Reactive Arthritis (Clinical)

Overview

Definition

Reactive arthritis Arthritis Acute or chronic inflammation of joints. Osteoarthritis ( ReA ReA 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) is an autoimmune, post-infectious, seronegative spondyloarthritis.

Mnemonic

The seronegative arthropathies Seronegative Arthropathies Ankylosing Spondylitis can be remembered as “PAIR.” 

• Psoriatic arthritis Arthritis Acute or chronic inflammation of joints. Osteoarthritis 
• Ankylosing spondylitis
• Inflammatory bowel disease–associated arthritis Arthritis Acute or chronic inflammation of joints. Osteoarthritis
• Reactive Arthritis Arthritis Acute or chronic inflammation of joints. Osteoarthritis

Epidemiology^[1–4,19]

• ReA ReA 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 develops in:
  • 1%–3% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with urethritis Urethritis Inflammation involving the urethra. Similar to cystitis, clinical symptoms range from vague discomfort to painful urination (dysuria), urethral discharge, or both. Urinary Tract Infections (UTIs)
  • 1%–4% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with an enteric infection
• Incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency: 0.6–27 cases per 100,000 worldwide
• Prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency: 30–40 per 100,000 adults
• More common in men 
• Occurs more frequently in young adults (< 40 years of age)
• 70%–90% have the HLA-B27 allele Allele Variant forms of the same gene, occupying the same locus on homologous chromosomes, and governing the variants in production of the same gene product. Basic Terms of Genetics

Etiology^{[1–4,13–15,17]}

• Generally occurs 1–4 weeks after certain infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease:
  • Genitourinary (GU):
    • Chlamydia trachomatis Chlamydia trachomatis Type species of Chlamydia causing a variety of ocular and urogenital diseases. Chlamydia (most common)
    • Neisseria gonorrhoeae Neisseria gonorrhoeae A species of gram-negative, aerobic bacteria primarily found in purulent venereal discharges. It is the causative agent of gonorrhea. Neisseria
    • Ureaplasma urealyticum
  • Gastrointestinal (GI):
    • Campylobacter jejuni Campylobacter jejuni A species of bacteria that resemble small tightly coiled spirals. Its organisms are known to cause abortion in sheep and fever and enteritis in man and may be associated with enteric diseases of calves, lambs, and other animals. Campylobacter (most common)
    • Shigella flexneri Shigella flexneri A bacterium which is one of the etiologic agents of bacillary dysentery and sometimes of infantile gastroenteritis. Shigella, S. dysenteriae S. dysenteriae A species of gram-negative, facultatively anaerobic, rod-shaped bacteria that is extremely pathogenic and causes severe dysentery. Infection with this organism often leads to ulceration of the intestinal epithelium. Shigella, and S. sonnei S. sonnei A lactose-fermenting bacterium causing dysentery. Shigella
    • Salmonella enterica Salmonella enterica A subgenus of Salmonella containing several medically important serotypes. The habitat for the majority of strains is warm-blooded animals. Salmonella
    • Yersinia enterocolitica Yersinia enterocolitica A species of the genus yersinia, isolated from both man and animal. It is a frequent cause of bacterial gastroenteritis in children. Yersinia spp./Yersiniosis and Yersinia pseudotuberculosis Yersinia pseudotuberculosis A human and animal pathogen causing mesenteric lymphadenitis, diarrhea, and bacteremia. Yersinia spp./Yersiniosis
    • Clostridioides difficile
    • Escherichia coli Escherichia coli The gram-negative bacterium Escherichia coli is a key component of the human gut microbiota. Most strains of E. coli are avirulent, but occasionally they escape the GI tract, infecting the urinary tract and other sites. Less common strains of E. coli are able to cause disease within the GI tract, most commonly presenting as abdominal pain and diarrhea. Escherichia coli
  • Pulmonary (less common):
    • Chlamydia Chlamydia Chlamydiae are obligate intracellular gram-negative bacteria. They lack a peptidoglycan layer and are best visualized using Giemsa stain. The family of Chlamydiaceae comprises 3 pathogens that can infect humans: Chlamydia trachomatis, Chlamydia psittaci, and Chlamydia pneumoniae. Chlamydia pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia
    • Mycobacterium tuberculosis Mycobacterium tuberculosis Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis
• Genetic associations:
  • HLA-B27 (most common)
  • HLA-B51
  • HLA-DRB1
• The exact pathophysiology is unknown.

