Ankylosing Spondylitis

Ankylosing spondylitis (also known as Bechterew’s disease or Marie-Strümpell disease) is a seronegative spondyloarthropathy characterized by chronic and indolent inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation of the axial skeleton. Severe disease can lead to fusion and rigidity of the spine. Ankylosing spondylitis is most often seen in young men and is strongly associated with HLA-B27. Patients will have progressive back pain Back pain Back pain is a common complaint among the general population and is mostly self-limiting. Back pain can be classified as acute, subacute, or chronic depending on the duration of symptoms. The wide variety of potential etiologies include degenerative, mechanical, malignant, infectious, rheumatologic, and extraspinal causes. Back Pain (which improves with activity), morning stiffness, and decreased range of motion of the spine. Extra-articular manifestations include fatigue, enthesitis, anterior uveitis Uveitis Uveitis is the inflammation of the uvea, the pigmented middle layer of the eye, which comprises the iris, ciliary body, and choroid. The condition is categorized based on the site of disease; anterior uveitis is the most common. Diseases of the Uvea, restrictive lung disease, and inflammatory bowel disease. The diagnosis is based on the clinical history, physical exam, and imaging demonstrating sacroiliitis and bridging syndesmophytes. Most patients are managed with physical therapy and nonsteroidal anti-inflammatory drugs (NSAIDs). More severe cases may require tumor necrosis factor Tumor necrosis factor Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF)-alpha inhibitors or surgery.

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Overview

Definition

Ankylosing spondylitis (AS) is a seronegative spondyloarthropathy characterized by chronic and indolent inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation of the axial skeleton.

Mnemonic

To remember the seronegative arthropathies, use the mnemonic “PAIR.” 

  • Psoriatic arthritis 
  • Ankylosing spondylitis
  • Inflammatory bowel disease–associated arthritis
  • Reactive arthritis

Epidemiology

  • Incidence: 0.4–14 per 100,000 people per year
  • Highest prevalence in northern European countries
  • Age at onset: 20–30 years
  • 3 times more common in men
  • 10–20 times more common in 1st-degree relatives of those with ankylosing spondylitits

Etiology

  • Exact cause unknown
  • Strong association with HLA-B27
  • Possible triggers:
    • Klebsiella Klebsiella Klebsiella are encapsulated gram-negative, lactose-fermenting bacilli. They form pink colonies on MacConkey agar due to lactose fermentation. The main virulence factor is a polysaccharide capsule. Klebsiella pneumoniae is the most important pathogenic species. Klebsiella infection
    • Trauma

Pathophysiology

Process of ankylosis

Pathogenesis of ankylosing spondylitis:
Inflammation induces the formation of syndesmophytes and the fusion of the intervertebral discs and vertebral bodies.

Image by Lecturio.
Ankylosing spondylitis

Pathogenesis of ankylosing spondylitis:
Erosion of the iliac side of sacroiliac joints is the earliest radiologic sign of ankylosing spondylitis.

Image by Lecturio.

Proposed mechanism of inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation

  • Innate immunity is triggered: 
    • Possibly from GI microbes invading the systemic circulation
    • Due to disruption of the gut mucosal barrier
  • Cytokines and interleukins Interleukins Interleukins are a type of cytokines (signaling proteins) that communicate messages between different parts of the immune system. The majority of interleukins are synthesized by helper CD4 T lymphocytes along with other cells such as monocytes, macrophages, and endothelial cells. Interleukins (ILs) are released: 
    • IL-17 and IL-23 
    • Tumor necrosis factor alpha ( TNF TNF Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF)-alpha)
    • Transforming growth factor beta (TGF-beta)
  • Development of enthesitis ( inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation at the site of ligament or tendon insertion into bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones):
    • Micro-injury from mechanical stress may make entheses susceptible to inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation.
    • Joints are infiltrated with macrophages and with CD4 and CD8 T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells.
    • Main joints involved:
      • Sacroiliac (SI) joints
      • Paravertebral joints

