitis, and hyperostosis. The disease may affect a variety of regions in the body, including the anterior chest wall, axial skeleton, sacroiliac joint and spine, and medium/large lower-extremity joints.
The skin manifestations include a spectrum of follicular occlusions and neutrophilic dermatoses including severe acne, hidradenitis suppurativa, palmoplantar pustulosis, and pyoderma gangrenosum. Most patients present with palmoplantar pustulosis and severe acne. It is important to note that the skin manifestations and skeletal abnormalities may not coexist and may be separated by many years.
Diagnosis & Diagnostic Criteria
The diagnosis of SAPHO syndrome can be challenging due to the wide variety of clinical features and should be suspected in patients with bone and joint issues, especially if they appear concurrently or formerly with skin manifestations including palmoplantar pustulosis (PPP), severe acne conglobate/ fulminans, psoriasis, and hidradenitis suppurativa. Pyoderma gangrenosum is a less frequent manifestation. Dermatological manifestations are often resistant to therapy and tend to have a chronic and protracted course.
A diagnosis of SAPHO syndrome is a diagnosis of exclusion to rule out infectious, malignant, or other rheumatic etiology including arthritis, axial spondyloarthritis, or psoriatic arthritis.
Bone scintigraphy, x-rays and MRI all help to identify features of SAPHO. It is also recommended to have an evaluation of your bone density every couple of years. Early SAPHO may be difficult to distinguish from osteomyelitis, as they may both present with a local site of bone pain, tenderness, warmth, and swelling, with an associated fever.
Malignant disorders of bone such as osteosarcoma and metastatic cancer should be considered. Both osteosarcoma and SAPHO may present with localized bone pain and surrounding swelling and without systemic symptoms. However, unlike SAPHO, osteosarcoma typically occurs in a single bone lesion, often affects the long bones, and has distinct radiographic features. A biopsy can establish a definitive diagnosis.
Treatments
Sapho may be treated with a variety of medications. The goals for treatment are to reduce the pain, improve the ability to move, and to improve the quality of life.
The first line of treatment remains NSAIDs (nonsteroidal anti-inflammatory drugs) on demand, which are effective for painful flare-ups. During the course of the disease, these and other medications may become insufficient or ineffective for reasons unknown. If NSAIDs are not effective, other drugs can be used:
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DMARDs (methotrexate (MTX), sulfasalazine, cyclosporine, thalidomide)
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Colchicine
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Corticosteroids (prednisone)
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Bisphosphonates (pamidronate)
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Anti-TNT biologics (etanercept, infliximab, adalimumab, certolizumab, certolizumab)
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IL-1 (anakinra)
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IL-6 (tocilizumab)
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IL-23 (ustekinumab)
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IL-17 (secukinumab)
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JAK inhibitors (tofacitinib, apremilast, abatacept, rituximab)
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Tripterygium wilfordii Hook F. (Chinese herb)
-
Antibiotic therapy targeted for acne is often used
Laboratory Tests & Findings
There are no specific laboratory findings of SAPHO. However, the following tests are recommended:
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Complete blood count and liver and kidney chemistries
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Markers of inflammation, including C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)
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Rheumatoid factor and anticyclic citrullinated peptide antibodies, which are often positive in patients with rheumatoid arthritis, and may be helpful if there is diagnostic uncertainty, depending upon the clinical findings
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Human leukocyte antigen (HLA)-B27 testing, which would be positive more often in patients with spondyloarthritis and may be helpful if there is diagnostic uncertainty, depending upon the clinical findings
Sarcoidosis
Sarcoidosis is the growth of tiny collections of inflammatory cells (granulomas) in different parts of your body – most commonly the lungs, lymph nodes, eyes and skin. It is believed that sarcoidosis results from the body's immune system responding to an unknown substance, most likely something inhaled from the air. There is no cure for sarcoidosis, but most people do very well with little or only minor treatment. In half of the cases, sarcoidosis goes away on its own. In a few cases, however, sarcoidosis may last for years and may cause organ damage.
Genetics & Epidemiology
The exact cause of sarcoidosis is not yet known. Some people appear to have a genetic predisposition to develop the disease, which may be triggered by bacteria, viruses, dust or chemicals. This triggers an overreaction of your immune system, and immune cells begin to collect in a pattern of inflammation called granulomas. As granulomas build up in an organ, the function of that organ can be affected.
While anyone can develop sarcoidosis, factors that may increase your risk include:
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Age and sex – Sarcoidosis often occurs between the ages of 20 and 40, women are slightly more likely to develop the disease
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Race – African-Americans have a higher incidence of sarcoidosis than do white Americans. Also, sarcoidosis may be more severe and may be more likely to recur and cause lung problems in African-Americans.