Clinical Presentation

Articular manifestations

Onset is acute, within 1–4 weeks of an inciting infection.^[1,3,15]

Peripheral arthritis Peripheral Arthritis Reactive Arthritis:^{[2–4,11–13,15]}

• Asymmetric oligoarthritis Oligoarthritis Ankylosing Spondylitis
• Predominantly of the large weight-bearing joints of the lower extremities:
  • Knees
  • Ankles
• Other common joints:
  • Shoulders
  • Wrists
  • Elbows
  • Small joints of hands and feet
• On exam, joints will be:
  • Tender
  • Warm
  • Swollen

Enthesopathy Enthesopathy Reactive Arthritis:^{[2–4,12,15]}

• 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, tendon, fascia Fascia Layers of connective tissue of variable thickness. The superficial fascia is found immediately below the skin; the deep fascia invests muscles, nerves, and other organs. Cellulitis, or joint capsule Capsule An envelope of loose gel surrounding a bacterial cell which is associated with the virulence of pathogenic bacteria. Some capsules have a well-defined border, whereas others form a slime layer that trails off into the medium. Most capsules consist of relatively simple polysaccharides but there are some bacteria whose capsules are made of polypeptides. Bacteroides insertion to 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. Bones: Structure and Types
• Causes focal tenderness and swelling Swelling Inflammation
• Common insertion sites:
  • Achilles tendon
  • Plantar fascia Plantar fascia Foot: Anatomy insertion site on the calcaneus Calcaneus The largest of the tarsal bones which is situated at the lower and back part of the foot, forming the heel. Foot: Anatomy
  • Ischial tuberosities
  • Iliac crests
  • Tibial tuberosities
  • Ribs Ribs A set of twelve curved bones which connect to the vertebral column posteriorly, and terminate anteriorly as costal cartilage. Together, they form a protective cage around the internal thoracic organs. Chest Wall: Anatomy

Tendonitis Tendonitis Reactive Arthritis and periostitis Periostitis Inflammation of the periosteum. The condition is generally chronic, and is marked by tenderness and swelling of the bone and an aching pain. Acute periostitis is due to infection, is characterized by diffuse suppuration, severe pain, and constitutional symptoms, and usually results in necrosis. Reactive Arthritis:^{[2–4,12,15]}

• 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 tendon or periosteum Periosteum Thin outer membrane that surrounds a bone. It contains connective tissue, capillaries, nerves, and a number of cell types. Bones: Structure and Types, respectively
• Common locations:
  • Achilles tendonitis Tendonitis Reactive Arthritis
  • Plantar fasciitis Plantar fasciitis Inflammation of the plantar fascia (aponeurosis) on the bottom of the foot causing heel pain. The etiology of plantar fasciitis remains controversial but is likely to involve a biomechanical imbalance. Though often presenting along with heel spur, they do not appear to be causally related. Ankle and Foot Pain
  • Digital periostitis Periostitis Inflammation of the periosteum. The condition is generally chronic, and is marked by tenderness and swelling of the bone and an aching pain. Acute periostitis is due to infection, is characterized by diffuse suppuration, severe pain, and constitutional symptoms, and usually results in necrosis. Reactive Arthritis

Dactylitis Dactylitis Ankylosing Spondylitis:^[2,3,12,15]

• Swollen fingers and toes (“ sausage digits Sausage Digits Reactive Arthritis”)

Sacroiliitis Sacroiliitis Inflammation of the sacroiliac joint. It is characterized by lower back pain, especially upon walking, fever, uveitis; psoriasis; and decreased range of motion. Many factors are associated with and cause sacroiliitis including infection; injury to spine, lower back, and pelvis; degenerative arthritis; and pregnancy. Ankylosing Spondylitis:^[2,3,12,15]

• 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 sacroiliac joints
• Signs and symptoms:
  • Low back pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways
  • Decreased lumbar flexion Flexion Examination of the Upper Limbs