Axioskeletal changes

  • Chronic inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation of the ligaments and the annulus fibrosus of the intervertebral disc → erosion of bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones and destruction of articular tissues
  • Erosion → fibrocartilage regeneration → fibrosis and ossification → syndesmophyte formation
  • Syndesmophytes bridge together → vertebral fusion

Clinical Presentation

Articular manifestations

  • Pain: 
    • Lower back and neck
    • Progressive
    • Often nocturnal
    • Varies in intensity
    • Present for > 3 months
  • Paraspinal muscle spasm
  • Morning stiffness:
    • Improves with activity or exercise 
    • Worsened by inactivity
  • Diminished range of motion of the spine
  • Oligoarthritis (50% of patients):
    • Asymmetrical involvement of ≤ 4 peripheral joints
    • Pain, warmth, swelling, and stiffness

Extra-articular manifestations

  • General:
    • Fatigue
    • Weakness
    • Low-grade fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
    • Anorexia
    • Weight loss
  • Periarticular:
    • Enthesitis
      • Plantar fasciitis
      • Costochondral junctions
    • Tendinitis
      • Achilles
      • Patellar
    • Dactylitis (sausage fingers)
  • Ocular:
    • Anterior uveitis Uveitis Uveitis is the inflammation of the uvea, the pigmented middle layer of the eye, which comprises the iris, ciliary body, and choroid. The condition is categorized based on the site of disease; anterior uveitis is the most common. Diseases of the Uvea
    • Conjunctivitis Conjunctivitis Conjunctivitis is a common inflammation of the bulbar and/or palpebral conjunctiva. It can be classified into infectious (mostly viral) and noninfectious conjunctivitis, which includes allergic causes. Patients commonly present with red eyes, increased tearing, burning, foreign body sensation, and photophobia. Conjunctivitis
  • Cardiac:
    • Aortitis
    • Aortic valve insufficiency
    • Conduction abnormalities 
      • Due to fibrosis of the conduction system
      • Varying degrees of atrioventricular block Atrioventricular block Atrioventricular (AV) block is a bradyarrhythmia caused by delay, or interruption, in the electrical conduction between the atria and the ventricles. Atrioventricular block occurs due to either anatomic or functional impairment, and is classified into 3 types. Atrioventricular Block may result.
    • Pericarditis Pericarditis Pericarditis is an inflammation of the pericardium, often with fluid accumulation. It can be caused by infection (often viral), myocardial infarction, drugs, malignancies, metabolic disorders, autoimmune disorders, or trauma. Acute, subacute, and chronic forms exist. Pericarditis
  • Pulmonary
    • Restrictive lung disease
    • Nontuberculous apical fibrosis
      • Can result in cavitation
      • Secondary bacterial or fungal (Aspergillus) infections
  • Cutaneous:
    • Psoriasis Psoriasis Psoriasis is a common T-cell-mediated inflammatory skin condition. The etiology is unknown, but is thought to be due to genetic inheritance and environmental triggers. There are 4 major subtypes, with the most common form being chronic plaque psoriasis. Psoriasis
    • Painless oral ulcerations
  • GI:
    • Asymptomatic ileal and colonic inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation
    • Inflammatory bowel disease
  • Renal:
    • Immunoglobulin A (IgA) nephropathy
    • Renal amyloidosis Amyloidosis Amyloidosis is a disease caused by abnormal extracellular tissue deposition of fibrils composed of various misfolded low-molecular-weight protein subunits. These proteins are frequently byproducts of other pathological processes (e.g., multiple myeloma). Amyloidosis
  • Genitourinary: prostatitis Prostatitis Prostatitis is inflammation or an irritative condition of the prostate that presents as different syndromes: acute bacterial, chronic bacterial, chronic prostatitis/chronic pelvic pain, and asymptomatic. Bacterial prostatitis is easier to identify clinically and the management (antibiotics) is better established. Prostatitis
  • Neurologic:
    • Radiculitis
    • Cauda equina syndrome

