Autoinflammatory diseases are rare disorders caused by a dysfunctional innate immune system, leading to recurrent or chronic inflammation without the involvement of the adaptive immune system.
The immune response consists of 2 components:
- a) innate immunity that is immediate, non-specific, and without memory, initiated by white blood cells like neutrophils and macrophages.
- b) adaptive immunity, a longer, specific response through T-lymphocytes and antibodies, that has memory.
Sometimes, any of these immune responses can mistakenly attack components of the host human tissues. In case of innate immunity, these are called autoinflammatory diseases, while for adaptive immunity, they are called autoimmune diseases. Autoimmunity and autoinflammation can have an overlap as they form two ends of a spectrum. Both can be either monogenic inheritance (rarer and involves a single gene) or polygenic inheritance involving multiple genes, often with environmental influence, creating a spectrum with continuous variation.
Read: Understanding Immunity
Autoinflammatory diseases consist of symptoms including recurring fevers (usually high, and is a hallmark symptom), rashes, mouth sores, and pain in joints or organs. They are often caused by gene mutations that trigger an overactive innate immune response, and diagnosis can be delayed because the symptoms can mimic other conditions.
MONOGENIC
Monogenic Autoinflammatory Diseases (MAIDs) are very rare and can be broadly categorized into several groups based on their clinical presentation and underlying genetic defects. These include:
- Hereditary Recurrent Fevers (Classic Periodic Fevers), such as Familial Mediterranean Fever (FMF), TNF Receptor-Associated Periodic Syndrome (TRAPS), and Mevalonate Kinase Deficiency (MKD/HIDS). These are often associated with dysfunction in pathways like the pyrin inflammasome, TNFRSF1A, or the mevalonate pathway.
- Cryopyrin-Associated Periodic Syndromes (CAPS), which involve the NLRP3 Inflammasome and include conditions like Familial Cold Autoinflammatory Syndrome (FCAS), Muckle-Wells Syndrome (MWS), and Neonatal-Onset Multisystem Inflammatory Disease (NOMID/CINCA).
- IL-1 Family Cytokine-Related Disorders (Beyond CAPS), which encompass conditions like Deficiency of Interleukin-1 Receptor Antagonist (DIRA), NLRP12-associated disease, and Deficiency of Interleukin-36 Receptor Antagonist (DITRA).
- Neutrophilic Dermatoses/Pustular Syndromes that can involve skin inflammation, including PAPA syndrome (Pyogenic Arthritis, Pyoderma Gangrenosum, Acne).
- Proteasome-Associated Autoinflammatory Syndromes (PRAAS), linked to proteasome dysfunction.
- Granulomatous Disorders, such as Blau Syndrome characterized by granuloma formation.
- Interferonopathies & Other Pathway-Specific Disorders, including conditions like Aicardi-Goutières Syndrome (AGS) and STING-associated vasculopathy with onset in infancy (SAVI), which involve interferon pathways.
POLYGENIC
The most well-known polygenic autoinflammatory disease is Gout and Pseudogout. Sometimes conditions like IBD, Psoriatic arthritis, some large vessel arteritis (vasculitis), sarcoidosis, and idiopathic uveitis are also considered in this category, or grouped under autoimmune or related conditions by others.
Gout is considered a polygenic auto-inflammatory disease where the innate immune system responds excessively to uric acid (monosodium urate – MSU) crystals. Gout mainly manifests as a joint disease (urate crystals deposit in joints, triggering autoinflammation). Risk factors include high uric acid levels, due to diet (red meat, seafood, sugary drinks, alcohol), genetics, being elderly (more in men), obesity, certain medications, associated health issues like high blood pressure, kidney disease, and diabetes, and joint surgery or trauma.
Pseudogout is similar clinically, but the crystals are those of calcium pyrophosphate dihydrate (CPPD) in the cartilage, not uric acid. Risk factors include age>60 years, associated metabolic conditions (hyperparathyroidism, hemochromatosis – iron overload, hypothyroidism, or low magnesium), or joint trauma or surgery.
Treatment of Gout typically follows the following line –
The first gout attack (pain and inflammation of joints) requires a detailed history, clinical evaluation of symptoms and joints affected, diet and lifestyle assessment, and estimation of serum uric acid, urinary urate excretion, and renal function.
It is important to treat the acute attack (gout flare) and also address long-term prevention of gout flares.