Extra-articular manifestations

Ocular:^{[1–4,11–13,15]}

• 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
• 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
• Episcleritis
• Keratitis Keratitis Inflammation of the cornea. Herpes Simplex Virus 1 and 2

Genitourinary:^{[1–4,11–13,15]}

• Urethritis Urethritis Inflammation involving the urethra. Similar to cystitis, clinical symptoms range from vague discomfort to painful urination (dysuria), urethral discharge, or both. Urinary Tract Infections (UTIs)
• Cervicitis Cervicitis Inflammation of the uterine cervix. Gonorrhea
• 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
• Cystitis Cystitis Inflammation of the urinary bladder, either from bacterial or non-bacterial causes. Cystitis is usually associated with painful urination (dysuria), increased frequency, urgency, and suprapubic pain. Urinary Tract Infections (UTIs)
• Salpingo-oophoritis

Mucocutaneous:^{[1–4,11–13,15]}

• Keratoderma blennorrhagicum
  • Vesicles Vesicles Female Genitourinary Examination of the palms, soles, and around nails
  • Become hyperkeratotic and form crusts
  • Appears similar to pustular psoriasis Pustular Psoriasis Psoriasis
• Balanitis Balanitis Inflammation of the head of the penis, glans penis. Penile Anomalies and Conditions circinata
  • Shallow, painless ulcers of the glans penis Glans Penis Penis: Anatomy
• Painless oral ulcers Oral ulcers A loss of mucous substance of the mouth showing local excavation of the surface, resulting from the sloughing of inflammatory necrotic tissue. It is the result of a variety of causes, e.g., denture irritation, aphthous stomatitis; necrotizing gingivitis, toothbrushing, and various irritants. Chédiak-Higashi Syndrome
• Nail dystrophy
• Erythema Erythema Redness of the skin produced by congestion of the capillaries. This condition may result from a variety of disease processes. Chalazion nodosum (uncommon)

GI:^[1–4,12]

• Intermittent diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
  • Abdominal pain Abdominal Pain Acute Abdomen
  • Colitis Colitis Inflammation of the colon section of the large intestine, usually with symptoms such as diarrhea (often with blood and mucus), abdominal pain, and fever. Pseudomembranous Colitis

Cardiac:^{[1–4,12,13,15]}

• Aortitis Aortitis Inflammation of the wall of the aorta. Ankylosing Spondylitis
• Aortic regurgitation Regurgitation Gastroesophageal Reflux Disease (GERD)
• Conduction abnormalities

Clinical triad^[11,15]

This classic triad of symptoms is found in only about 30% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with ReA ReA 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: 

• Post-infectious arthritis Post-Infectious Arthritis Reactive Arthritis
• 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
• Urethritis Urethritis Inflammation involving the urethra. Similar to cystitis, clinical symptoms range from vague discomfort to painful urination (dysuria), urethral discharge, or both. Urinary Tract Infections (UTIs) 

Mnemonic: “Can’t see, can’t pee, and can’t climb a tree.”

Diagnosis

Reactive arthritis Arthritis Acute or chronic inflammation of joints. Osteoarthritis is a clinical diagnosis based on: ^{[5,6,13,15,17]}

• Acute oligoarthritis Oligoarthritis Ankylosing Spondylitis and typical articular manifestations
• Preceding GI or genitourinary (GU) infection
• Presence of ≥ 1 extra-articular manifestation
• Exclusion of other diagnoses 

Supporting workup

Synovial fluid analysis Synovial Fluid Analysis Rheumatoid Arthritis:^[5,6,11,15]

• Performed in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with joint effusions
• Findings are nonspecific.
• ↑ Leukocytes Leukocytes White blood cells. These include granular leukocytes (basophils; eosinophils; and neutrophils) as well as non-granular leukocytes (lymphocytes and monocytes). White Myeloid Cells: Histology with neutrophil predominance may be seen (5,000‒50,000 WBCs per high-power field (HPF))^[10]
• Evaluations to rule out other etiologies:
  • Crystal analysis
  • Gram stain Gram stain Klebsiella and culture → rule out gonococcal arthritis Arthritis Acute or chronic inflammation of joints. Osteoarthritis