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Family history – If someone in your family has had sarcoidosis, you're more likely to develop the disease
For most people, sarcoidosis resolves on its own with no lasting consequences. But sometimes it may cause long-term problems.
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Lungs – Untreated pulmonary sarcoidosis can lead to permanent scarring in your lungs, making it difficult to breathe.
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Eyes – Inflammation can affect almost any part of your eye and can eventually cause blindness. Rarely, sarcoidosis also can cause cataracts and glaucoma.
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Kidneys – Sarcoidosis can affect how your body handles calcium, which can lead to kidney failure.
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Heart – Granulomas in your heart can cause abnormal heart rhythms and other heart problems. In rare instances, this may lead to death.
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Nervous system – A few people with sarcoidosis develop problems related to the central nervous system when granulomas form in the brain and spinal cord. Inflammation in the facial nerves, for example, can cause facial paralysis.
Symptoms, Flares & Triggers
Signs and symptoms of sarcoidosis vary depending on which organs are affected. Sarcoidosis sometimes develops gradually and produces symptoms that last for years. Other times, symptoms appear suddenly and then disappear just as quickly. Many people with sarcoidosis have no symptoms, so the disease may be discovered only when you have a chest X-ray for another reason.
General symptoms
For many people, sarcoidosis begins with these symptoms:
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Fatigue
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Fever
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Swollen lymph nodes
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Weight loss
Lung symptoms
Many patients with sarcoidosis experience lung problems, which may include:
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Persistent dry cough
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Shortness of breath
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Wheezing
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Chest pain
Skin symptoms
Some people who have sarcoidosis develop skin problems, which may include:
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A rash of red or reddish-purple bumps, usually located on the shins or ankles, which may be warm and tender to the touch
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Disfiguring sores (lesions) on the nose, cheeks and ears
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Areas of skin that are darker or lighter in colour Growths under the skin (nodules), particularly around scars or tattoos
Eye symptoms
Sarcoidosis can affect the eyes without causing any symptoms, so it's important to have your eyes checked. In case eye symptoms occur, these may include:
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Blurred vision
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Eye pain Severe redness
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Sensitivity to light
Diagnosis & Diagnostic Criteria
Sarcoidosis can be difficult to diagnose because the disease produces few signs and symptoms in its early stages. When symptoms do occur, they may mimic those of other disorders. Your doctor will likely start with a physical exam, including a close examination of any skin lesions you have. He or she will also listen carefully to your heart and lungs and check your lymph nodes for swelling.
Diagnostic tests can help exclude other disorders and determine what body systems may be affected by sarcoidosis.
The following tests may be recommended:
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Chest X-ray to check for lung damage or enlarged lymph nodes
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Computerized tomography (CT scan) if complications are suspected
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Positron emission tomography (PET) scan or magnetic resonance imaging (MRI) if sarcoidosis seems to be affecting your heart or central nervous system
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Blood tests to assess your overall health and how well your kidneys and liver are functioning
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Lung (pulmonary) function tests to measure lung volume and how much oxygen your lungs deliver to your blood
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Eye exam to check for vision problems that may be caused by sarcoidosis
Treatments
There's no cure for sarcoidosis, but in half of cases it goes away on its own. You may not even need treatment if you don't have significant signs and symptoms of the condition, but you should be monitored with regular chest X-rays and exams of the eyes, skin and any other organ involved.
Laboratory Tests & Findings
Your doctor may order a small sample of tissue (biopsy) be taken from a part of your body believed to be affected by sarcoidosis to look for the granulomas commonly seen with the condition. Biopsies can most easily be taken from your skin if you have skin lesions. Biopsies can also be taken from the lungs and lymph nodes if needed.
PLAID/APLAID Syndrome
STING-Associated Vasculopathy with Onset in Infancy (SAVI) is a type I interferonopathy autoinflammatory disease causing abnormal inflammation throughout the body, especially in the skin, blood vessels, lungs, and joints. There are multiple genetic pathways within STING1 that cause a variety of symptoms that may impact each patient differently.
Genetics & Epidemiology
SAVI is caused by gain-of-function mutations in TMEM173. This gene provides instructions for the production of a protein called STING, which is involved in production of beta-interferon. This disease is inherited in an autosomal dominant pattern, which means a single copy of the gene may be pathogenic. Its prevalence is unknown with 70 plus cases appearing in the medical literature to-date.