Physical examination

  • Spine:
    • Cervical and upper thoracic vertebrae:
      • Accentuated thoracic kyphosis
      • Stooped, forward-flexed position (when fused)
      • Distance between chin and sternum with flexed head > 2 cm
    • Lumbar vertebrae:
      • Reduced range of motion (Schober’s test)
      • Loss of lumbar lordosis 
  • Sacroiliac joint:
    • Localized tenderness
    • Mennell’s sign
    • FABER (Flexion, Abduction, and External Rotation) test
  • Tenderness at the following points:
    • Achilles tendon insertion
    • Insertion of the plantar fascia on the calcaneus or the metatarsal heads
    • Base of the 5th metatarsal head
    • Tibial tuberosity
    • Superior and inferior poles of the patella
    • Iliac crest
  • Reduced chest expansion (< 4 cm) on deep inspiration
Preoperative imaging findings of a 47-year-old female patient with ankylosing spondylitis

Stooped, forward-flexed position in a patient with ankylosing spondylitis

Image: “Preoperative imaging” by Hongqi Zhang et al. License: CC BY 4.0, cropped by Lecturio.

Diagnosis

Physical examination tests

  • Schober’s test:
    • Tests limitation of lumbar movement 
    • Procedure:
      • Place a mark 5 cm below and 10 cm above the L5 spinous process. 
      • Have the patient touch the toes.
      • If distance does not increase by > 5 cm, the patient has reduced lumbar flexion.
  • FABER test:
    • Also known as Patrick’s test
    • Nonspecific test that detects joint dysfunction in the sacroiliac joint 
    • Procedure:
      • The patient’s leg Leg The lower leg, or just "leg" in anatomical terms, is the part of the lower limb between the knee and the ankle joint. The bony structure is composed of the tibia and fibula bones, and the muscles of the leg are grouped into the anterior, lateral, and posterior compartments by extensions of fascia. Leg is flexed at the hip, abducted, and placed in a figure-4 position.
      • Force is applied to the ipsilateral knee.
      • Test is deemed positive if it reproduces pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain in the ipsilateral sacroiliac joint.
  • Mennell’s sign: 
    • Helps determine whether pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain is coming from the hip, lumbar spine, or sacroiliac joint
    • Procedure:
      • Performed with the patient facedown
      • Passive hyperextension of the upper leg Leg The lower leg, or just "leg" in anatomical terms, is the part of the lower limb between the knee and the ankle joint. The bony structure is composed of the tibia and fibula bones, and the muscles of the leg are grouped into the anterior, lateral, and posterior compartments by extensions of fascia. Leg 
      • This procedure provokes pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain in the sacroiliac joint, hip, or lumbar spine depending on where the physician fixates (places the hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand) on the spine or hip.
  • Chin–brow vertical angle (CBVA)
    • An assessment for kyphotic deformity 
    • Procedure:
      • Measures the angle between a vertical line and a line connecting the brow to the chin while the patient is standing
      • Any degree greater than zero is abnormal.

Imaging

  • Radiography:
    • Diagnostic and assesses severity of the disease
    • Should be performed in all patients in whom AS is suspected
    • Bilateral sacroiliitis:
      • Subchondral erosions (“pseudo-widening” of the SI joint)
      • Subchondral sclerosis
      • SI joint narrowing
      • Fusion of the SI joint (end-stage)
    • Spine findings: 
      • Small erosions with reactive sclerosis
      • Squaring of vertebrae
      • Ligament calcifications
      • Evolving syndesmophytes
      • Bridging syndesmophytes (“bamboo spine”)
  • MRI: 
    • Aids in early detection
    • May reveal inflammatory changes not seen on radiographs

Laboratory Tests

  • Nonspecific
  • ↑ CRP 
  • ↑ Erythrocyte sedimentation rate (ESR)
  • Mildly ↑ alkaline phosphatase
  • Negative rheumatoid factor (RF)
  • Negative ANA test
  • Genetic testing for HLA-B27: 
    • May be considered if clinical evaluation and radiography are inconclusive
    • Positive in approximately 90% of Caucasian patients with AS
    • Not required for diagnosis

Management and Complications

Management requires a multidisciplinary approach to reduce pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, increase range of motion, decrease inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation, and improve quality of life.