Laboratory findings:^{[5,6,10,13,15–17]} 

• ↑ or normal erythrocyte sedimentation rate Erythrocyte Sedimentation Rate Soft Tissue Abscess ( ESR ESR Soft Tissue Abscess) and C-reactive protein (CRP)
• Mild leukocytosis Leukocytosis A transient increase in the number of leukocytes in a body fluid. West Nile Virus on complete blood cell count (CBC)
• Stool PCR Stool PCR Norovirus and/or cultures → evaluate for causative organisms if the patient has diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
• Urine or genital swab → evaluate for C. trachomatis
• Urine culture Urine culture Urinary Tract Infections (UTIs) → Ureaplasma or Chlamydia Chlamydia Chlamydiae are obligate intracellular gram-negative bacteria. They lack a peptidoglycan layer and are best visualized using Giemsa stain. The family of Chlamydiaceae comprises 3 pathogens that can infect humans: Chlamydia trachomatis, Chlamydia psittaci, and Chlamydia pneumoniae. Chlamydia
• HLA-B27 testing → supports the diagnosis in conjunction with the clinical picture
• HIV HIV Anti-HIV Drugs and tuberculin Tuberculin A protein extracted from boiled culture of tubercle bacilli (Mycobacterium tuberculosis). It is used in the tuberculin skin test (tuberculin test) for the diagnosis of tuberculosis infection in asymptomatic persons. Type IV Hypersensitivity Reaction skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions testing in high-risk individuals (high association with ReA ReA 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)
• Rheumatoid factor Rheumatoid factor Antibodies found in adult rheumatoid arthritis patients that are directed against gamma-chain immunoglobulins. Autoimmune Hepatitis ( RF RF Rheumatoid Arthritis) and anti–cyclic citrullinated peptide (anti-CCP) → rule out rheumatoid arthritis Arthritis Acute or chronic inflammation of joints. Osteoarthritis

Radiographs of affected joints:^[5,6,13,17]

• Findings are generally nonspecific.
• Can be used to evaluate for evidence of:
  • Fractures
  • Ankylosing spondylitis Ankylosing spondylitis Ankylosing spondylitis (also known as Bechterew’s disease or Marie-Strümpell disease) is a seronegative spondyloarthropathy characterized by chronic and indolent inflammation of the axial skeleton. Severe disease can lead to fusion and rigidity of the spine. Ankylosing Spondylitis in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with sacroiliitis Sacroiliitis Inflammation of the sacroiliac joint. It is characterized by lower back pain, especially upon walking, fever, uveitis; psoriasis; and decreased range of motion. Many factors are associated with and cause sacroiliitis including infection; injury to spine, lower back, and pelvis; degenerative arthritis; and pregnancy. Ankylosing Spondylitis
• May show:
  • Joint space narrowing
  • Soft tissue Soft Tissue Soft Tissue Abscess edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema
  • Erosions Erosions Corneal Abrasions, Erosion, and Ulcers
  • Periosteal new 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. Bones: Structure and Types formation
  • Bony spurs at sites of enthesitis Enthesitis Ankylosing Spondylitis

Management

Management may vary depending on practice location. The following information is based on US, UK, and European literature.

Treatment of ReA ReA 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 is supportive. Symptoms of ReA ReA 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 typically resolve in 3‒4 months, but prolonged or recurrent symptoms can occur in up to 50% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship.

Management of acute ReA Acute ReA Reactive Arthritis (duration < 6 months)

1st-line therapy:

• Physical therapy Physical Therapy Becker Muscular Dystrophy^[15,16]
• Nonsteroidal antiinflammatory drugs Nonsteroidal Antiinflammatory Drugs 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 (NSAIDs) ( NSAIDs NSAIDS Primary vs Secondary Headaches):^{[5,6,13–17]}
  • Naproxen Naproxen An anti-inflammatory agent with analgesic and antipyretic properties. Both the acid and its sodium salt are used in the treatment of rheumatoid arthritis and other rheumatic or musculoskeletal disorders, dysmenorrhea, and acute gout. Nonsteroidal Antiinflammatory Drugs (NSAIDs) 500 mg orally 2‒3 times/day; maximum, 1,250 mg/day
  • Ibuprofen Ibuprofen A nonsteroidal anti-inflammatory agent with analgesic properties used in the treatment of rheumatism and arthritis. Nonsteroidal Antiinflammatory Drugs (NSAIDs) 300‒400 mg orally 3‒4 times/day; maximum, 2,400 mg/day 
  • Diclofenac Diclofenac A non-steroidal anti-inflammatory agent (nsaid) with antipyretic and analgesic actions. It is primarily available as the sodium salt. Nonsteroidal Antiinflammatory Drugs (NSAIDs) 50 mg orally 3 times/day
  • Indomethacin Indomethacin A non-steroidal anti-inflammatory agent (nsaid) that inhibits cyclooxygenase, which is necessary for the formation of prostaglandins and other autacoids. It also inhibits the motility of polymorphonuclear leukocytes. Nonsteroidal Antiinflammatory Drugs (NSAIDs) 50 mg orally 3 times/day
  • Try 2 different classes for 3‒4 weeks, then proceed to alternative treatment 
• Intra-articular glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids:^{[5‒7,13,16,17]}
  • Reserved for those with an inadequate response to NSAIDs NSAIDS Primary vs Secondary Headaches
  • Monoarticular and oligoarticular forms
  • Triamcinolone Triamcinolone A glucocorticoid given, as the free alcohol or in esterified form, orally, intramuscularly, by local injection, by inhalation, or applied topically in the management of various disorders in which corticosteroids are indicated. Glucocorticoids acetonide 10‒40 mg in affected joint(s)
  • Methylprednisolone Methylprednisolone A prednisolone derivative with similar anti-inflammatory action. Immunosuppressants acetate 40‒80 mg in affected joint(s)
  • May repeat after 3 months if adequate pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways relief after 1st injection and symptoms have returned

2nd-line therapy:^{[5–7,13,15,17]} 

• Indicated if the above treatments fail
• Systemic corticosteroids Corticosteroids Chorioretinitis ( prednisone Prednisone A synthetic anti-inflammatory glucocorticoid derived from cortisone. It is biologically inert and converted to prednisolone in the liver. Immunosuppressants/ prednisolone Prednisolone A glucocorticoid with the general properties of the corticosteroids. It is the drug of choice for all conditions in which routine systemic corticosteroid therapy is indicated, except adrenal deficiency states. Immunosuppressants): 0.5‒1 mg/kg/day orally, gradual taper, as soon as possible
• 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) ( DMARDs DMARDs 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 Sulfasalazine A drug that is used in the management of inflammatory bowel diseases. Its activity is generally considered to lie in its metabolic breakdown product, 5-aminosalicylic acid released in the colon. Sulfonamides and Trimethoprim 500 mg by mouth once daily; may increase by 500 mg/day on a weekly basis; maximum, 2‒3 g/day divided into 2‒3 doses
  • Methotrexate Methotrexate An antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of tetrahydrofolate dehydrogenase and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA. Antimetabolite Chemotherapy (psoriatic/rheumatoid arthritis Arthritis Acute or chronic inflammation of joints. Osteoarthritis dosing): 15‒25 mg by mouth, once a week

Chronic ReA Chronic ReA Reactive Arthritis (duration > 6 months):

• DMARDs DMARDs 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 Sulfasalazine A drug that is used in the management of inflammatory bowel diseases. Its activity is generally considered to lie in its metabolic breakdown product, 5-aminosalicylic acid released in the colon. Sulfonamides and Trimethoprim
  • Methotrexate Methotrexate An antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of tetrahydrofolate dehydrogenase and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA. Antimetabolite Chemotherapy
• Tumor Tumor Inflammation necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage factor ( 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
  • Considered in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship who do not respond to DMARDs DMARDs 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)
  • Limited data 

Management of chronic ReA Chronic ReA Reactive Arthritis (duration > 6 months)^[5,6,15,17]