Symptoms, Flares & Triggers
The signs and symptoms of SAVI begin in the first months of life, and typically present as fever (high or low temperatures), rash, swollen lymph nodes, peripheral acral vasculitis (small vessel)/livedo reticularis, muscular weakness (hypotonia), musculoskeletal involvement (myositis and arthritis), respiratory issues (interstitial lung disease and pulmonary fibrosis), and fatigue.
Skin lesions (neutrophilic infiltrate) may appear on the face, ears, nose, fingers, and toes, and may range in severity. Complications may include a nasal septum perforation or amputation of a fingers or toes. Nail clubbing has been described in some patients. Neurodevelopmental delay and failure to thrive have been noted.
Triggers to cold may set off episodes of Raynaud’s, where fingers and toes turn white or blue in response to cold temperatures.
Diagnosis & Diagnostic Criteria
SAVI is diagnosed through genetic testing where variants are found in the TMEM173 gene.
Treatments
Treatment regimens include steroids and immunosuppressive therapies have shown mixed results. JAK inhibitors such as tofacitinib, ruxolitinib, and baricitinib block the effect of the antiviral molecules, and have shown clinical efficacy. However, infections (shingles, viral respiratory infections, rotavirus enteritidis, and aspergilloma in lung) on these medications must be carefully monitored.
Laboratory Tests & Findings
SAVI presents with elevations in erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP).
Schnitzler Syndrome
Schnitzler syndrome is a rare autoinflammatory disease usually of adult-onset, with the main features being chronic urticarial rash, recurrent fever, arthralgia, or arthritis, monoclonal gammopathy of undetermined significance (MGUS), and marked systemic inflammation. The exact underlying cause of this condition is unknown; however, most cases occur sporadically in patients with no family history of the condition.
Genetics & Epidemiology
There has been no identifiable gene for Schnitzler syndrome.
It is estimated that >300 cases are reported in the literature. The majority of reported cases are from the United States, France, and Germany, with all patients being of Caucasian origin. A few cases have been reported in China and Japan, thus expanding the ethnic populations affected. Schnitzler syndrome has a slight male predominance, and the mean age of onset is middle age (35 to 55 years old).
Symptoms, Flares & Triggers
The first clinical sign is a chronic urticarial rash. Skin lesions appear as rose or red macules (area of skin discoloration) or slightly elevated plaques, which resolve within 24 hours. Lesions present with neutrophilic infiltrate and can occur on any body part, though involvement of the face and extremities is rare. The frequency and duration of flares are variable, and patients will develop intermittent fever which may rise above 40 °C (104 °F) and usually do not have associated chills. Often headaches and fatigue will accompany the fevers. Approximately 80% of patients experience bone and/or joint pain, as bone involvement is common. Patients may have bone lesions on imaging studies and, additionally, may have enlarged liver or spleen. Vasculitis is noted in 20% of patients, and a few patients have developed amyloidosis.
Flares usually last 12 to 36 hours and usually begin with a rash.
Fevers may present separately from the rash. Common triggers include temperature change, stress and exercise.
Diagnosis & Diagnostic Criteria
Strasbourg diagnostic criteria 2012
Obligate criteria:
-
Chronic urticarial rash
-
Monoclonal IgM or IgG
Minor criteria
-
Recurrent fever
-
Objective findings of abnormal bone remodeling with or without bone pain
-
A neutrophilic dermal infiltrate on skin biopsy
-
Leukocytosis and/or elevated CRP
Definite diagnosis if
-
Two obligate criteria AND at least two minor criteria if IgM, and three minor criteria if IgG
Probable diagnosis if
-
Two obligate criteria AND at least one minor criterion if IgM, and two minor criteria if IgG
Treatments
Treatment is focused on alleviating the symptoms and may include a variety of medications including: NSAIDs, corticosteroids, immunosuppressive agents, interleukin-1 inhibitors, colchicine, Dapsone, Thalidomide, Rituximab, and/or phototherapy.
Interleukin-1 therapy is effective in the majority of cases, and patients may achieve and maintain long-term remission. Patients who present with similar clinical features but do not meet the diagnostic criteria for Schnitzler syndrome have also shown a dramatic response to IL-1 treatments.
Laboratory Tests & Findings
Lab tests should include erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), CBC with differential, immunoglobulins (especially IgM, IgG and IgG subsets), serum amyloid A (SAA), Immunofixation (IFE), Serum, Protein Electrophoresis (PE), bone scans, and rash biopsy if necessary.
Typical findings include monoclonal gammopathy of IgM or IgG, which is elevated in more than 90% of cases. Anemia with thrombocytosis occurs in up to 50% of cases, while palpable lymph nodes, and hepatic or splenic enlargement may also present. The monoclonal IgM component is a defining feature of the disease. Inflammatory AA amyloidosis may be a serious complication.