Conservative measures

  • Lifestyle changes:
    • Urge smoking cessation.
    • Encourage regular physical activity.
  • Physical therapy:
    • Crucial for maintaining mobility
    • Exercises for: 
      • Mobilization of the vertebral joints and muscle stability 
      • Maintenance of adequate posture and range of motion
  • Depression and anxiety screening
  • Psychosocial support

Medical management

  • Initial therapy: 
    • Nonsteroidal anti-inflammatory drugs (NSAIDs)
    • 70% of patients achieve clinical improvement.
  • 2nd line: 
    • TNF TNF Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF) inihibitors 
      • Etanercept, adalimumab, golimumab, infliximab
      • Used in patients in whom NSAID NSAID Nonsteroidal antiinflammatory drugs (NSAIDs) are a class of medications consisting of aspirin, reversible NSAIDs, and selective NSAIDs. NSAIDs are used as antiplatelet, analgesic, antipyretic, and antiinflammatory agents. Nonsteroidal Antiinflammatory Drugs therapy fails
    • IL-17 inhibitors
      • Secukinumab or ixekizumab
      • Alternative to TNF TNF Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF) inhibitors
    • Disease-modifying antirheumatic drugs Disease-modifying antirheumatic drugs Disease-modifying antirheumatic drugs are antiinflammatory medications used to manage rheumatoid arthritis. The medications slow, but do not cure, the progression of the disease. The medications are classified as either synthetic or biologic agents and each has unique mechanisms of action and side effects. Disease-modifying Antirheumatic Drugs (DMARDs)
      • Sulfasalazine or methotrexate
      • Used for persistent peripheral arthritis

Surgical interventions

  • Indications:
    • Severe deformities resulting in functional impairment
    • Severe pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain causing diminished quality of life
    • Acute fracture Fracture A fracture is a disruption of the cortex of any bone and periosteum and is commonly due to mechanical stress after an injury or accident. Open fractures due to trauma can be a medical emergency. Fractures are frequently associated with automobile accidents, workplace injuries, and trauma. Overview of Bone Fractures
    • Neurologic deficits
  • Options:
    • Spinal fusion
    • Osteotomy
    • Total hip arthroplasty

Complications

  • In addition to the manifestations of this disease, patients may develop:
    • Osteoporosis Osteoporosis Osteoporosis refers to a decrease in bone mass and density leading to an increased number of fractures. There are 2 forms of osteoporosis: primary, which is commonly postmenopausal or senile; and secondary, which is a manifestation of immobilization, underlying medical disorders, or long-term use of certain medications. Osteoporosis
      • Most frequent complication
      • Predisposes patients to fractures
    • Vertebral fracture Fracture A fracture is a disruption of the cortex of any bone and periosteum and is commonly due to mechanical stress after an injury or accident. Open fractures due to trauma can be a medical emergency. Fractures are frequently associated with automobile accidents, workplace injuries, and trauma. Overview of Bone Fractures
      • Most serious complication
      • Cervical spine fractures can lead to paralysis or death.
    • Respiratory compromise
  • Adverse effects on the patient’s quality of life:
    • Sleep Sleep Sleep is a reversible phase of diminished responsiveness, motor activity, and metabolism. This process is a complex and dynamic phenomenon, occurring in 4-5 cycles a night, and generally divided into non-rapid eye movement (NREM) sleep and REM sleep stages. Physiology of Sleep disturbances
    • Disability
    • Diminished psychologic health (depression)

Prognosis

  • Ankylosing spondylitis is a chronic disease.
  • Most patients retain complete functionality.
  • Indicators of a poor prognosis:
    • Younger age at onset
    • Peripheral arthritis
    • ↑ Inflammatory markers
    • Poor response to NSAIDs
  • Severe and long-standing AS is associated with ↑ risk of mortality.