• Consider rheumatology consult.
• DMARDs DMARDs 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 Sulfasalazine A drug that is used in the management of inflammatory bowel diseases. Its activity is generally considered to lie in its metabolic breakdown product, 5-aminosalicylic acid released in the colon. Sulfonamides and Trimethoprim
  • Methotrexate Methotrexate An antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of tetrahydrofolate dehydrogenase and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA. Antimetabolite Chemotherapy
  • Consider a 12-week course before advancing to tumor Tumor Inflammation necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage factor ( 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.
• TNF inhibitors TNF inhibitors Ankylosing Spondylitis:
  • Considered in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship who do not respond to DMARDs DMARDs 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)
  • Limited data 

Management of extra-articular manifestations

Ocular:^[5,6,11,15]

• Referral for ophthalmologic evaluation
• 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: corticosteroid and mydriatic eye drops
• 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: symptomatic treatment

Mucocutaneous:^[5,6,15,17]

• Symptomatic treatment for mild lesions
• Topical steroids Steroids A group of polycyclic compounds closely related biochemically to terpenes. They include cholesterol, numerous hormones, precursors of certain vitamins, bile acids, alcohols (sterols), and certain natural drugs and poisons. Steroids have a common nucleus, a fused, reduced 17-carbon atom ring system, cyclopentanoperhydrophenanthrene. Most steroids also have two methyl groups and an aliphatic side-chain attached to the nucleus. Benign Liver Tumors
• Topical salicylates
• Vitamin D Vitamin D A vitamin that includes both cholecalciferols and ergocalciferols, which have the common effect of preventing or curing rickets in animals. It can also be viewed as a hormone since it can be formed in skin by action of ultraviolet rays upon the precursors, 7-dehydrocholesterol and ergosterol, and acts on vitamin D receptors to regulate calcium in opposition to parathyroid hormone. Fat-soluble Vitamins and their Deficiencies analogs
• Severe keratoderma blennorrhagica:
  • Topical steroids Steroids A group of polycyclic compounds closely related biochemically to terpenes. They include cholesterol, numerous hormones, precursors of certain vitamins, bile acids, alcohols (sterols), and certain natural drugs and poisons. Steroids have a common nucleus, a fused, reduced 17-carbon atom ring system, cyclopentanoperhydrophenanthrene. Most steroids also have two methyl groups and an aliphatic side-chain attached to the nucleus. Benign Liver Tumors
  • DMARDs DMARDs 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)
  • TNF inhibitors TNF inhibitors Ankylosing Spondylitis
• Balanitis Balanitis Inflammation of the head of the penis, glans penis. Penile Anomalies and Conditions circinata: genital hygiene and topical steroids Steroids A group of polycyclic compounds closely related biochemically to terpenes. They include cholesterol, numerous hormones, precursors of certain vitamins, bile acids, alcohols (sterols), and certain natural drugs and poisons. Steroids have a common nucleus, a fused, reduced 17-carbon atom ring system, cyclopentanoperhydrophenanthrene. Most steroids also have two methyl groups and an aliphatic side-chain attached to the nucleus. Benign Liver Tumors

Management of underlying infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease

GI infection GI infection Microsporidia/Microsporidiosis:^[10,17]

• Antibiotics are generally not indicated.
• Exceptions:
  • Severe disease
  • Elderly
  • Immunocompromised immunocompromised A human or animal whose immunologic mechanism is deficient because of an immunodeficiency disorder or other disease or as the result of the administration of immunosuppressive drugs or radiation. Gastroenteritis patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship

GU infection:

• C. trachomatis treatment:^[8,15,16]
  • Doxycycline 100 mg by mouth twice daily for 7 days (recommended)
  • Alternatives:
    • Azithromycin Azithromycin A semi-synthetic macrolide antibiotic structurally related to erythromycin. It has been used in the treatment of Mycobacterium avium intracellulare infections, toxoplasmosis, and cryptosporidiosis. Macrolides and Ketolides (used in pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care) 1 g by mouth for 1 dose 
    • Levofloxacin Levofloxacin The l-isomer of ofloxacin. Fluoroquinolones 500 mg by mouth daily for 7 days
• N.gonorrhoeae: ceftriaxone Ceftriaxone A broad-spectrum cephalosporin antibiotic and cefotaxime derivative with a very long half-life and high penetrability to meninges, eyes and inner ears. Cephalosporins:^[9,15,16]
  • < 150 kg: 500 mg IM in a single dose
  • ≥ 150 kg: 1 g IM in a single dose

Prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas^[10–13,17]

• Most cases resolve within 6 months.
• Factors associated with more severe or persistent disease):
  • Male sex Sex The totality of characteristics of reproductive structure, functions, phenotype, and genotype, differentiating the male from the female organism. Gender Dysphoria
  • Oligoarthritis Oligoarthritis Ankylosing Spondylitis
  • HLA-B27 positivity
  • Poor response to NSAIDs NSAIDS Primary vs Secondary Headaches
  • ↑ ESR ESR Soft Tissue Abscess
  • Some studies include dactylitis Dactylitis Ankylosing Spondylitis

Differential Diagnosis

• Gonococcal arthritis Arthritis Acute or chronic inflammation of joints. Osteoarthritis: an infection due to N. gonorrhoeae. Disseminated disease can present similar to ReA ReA 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 with an acute, inflammatory, asymmetric arthritis Arthritis Acute or chronic inflammation of joints. Osteoarthritis with urethritis Urethritis Inflammation involving the urethra. Similar to cystitis, clinical symptoms range from vague discomfort to painful urination (dysuria), urethral discharge, or both. Urinary Tract Infections (UTIs). Diagnosis is based on the clinical history, synovial fluid analysis Synovial Fluid Analysis Rheumatoid Arthritis, and culture results. Management includes antibiotics. 
• Behcet’s disease: an inflammatory vasculitis Vasculitis Inflammation of any one of the blood vessels, including the arteries; veins; and rest of the vasculature system in the body. Systemic Lupus Erythematosus of small and large vessels. Symptoms can include arthritis Arthritis Acute or chronic inflammation of joints. Osteoarthritis and painful oral and genital ulcers, unlike the painless lesions in ReA ReA 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. Ocular, neurologic, GI, and vascular manifestations are also seen. Diagnosis is based on clinical criteria. Management depends on the clinical manifestations and includes corticosteroids Corticosteroids Chorioretinitis, DMARDs DMARDs 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), and TNF inhibitors TNF inhibitors Ankylosing Spondylitis.
• Rheumatoid arthritis Arthritis Acute or chronic inflammation of joints. Osteoarthritis: an 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 Arthritis Acute or chronic inflammation of joints. Osteoarthritis is typically symmetric, and patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship 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 Axial Computed Tomography (CT) skeleton is less commonly included. Diagnosis is made with positive RF RF Rheumatoid Arthritis and anti-CCP laboratory studies. Management includes NSAIDs NSAIDS Primary vs Secondary Headaches, DMARDs DMARDs 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), corticosteroids Corticosteroids Chorioretinitis, immunosuppressive medications, biologics, and TNF inhibitors TNF inhibitors Ankylosing Spondylitis.
• Psoriatic arthritis Psoriatic Arthritis A type of inflammatory arthritis associated with psoriasis, often involving the axial joints and the peripheral terminal interphalangeal joints. It is characterized by the presence of hla-b27-associated spondyloarthropathy, and the absence of rheumatoid factor. Psoriasis: a spondyloarthropathy Spondyloarthropathy Ankylosing Spondylitis that occurs in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with 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. This inflammatory arthritis Arthritis Acute or chronic inflammation of joints. Osteoarthritis is frequently asymmetric. The small and large joints are involved, including the distal interphalangeal joints Interphalangeal joints Hand: Anatomy and the sacroiliac spine Spine The human spine, or vertebral column, is the most important anatomical and functional axis of the human body. It consists of 7 cervical vertebrae, 12 thoracic vertebrae, and 5 lumbar vertebrae and is limited cranially by the skull and caudally by the sacrum. Vertebral Column: Anatomy. Enthesopathy Enthesopathy Reactive Arthritis and dactylitis Dactylitis Ankylosing Spondylitis are also seen. The diagnosis is clinical, and the condition should be suspected in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with 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. Management includes DMARDs DMARDs 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) and biologic agents Biologic Agents Immunosuppressants.