Pregnancy
Pregnancy is rare in patients with Schnitzler's syndrome, as the mean age of first symptoms usually appear after the childbearing years.
PAPA
Systemic juvenile idiopathic arthritis (sJIA) is a rare autoinflammatory disease and is characterized by daily fever, salmon-colored rash, joint pain, or arthritis. It is a subtype of the more commonly seen Juvenile Idiopathic Arthritis (JIA), and only affects a small portion of children. sJIA affects males and females equally and may present any time during childhood, with a broad peak of onset between 1 and 5 years of age. “Systemic” identifies that this disease may affect the entire body, and “idiopathic” means, it is unknown as to what causes the disease. For many patients, it is a lifelong disease that continues into adulthood and is then referred to as Adult-Onset Still's Disease (AOSD), after the age of 16.
Genetics & Epidemiology
The genetic investigation for the cause of sJIA disease is ongoing. Current research suggests that genetic biomarkers may include a variety of dysregulated pathways including HLA-DRB1*11 (several related haplotypes), MIF-173, IRF5, and NLRC4. Additional findings have demonstrated that patients with IL1RN expression may have lacking response to Anakinra therapy. Systemic-onset JIA has an estimated incidence of 1/166,000 and prevalence at 1/32,000 in the pediatric population and is thought to arise from a combination of genetic and environmental factors.
Symptoms, Flares & Triggers
In sJIA, the symptoms may occur at the same time or be spread out through the day or even last weeks and are characterized by flares, which include periods of severe inflammation or worsening of symptoms, which may last days or months and then go into remission.
Fevers are recurring and often high as temperature reaches 103 °F/39.5 °C and typically spikes in the evenings, normalizing within a few hours. This is a major criterion for diagnosing sJIA. However, the pattern of fevers may vary from patient to patient and occur twice daily (morning and evening) or may continue throughout the day.
Rash: A flat, pale or pink rash, depending on the child's skin color, often appears on the trunk, arms or legs, and may move around in the body. The rash may or may not be itchy and presents from a few minutes to a few hours, and is often associated with fever spikes.
Arthritis: Arthritis is the second and most common sign of sJIA. The symptoms of joint swelling, pain, stiffness, and warmth, tend to worsen in the morning, after a nap or prolonged rest/immobility. It may affect 5 or more joints, or it may only affect one and commonly impacts the knees, wrists, and ankles. Children with sJIA may also develop arthritis in the spine (in the neck area), jaw and hip joint.
Joint problems may develop over time after the onset of fevers and rashes. Young children often cannot verbalize or complain about any joint pain, making the diagnosis process more difficult. It is recommended to observe the child for limping or favoring use of one leg, inactivity, or stiffness in the mornings.
Lung and organ problems
The inflammation or swelling of the internal organs such as the heart, liver, lungs, spleen and lymph nodes may occur in sJIA. Anemia is also a common finding. Lung diseases seen in children with sJIA include pulmonary artery hypertension and interstitial lung disease. Pulmonary artery hypertension is high blood pressure affecting the arteries in the lungs and the right side of the heart. Interstitial lung disease is when lung tissue becomes scarred, impacting the oxygen levels in the bloodstream. Should any signs of breathing problems such as shortness of breath occur along with blue lips, nails or fingers, parents should notify their treating physician immediately.
High blood pressure (hypertension)
Atherosclerosis is the build-up of plaques (fats and other substances) occurring on the artery walls, which causes hypertension, as seen in children with sJIA. This issue is most likely due to the ongoing inflammation or caused by the heavy use of corticosteroids.
Macrophage Activation Syndrome (MAS)
MAS is the most serious and life-threatening complication of sJIA affecting about 10% of the patients. It causes a rapid and massive inflammatory response that overwhelms the body and includes unremitting fever, hepatosplenomegaly, hepatic dysfunction, lymphadenopathy, encephalopathy, purpura, and bleeding. Severely affected MAS patients often develop life-threatening multiorgan failure involving dysregulation of the central nervous system, renal malfunction, respiratory distress, and a variety of cardiovascular issues including hypotension and shock.
Triggers of MAS may include viral infections, medication changes, or an underlying inflammation process. A majority of MAS patients have elevated ferritin and liver enzymes, anemia, abnormal lactase dehydrogenase, frequent thrombocytopenia and neutropenia. Triglycerides are often elevated due to intravascular coagulation, as demonstrated by elevated d-dimer.
For more information on MAS, please read the EULAR Classification Criteria for Macrophage Activation Syndrome in patients with Systemic Juvenile Idiopathic Arthritis.