Acute Flares
To manage pain and inflammation, the NSAIDs (Nonsteroidal Anti-Inflammatory Drugs are first-line, best started early (within 48 hrs). These include specific ones like etoricoxib, celecoxib, or aceclofenac, or non-specific ones like naproxen, ibuprofen, or diclofenac. Oral colchicine is used when the response to first-line drugs is sub-optimal, or they are contraindicated.
If acute gout flares are not responding to, or patient is not tolerating NSAIDs or colchicine (gastrointestinal issues like diarrhea, nausea, vomiting, and stomach cramps, muscle pain or weakness, tingling or numbness or blood disorders-easy bruising or bleeding, and fever), then a corticosteroid is to be started as oral, intra-articular (if gout affecting only one or two joints), or intramuscular (for patients who cannot take oral medication) dosage, to provide rapid relief from severe attacks (corticosteroids are to be avoided in diabetes and hypertension).
Resting and elevating the joint, and applying ice packs (wrapped in a towel) can be done along side.
Long-Term Management
This is done for preventing flares.
DRUGS
- Urate-Lowering Therapies: ULTs are medications like allopurinol or febuxostat (Xanthine Oxidase enzyme Inhibitors) that reduce uric acid production.
- Uricosurics: Probenecid helps the kidneys excrete uric acid.
- Prophylaxis: Low-dose colchicine is sometimes used for the first few months when starting ULT to prevent initial flares.
LIFESTYLE AND DIET
- Hydration: Drinking plenty of water helps flush uric acid, and also, preventing the formation of urate urinary stones.
- Limit Purines: Reducing red meat, organ meats, certain seafood (sardines, anchovies).
- Avoiding Sugary Drinks and Alcohol: High fructose corn syrup and beer/spirits are known to trigger gout.
- Healthy Proteins: Like low-fat dairy
- Exercise and Weight management: Regular, low-impact exercise and achieving a healthy weight
Recurrent Gout Flares and Refractory Gout
If acute gout flares are frequent (>2/year), the patient is not responsive to or tolerating NSAIDs or colchicine, and is contraindicated for or not responding to corticosteroid, then stronger drugs or biologicals or monoclonal antibody drugs (MAbs) may be needed. This is usually seen in <5% gout patients.
- Currently, in such patients, anakinra, canakinumab, and rilonacept are used (IL-1 inhibitors).
- Sometimes, when the above IL-1 MAbs are not available or affordable, other anti-inflammatory MAbs like infliximab or etanercept (anti-TNF) may be used off-label.
- Pegloticase is another important drug for such severe refractory gout patients. It is a modified uricase (urate oxidase) enzyme from pigs, engineered to be long-lasting by attaching polyethylene glycol (PEG) that breaks down uric acid into allantoin, a harmless, water-soluble substance the kidneys can easily flush out. Such patients are also given oral methotrexate.
Some patients may not have gout symptoms or flares, or evidence of urate urinary stones, but still have hyperuricemia (high blood uric acid levels >7 mg/dL for men and >6 mg/dL for women). Such patients should be treated only if the levels are very high (>9-10 mg/dL) to prevent long-term damage, even without symptoms. Others only need lifestyle changes.
Differentiating Gout from Pseudogout
While both gout and pseudogout manifest similarly as pain and inflammation of joints, gout tends to affect small joints like toes and fingers, while pseudogout affects the knee, or the elbow and wrist more.
This gold standard for diagnosis is the analysis of the joint fluid with a needle to withdraw fluid from the inflamed joint and examine the crystals under a microscope. Urate crystals in gout are needle-shaped crystals that appear to glow blue when viewed with a polarized microscope (negatively birefringent), while CPPD crystals in pseudogout are rhomboid-shaped crystals that appear to glow yellow (positively birefringent).
The medical treatment for pseudogout flares is similar to that of gout flares however, there are no long-term specific drugs for preventing flares, so sometimes low-dose colchicine may be used for the same.
While diet and lifestyle do not stop crystal formation directly, drinking lots of water, eating a balanced anti-inflammatory diet (fruits, veggies, nuts), avoiding alcohol/excess sugar, maintaining a healthy weight, and physical activity like walking or swimming, are recommended. Underlying conditions like hyperparathyroidism or hemochromatosis should be diagnosed and managed to help prevent attacks.
Also read:
Autoimmune Diseases: 15 Well-Known Types and Medical Management