• Ankylosing spondylitis Ankylosing spondylitis Ankylosing spondylitis (also known as Bechterew’s disease or Marie-Strümpell disease) is a seronegative spondyloarthropathy characterized by chronic and indolent inflammation of the axial skeleton. Severe disease can lead to fusion and rigidity of the spine. Ankylosing Spondylitis: a spondyloarthropathy Spondyloarthropathy Ankylosing Spondylitis involving 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 Axial Computed Tomography (CT) skeleton, resulting in back pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways, kyphosis Kyphosis Deformities of the spine characterized by an exaggerated convexity of the vertebral column. The forward bending of the thoracic region usually is more than 40 degrees. This deformity sometimes is called round back or hunchback. Osteoporosis, and loss of lumbar lordosis. Some patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship may also have peripheral joint involvement, 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, aortic insufficiency, aortitis Aortitis Inflammation of the wall of the aorta. Ankylosing Spondylitis, cardiac conduction abnormalities, and cavitary lung lesions. Diagnosis is based on lumbosacral radiographic findings ( sacroiliitis Sacroiliitis Inflammation of the sacroiliac joint. It is characterized by lower back pain, especially upon walking, fever, uveitis; psoriasis; and decreased range of motion. Many factors are associated with and cause sacroiliitis including infection; injury to spine, lower back, and pelvis; degenerative arthritis; and pregnancy. Ankylosing Spondylitis and “ bamboo spine Bamboo Spine Ankylosing Spondylitis”) and the presence of HLA-B27. Management includes NSAIDs NSAIDS Primary vs Secondary Headaches, TNF inhibitors TNF inhibitors Ankylosing Spondylitis, or interleukin-17 Interleukin-17 A proinflammatory cytokine produced primarily by T-lymphocytes or their precursors. Several subtypes of interleukin-17 have been identified, each of which is a product of a unique gene. Interleukins antagonists.
• Inflammatory bowel disease (IBD): includes Crohn’s disease and ulcerative colitis Colitis Inflammation of the colon section of the large intestine, usually with symptoms such as diarrhea (often with blood and mucus), abdominal pain, and fever. Pseudomembranous Colitis, and is characterized by chronic inflammation Chronic Inflammation Inflammation of the GI tract due to a cell-mediated immune response to the GI mucosa. Symptoms include diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea, abdominal pain Abdominal Pain Acute Abdomen, and weight loss Weight loss Decrease in existing body weight. Bariatric Surgery. Extraintestinal manifestations can include a migratory peripheral arthritis Peripheral Arthritis Reactive Arthritis of large joints. Inflammatory bowel disease is also associated with other disorders, such as ankylosing spondylitis Ankylosing spondylitis Ankylosing spondylitis (also known as Bechterew’s disease or Marie-Strümpell disease) is a seronegative spondyloarthropathy characterized by chronic and indolent inflammation of the axial skeleton. Severe disease can lead to fusion and rigidity of the spine. Ankylosing Spondylitis, sacroillitis, and 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. Diagnosis includes imaging, endoscopy Endoscopy Procedures of applying endoscopes for disease diagnosis and treatment. Endoscopy involves passing an optical instrument through a small incision in the skin i.e., percutaneous; or through a natural orifice and along natural body pathways such as the digestive tract; and/or through an incision in the wall of a tubular structure or organ, i.e. Transluminal, to examine or perform surgery on the interior parts of the body. Gastroesophageal Reflux Disease (GERD), and biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma. Treatment involves steroids Steroids A group of polycyclic compounds closely related biochemically to terpenes. They include cholesterol, numerous hormones, precursors of certain vitamins, bile acids, alcohols (sterols), and certain natural drugs and poisons. Steroids have a common nucleus, a fused, reduced 17-carbon atom ring system, cyclopentanoperhydrophenanthrene. Most steroids also have two methyl groups and an aliphatic side-chain attached to the nucleus. Benign Liver Tumors, aminosalicylates, immunomodulators, and biologic agents Biologic Agents Immunosuppressants