Diagnosis & Diagnostic Criteria
The sJIA diagnostic criteria developed by the International League of Associations for Rheumatology (ILAR) requires:
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High fever for at least two weeks
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Arthritis (joint pain and inflammation) in one or more joints for at least six weeks
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Nonpruritic macular or maculopapular salmon colored rash (usually located on trunk or extremities while febrile)
Since there are no specific medical or genetic tests for sJIA, a doctor will typically make a diagnosis based on medical history (recollection of all medical events and family history), physical exam, clinical findings, laboratory tests, imaging scans or ultrasound, and possibly skin biopsy. An eye exam to evaluate any ocular inflammation (uveitis) may be warranted.
Treatments
The overall aim of treatment is to reduce inflammation, which may require several types of interventions including medications, physiotherapy, and surgery. While there is no cure, a spontaneous remission is possible.
Early treatment is essential for prompt disease control. The past few years have seen a revolution in treatments for sJIA to include biologic medications. However, the standard approach typically begins with NSAIDs and corticosteroids.
Once systemic symptoms of SJIA have disappeared, nonbiologic, conventional disease-modifying antirheumatic drugs (DMARDs) may be used alone or in combination with biologics for continued therapy for arthritis. Unlike NSAIDs or corticosteroids, conventional synthetic DMARDs may slow joint damage. The treatment goal is to relieve pain and control symptoms.
Biologic medications that target proinflammatory cytokines, such as anakinra (IL-1α), canakinumab (IL-1β) and tocilizumab (IL-6), help treat both the systemic inflammation and the arthritis, significantly improving the prognosis for pediatric patients. These medications are given by injection or IV infusion.
A percentage (20 to 40%) of sJIA patients may fail anti-cytokine biological treatment due to adverse reactions or the drugs losing efficacy over time. Newer biologics such as IL-18 and JAK inhibitors targeting IFNs (interferon pathways) appear to be promising therapies for sJIA and its complications SJIA-MAS and SJIA-LD.
Most children are given calcium and vitamin D supplements and encouraged to eat a diet high on calcium. Physical therapy is also likely recommended to help build up muscle strength and reduce pain and stiffness.
Laboratory Tests & Findings
sJIA cannot be diagnosed with blood tests. However, certain laboratory findings may support or disprove the diagnosis. It is commonly seen in children with sJIA to have the following lab results:
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Extremely elevated white blood cell (WBC) and platelet counts
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Severe anemia due to poor iron absorption
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Extremely elevated ferritin levels
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Elevated inflammatory markers (ESR and CRP)
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Negative antinuclear antibodies (ANA) and rheumatoid factor antibodies
Sweet's Syndrome
Sweet’s syndrome, also known as Acute Febrile Neutrophilic Dermatosis, is a rare skin disorder characterized by fever and the appearance of inflamed or blistered skin and mucosal lesions. The etiology of this disease remains unclear, but it may be associated with the dysfunction of the immune system, genetic predisposition, or neoplastic process. The disease also may impact the nervous system in rare cases.
Genetics & Epidemiology
The cause of Sweet's syndrome remains unknown and may be triggered by an infection (upper respiratory tract or gastrointestinal infection), illness (inflammatory bowel disease, lupus erythematosus or rheumatoid arthritis) or certain medications (NSAIDs, DMARDs, antibiotics, etc). Occasionally, it may occur with some types of cancer. The average age of onset is 30 to 60 years but can occur in infants and in the elderly. There is a 4:1 female to male predominance, which may suggest a hormonal origin. The disease may present in any ethnicity and skin type.
In a few cases, the disease may be a result of hormonal changes induced by pregnancy or in thyroid gland disorders. Dermatologic manifestations of Sweet’s syndrome may rarely be a sign of blood, breast or bowel cancer.
Symptoms & Flares
Sweet's syndrome symptoms include high or moderate fevers, painful skin lesions that appear mostly on arms, neck, head & trunk, aching joints and muscles, mouth ulcers, tiredness, lack of energy and malaise, sore red eyes, headache, etc. The disease may also impact the bones, the nervous system, kidneys, intestines, liver, heart, lungs, muscles, and spleen.
Involvement of the nervous system, referred to as Neuro-Sweet syndrome (NSS), is a rare manifestation that may present with an encephalitic syndrome in addition to the fevers and dermal lesions.
Sweet’s syndrome’s flares may present with variable symptoms at a time that may arise individually or together over a period of hours or days.