Differential Diagnosis

  • Lumbar spinal stenosis Spinal stenosis Spinal stenosis is the progressive narrowing of the central spinal canal, intervertebral foramen, and lateral recess, leading to compression of the nerve root. Spinal stenosis can occur in the cervical, thoracic, and lumbar spine and is commonly caused by degenerative bone disease (mostly affecting the elderly). Spinal Stenosis: narrowing of the lumbar spinal canal resulting in compression of nerve rootlets. This condition is more common in older patients. Patients may experience chronic back, buttock, and thigh Thigh The thigh is the region of the lower limb found between the hip and the knee joint. There is a single bone in the thigh called the femur, which is surrounded by large muscles grouped into 3 fascial compartments. Thigh pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain that is relieved by flexing the back. Neurologic signs and symptoms, including paresthesias, weakness, and diminished reflexes, are also prominent. The diagnosis is based on clinical evaluation and MRI. Management includes physical therapy, analgesics, and surgery for severe cases.
  • Psoriatic arthritis: a seronegative spondyloarthropathy that occurs in patients with psoriasis. This asymmetric, inflammatory arthritis involves small and large joints, including the distal interphalangeal joints and the sacroiliac spine. Enthesopathy and dactylitis are also seen. The diagnosis is clinical, and the condition should be suspected in patients with psoriasis. Management includes DMARDs and biologic agents.
  • Reactive arthritis Reactive arthritis Reactive arthritis is a seronegative autoimmune spondyloarthropathy that occurs in response to a previous gastrointestinal (GI) or genitourinary (GU) infection. The disease manifests as asymmetric oligoarthritis (particularly of large joints in the lower extremities), enthesopathy, dactylitis, and/or sacroiliitis. Reactive Arthritis: a seronegative spondyloarthropathy that is often precipitated by a GI or genitourinary infection. Patients may present with asymmetric arthritis, typically of the lower extremities. This arthritis can be associated with fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, tendinitis, enthesitis, mucocutaneous ulcers, and conjunctivitis. The diagnosis is clinical. Treatment includes NSAIDs, DMARDs, and treatment of the underlying infection.
  • Rheumatoid arthritis (RA): a seropositive autoimmune disease resulting in joint inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation and destruction. This arthritis is typically symmetric, and patients will frequently have tender inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation in the joints of the hands and feet (although any peripheral joints can be involved). The axial skeleton is less commonly included. The diagnosis is made with the presence of positive RF and anti–cyclic citrullinated peptide (anti-CCP) laboratory studies. Management includes NSAIDs, DMARDs, corticosteroids, immunosuppressive medications, biologics, and TNF TNF Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF) inhibitors. 
  • Fibromyalgia Fibromyalgia Fibromyalgia is a chronic pain syndrome characterized by widespread body pain, chronic fatigue, mood disturbance, and cognitive disturbance. It also presents with other comorbid symptoms such as migraine headaches, depression, sleep disturbance, and irritable bowel syndrome. Fibromyalgia: a nonarticular disorder of unknown etiology that causes generalized pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, including the muscles, points of tendon insertion (which can mimic enthesitis), and soft tissues. Associated symptoms include fatigue, muscle stiffness, cognitive disturbances, depression, and anxiety. The diagnosis is based on clinical criteria. Imaging and laboratory testing will be unrevealing. Management includes exercise, nonopioid analgesics, and efforts to improve sleep and stress.
  • Diffuse idiopathic skeletal hyperostosis: a noninflammatory disease causing ossification of spinal ligaments and entheses. Patients may be asymptomatic or may have progressive back and neck pain Neck Pain Neck pain is one of the most common complaints in the general population. Depending on symptom duration, it can be acute, subacute, or chronic. There are many causes of neck pain, including degenerative disease, trauma, rheumatologic disease, and infections. Neck Pain with reduced range of motion (particularly of the thoracic spine). The diagnosis is made with imaging, which may show the changes of AS. However, the SI joints are usually spared, and there may be extra-axial joint involvement. Management involves analgesics and physical therapy for pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain relief.

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  12. Yu, D.T., and van Tubergen, A. (2020). Treatment of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults. In Romain, P.L. (Ed.), UpToDate. Retrieved February 4, 2021, from https://www.uptodate.com/contents/treatment-of-axial-spondyloarthritis-ankylosing-spondylitis-and-nonradiographic-axial-spondyloarthritis-in-adults

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