Diagnosis & Diagnostic Criteria
Revised Sweet's syndrome diagnostic criteria include the following:
Major Criteria
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Abrupt onset of painful erythematous plaques or nodules
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Predominantly neutrophilic infiltration in the dermis without evidence of leukocytoclastic vasculitis
Minor Criteria
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Preceded by a nonspecific respiratory or gastrointestinal tract infection or vaccination OR associated with an underlying hematologic or visceral malignancy, inflammatory disease, or pregnancy
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Temperature >38°C
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Laboratory values during onset: ESR >20 mm/hr, positive C-reactive protein, segmented-nuclear neutrophils and bands >70% in peripheral blood smear, leukocytes >8000/microliter (three out of four of these values are necessary)
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Excellent response to treatment with systemic steroids (anti-inflammatory glucocorticoids or steroids) or potassium iodide
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Skin biopsy is one of the major criteria for diagnosis, all patients have a neutrophilic infiltrate on skin histology.
Lab tests required to confirm the diagnosis:
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Skin biopsy is one of the major criteria for diagnosis, all patients have a neutrophilic infiltrate on skin histology.
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Blood tests with high levels of neutrophils may help to make a diagnosis. CBC with differential: Greater than 95% of patients have leukocytosis (>8 x 109/L) and anemia (Hg < 12 g/dL). In almost half of the patients there is neutrophilia (>70% neutrophils) and thrombocytosis (Plt > 400,000/mm3).
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Inflammatory markers: Over 95% of patients have an elevated erythrocyte sedimentation rate (ESR) (> 20 mm/hour).
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Pregnancy test: Pregnancy testing should be performed in all menstruating females to help diagnose or rule out pregnancy-induced Sweet’s syndrome.
Treatments
Systemic corticosteroids such as prednisone or prednisolone are the first-line therapy for the majority of patients, including patients with known underlying malignancy. There is no standard dosing regimen, although a commonly used dose is 2 mg/kg/day followed by a tapering dose. Tapering needs to be slow as the disease can flare with lower doses of systemic corticosteroids. Other immunosuppressant drugs such as cyclosporine, dapsone, or indomethacin may be prescribed. Alternatives to corticosteroids are: dapsone, potassium iodide and colchicine (Colcrys, Mitigare). Topical treatments including strong steroid creams or ointments may alleviate skin rash or tenderness.
Laboratory Tests & Findings
Blood tests should include CBC with differential, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), p-ANCA (antineutrophil cytoplasmic antibody) and c-ANCA panel.
Pregnancy
Pregnancy induced Sweet's syndrome is a rare occurrence (2%), with good prognosis of spontaneous resolution after delivery. The disease does not increase infant morbidity and mortality. There are no recommended treatments for Sweet’s syndrome during pregnancy.
SAVI
TNF receptor-associated periodic fever syndrome (TRAPS) is an autoinflammatory disease characterized by long-lasting fever episodes that typically occur for about 2–3 weeks, but may be as short as a few days or as long as a few months. The frequency of the flares may be different for each patient. The disease typically begins in childhood before the age of 4. However, some cases have presented in adolescence and even into adulthood. Adult onset of TRAPS (over 30 years old) has been reported in about 10% of the patients. TRAPS can lead to kidney failure as a result of amyloidosis. Amyloidosis is the buildup of protein in the organs, and it has been reported to affect approximately 15% to 20% of patients and is a critical cause of morbidity and mortality.
Genetics & Epidemiology
TRAPS is an autosomal dominant and is caused by variants in the TNFRSF1A gene, which encodes the TNFR1 (tumor necrosis factor receptor-1) receptor. It has a prevalence of approximately one per million. Each child of an individual with TRAPS has a 50% chance of inheriting the TNFRSF1A pathogenic variant. Approximately a thousand cases have been reported in multiple ethnic groups worldwide and is prevalent in Caucasian and Asian populations.
Although R92Q is classified as uncertain significance, it is associated with the symptoms of TRAPS. Clinical studies have shown that TRAPS patients with this variant suffer from recurrent inflammatory episodes that benefit from treatment with IL-1 inhibitors.
Symptoms, Flares & Triggers
Recurrent fevers and abdominal pain are the main features of TRAPS with their frequency and intensity being patient specific. Additionally, distinctive features of an attack include migratory myalgia, swelling in the extremities, and ocular manifestations. When a rash presents, the overlying skin may be red, tender, and painful. The skin lesions associated usually begin as tiny bumps (macules or papules) that spread to form larger lesions (plaques).
Eye involvement can manifest in the form of conjunctivitis, puffiness or swelling in the skin around the eyes (periorbital edema) or uveitis. Affected individuals may also experience joint pain, and inflammation in various areas of the body including heart muscle, certain joints, throat, or mucous membranes as found in the mouth and digestive tract.
Other symptoms include:
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Nausea or vomiting
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Aphthous ulcers
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Arthritis (joint pain)
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Thoracic pain
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Pleuritis
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Pharyngitis
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Chills
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Testicular pain and inguinal hernias (males only)
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Diarrhea or constipation
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Headaches
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Arthralgia (joint swelling)
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Pericarditis
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Lymphadenitis (cervical adenitis)
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Asthenia/fatigue
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Odynophagia (painful swallowing)
Flares are approximately 3 weeks long, but they may be shorter or longer depending on the disease severity. Flares may occur spontaneously, in a pattern, or after exposure to a trigger.
Triggers may vary across the patient population and may be caused by emotional and physical stress, physical activity/exercise, illness/infection, trauma, hormonal changes, menstruation, fatigue, vaccinations, etc.
Diagnosis & Diagnostic Criteria
TRAPS is diagnosed based upon genetic testing, examination, lab results and family/medical history.
Treatments
Interleukin-1 (IL-1) inhibitors are used to control disease activity and prevent SAA amyloidosis. IL-1β inhibitor canakinumab (Ilaris) is often given at 150 mg every 4 weeks, and based on efficacy, it can be increased up to 300 mg every 4 weeks. Patients who do not have access to this medication may try IL-1 (Kineret/anakinra), IL-6 (Actemra/tocilizumab) or a TNF -α blocker (Enbrel/etanercept).
Adjunct medications may include use of non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids in addition to the biologic medication. Patients presenting with mouth ulcers or canker sores may benefit from using colchicine.
Laboratory Tests & Findings
Laboratory parameters should include complete blood cell counts with differential (CBC), C-reactive protein (CRP) and/or serum amyloid A (SAA) levels, erythrocyte sedimentation rate (ESR), urinalysis with proteinuria (helps to monitor evolution of renal amyloidosis), and markers of autoimmunity, such as antinuclear antibodies, rheumatoid factor, and complement levels.
During flares, laboratory tests often reveal increased indicators of inflammation: raised erythrocyte sedimentation rate (ESR), C reactive protein (CRP), fibrinogen, and serum amyloid A (SAA). Urinary protein analysis helps to monitor the evolution of renal amyloidosis.
Vexas Syndrome
VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is a monogenic autoinflammatory disease and is characterized by systemic symptoms and multiorgan involvement. This disease causes inflammatory and hematologic (blood) manifestations.
VEXAS syndrome typically affects older adults, primarily males, with signs and symptoms of the condition developing at ages between 50 and 70.
Genetics & Epidemiology
VEXAS syndrome is caused by somatic mutations in the UBA1 gene and acquired later in life. This disease is acquired, rather than inherited, and therefore, it is not passed down to children of affected individuals. Progressive bone marrow failure and myeloid-driven autoinflammation lead to substantial morbidity and mortality. Depending on the severity of the disease, some patients may qualify for bone marrow transplantation.
Symptoms, Flares & Triggers
Patients with VEXAS can have a wide range of inflammatory symptoms affecting multiple organs, including:
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Fevers
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Skin rashes (dermatitis)
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Cartilage in the ear and nose (chondritis)
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Lung issues (cough and shortness of breath)
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Joint swelling (arthritis)
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Inflammation of blood vessels (vasculitis)
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Extreme fatigue
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Reduced red blood cells
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Elevated inflammatory markers
Haematological features of VEXAS include:
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Anaemia
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Low platelet count (Thrombocytopenia)
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Blood clots
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Myelodysplastic syndrome, multiple myeloma, monoclonal gammopathy of undetermined significance (MGUS)
Diagnosis & Diagnostic Criteria
VEXAS syndrome should be considered in older male patients presenting with complex overlapping inflammatory and haematological features.
Investigations may include:
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Blood tests (elevated inflammatory markers, anaemia, thrombocytopenia, and lymphopenia)
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Bone marrow biopsy
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Skin biopsy of infiltrated skin lesions
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Genetic testing to identify the UBA1 gene mutation
Treatments
There is currently no standardized treatment for VEXAS. Patients affected by this disease typically respond poorly to treatment. High doses of corticosteroids provide the most consistent benefit for the inflammatory features of this disease. Other DMARDs and immunosuppressive drugs are ineffective. Colchicine may reduce the need for steroids.
Since VEXAS can affect multiple organs, a multidisciplinary medical team is required, in particular, a rheumatologist and a hematologist.
The long-term prognosis for patients with VEXAS syndrome is rather poor, and due to most patients becoming refractory to treatment, it has a high mortality rate of 50%.
Laboratory Tests & Findings
Laboratory tests should include complete blood count (CBC) with differential, ferritin and iron storage, inflammatory acute phase reactants such as erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and serum amyloid A (SAA), platelets, immunoglobulins (rule out for monoclonality), and serum electrophoresis testing (SEP).
Common findings for Vexas patients per the Vexas Foundation include:
Hematologic diagnoses:
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Myelodysplastic syndrome (49%)
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Multiple myeloma/Monoclonal gammopathy of unknown origin (11%)
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Cytopenia(s) of an unknown cause
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Macrocytic anemia (MCV > 100 fL)
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Thrombocytopenia (platelet count < 200 K/μL)
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Venous and arterial thrombosis (blood clots)
Inflammatory diagnoses
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Relapsing polychondritis (49%)
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Neutrophilic dermatosis/Cutaneous vasculitis (82%)
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Sweet syndrome
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Giant cell arteritis
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Polyarteritis nodosa
SJIA
Yao syndrome (formerly called NOD2-associated autoinflammatory disease) is a multiorgan polygenic systemic autoinflammatory periodic disease characterized by recurrent episodes of fever, dermatitis, arthralgias, distal leg swelling, gastrointestinal complaints, sicca-like symptoms, and eyelid swelling. As a systemic disease, Yao syndrome uncommonly affects the solid internal organs, but it can be complicated with chronic pain syndrome and even disability
Genetics & Epidemiology
Yao syndrome is an autoinflammatory disease associated with NOD2 gene mutations. It is genetically linked to specific NOD2 sequence variants, but it is different than Blau syndrome.
Yao syndrome has an estimated prevalence of 1 in 100,000 patients worldwide, with most cases reported in America, Europe, and Asia. Studies suggest that while rare, it may be more prevalent in adults. It is unknown, based on limited research, how many cases of Yao’s exist globally and it appears to affect women more frequently than men.
Symptoms, Flares & Triggers
The most common symptoms are:
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Rash
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Arthritis
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Fever
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Abdominal pain
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Diarrhea
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Sicca-like symptoms
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Lower extremity swelling
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Oral ulcer
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Chest pain
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Pleuritis
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Pericarditis
Episodes of joint pain and inflammation similar to arthritis are common, particularly in the legs, as is swelling of the ankles and feet. The inflammation also affects the gastrointestinal system, causing attacks of abdominal pain, bloating, and cramping with diarrhoea in more than half of affected individuals. Dry eyes and dry mouth (described as "sicca-like" symptoms, which refers to dryness) are reported in about half of people with this disease. Other potential symptoms include mouth sores, chest pain, and enlargement of various glands.
Most affected individuals develop reddened, inflamed areas on the skin called erythematous patches or plaques. This reddening occurs most commonly on the face, chest, and back but can also affect the arms and legs. Individuals may present with a variety of skin rashes.
Some patients report their symptoms manifest with neurological issues and muscle weakness. This is currently being investigated.
The episodes of fever and inflammation associated with Yao syndrome tend to be short and recurrent despite being on treatment. In other cases, flares may last for several days and occur weeks to months apart. Common triggers reported by patients include: cold and hot temperatures, physical exertion, dehydration, surgical procedures, infections, menstruation, stress, certain foods, lack of sleep, vaccinations, etc.
Diagnosis & Diagnostic Criteria
Yao syndrome is diagnosed if 2 major criteria, at least one minor criterion, the molecular criterion, and exclusion criteria are fulfilled as shown below.
Clinical diagnostic criteria:
Major:
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Periodic occurrence > twice
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Recurrent fever or dermatitis or both
Minor:
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Oligo- or polyarthralgia/inflammatory arthritis, or distal extremity swelling
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Abdominal pain or diarrhea or both
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Sicca-like symptoms
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Pericarditis or pleuritis or both
Molecular criterion:
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NOD2 IVS8 + 158 or R702W or both, or other rare variants
Exclusion criteria:
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High titer antinuclear antibodies
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Inflammatory bowel disease
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Blau syndrome
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Adult sarcoidosis
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Primary Sjögren syndrome
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Monogenic autoinflammatory diseases
Yao syndrome is usually diagnosed in adulthood. It is a long-lasting (chronic) disease, and episodes can recur for many years.
Treatments
Glucocorticoids or sulfasalazine may be considered as first-line treatment options. Some patients may respond to dapsone and colchicine. Biologic therapy with interleukin IL-1, IL-6, and tumor necrosis factor-alfa inhibitors may be effective in some patients with refractory disease. Plaquenil and other medications are currently being investigated.
Laboratory Tests & Findings
Patients often do not present with elevated inflammatory markers. Complete blood count (CBC), comprehensive metabolic panel (CMP), ferritin, immunoglobulin panel, and tryptase are usually part of a routine blood test.