Dry Eye Syndrome

Author: C Stephen Foster, MD, FACS, FACR, FAAO, Clinical Professor of Ophthalmology, Harvard Medical School; Consulting Staff, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary; Founder and President, Ocular Immunology and Uveitis Foundation, Massachusetts Eye Research and Surgery Institution
Coauthor(s): Erdem Yuksel, MD, Fellow, Department of Ophthalmology, Massachusetts Eye Research and Surgery Institute, Medical School of Gazi University; Fahd Anzaar, MD, Fellow, Massachusetts Eye Research and Surgery Institute; Clinical Research and Education Coordinator, Ocular Immunology and Uveitis Foundation; Anthony S Ekong, MD, Consulting Staff, Department of Ophthalmology, Marshfield Clinic
Contributor Information and Disclosures

Updated: May 13, 2009

Introduction

Background

Dry eye is a multifactorial disease of the tears and the ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface.¹ Dry eye is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface.¹

The tear layer covers the normal ocular surface. Generally, it is accepted that the tear film is made up of 3 intertwined layers, as follows:

1. A superficial thin lipid layer (0.11 µm) is produced by the meibomian glands, and its principal function is to retard tear evaporation and to assist in uniform tear spreading.
2. A middle thick aqueous layer (7 µm) is produced by the main lacrimal glands (reflex tearing), as well as the accessory lacrimal glands of Krause and Wolfring (basic tearing).
3. An innermost hydrophilic mucin layer (0.02-0.05 µm) is produced by both the conjunctiva goblet cells and the ocular surface epithelium and associates itself with the ocular surface via its loose attachments to the glycocalyx of the microplicae of the epithelium. It is the hydrophilic quality of the mucin that allows the aqueous to spread over the corneal epithelium.

The lipid layer produced by the meibomian glands acts as a surfactant, as well as an aqueous barrier (retarding evaporation of the underlying aqueous layer), and provides a smooth optical surface. It may also act as a barrier against foreign particles and may also have some antimicrobial properties. The glands are holocrine in nature, and so the secretions contain both polar lipids (aqueous-lipid interface) and nonpolar lipids (air-tear interface) as well as proteinaceous material. All of these are held together by ionic bonds, hydrogen bonds, and van der Waals forces. The secretions are subject to neuronal (parasympathetic, sympathetic, and sensory sources), hormonal (androgen and estrogen receptors), and vascular regulation. Evaporative loss is predominantly due to meibomian gland dysfunction (MGD).

The aqueous component is produced by the lacrimal glands. This component includes about 60 different proteins, electrolytes, and water. Lysozyme is the most abundant (20-40% of total protein) and also the most alkaline protein present in tears. It is a glycolytic enzyme that is capable of breaking down bacterial cell walls. Lactoferrin has antibacterial and antioxidant functions, and the epidermal growth factor (EGF) plays a role in maintaining the normal ocular surface and in promoting corneal wound healing. Albumin, transferrin, immunoglobulin A (IgA), immunoglobulin M (IgM), and immunoglobulin G (IgG) are also present.

Aqueous tear deficiency (ATD) is the most common cause of dry eye, and it is due to insufficient tear production. The secretion of the lacrimal gland is controlled by a neural reflex arc, with afferent nerves (trigeminal sensory fibers) in the cornea and the conjunctiva passing to the pons (superior salivary nucleus), from which efferent fibers pass, in the nervus intermedius, to the pterygopalatine ganglion and postganglionic sympathetic and parasympathetic nerves terminating in the lacrimal glands.

Keratoconjunctivitis sicca (KCS) is the name given to this ocular surface disorder. KCS is subdivided into Sjögren syndrome (SS) associated KCS and non-SS associated KCS. Patients with aqueous tear deficiency have SS if they have associated xerostomia and/or connective tissue disease. Patients with primary SS have evidence of a systemic autoimmune disease as manifested by the presence of serum autoantibodies and very severe aqueous tear deficiency and ocular surface disease. These patients, mostly women, do not have a separate, identifiable connective tissue disease. Subsets of patients with primary SS lack evidence of systemic immune dysfunction, but they have similar clinical ocular presentation. Secondary SS is defined as KCS associated with a diagnosable connective tissue disease, most commonly rheumatoid arthritis but also SLE and systemic sclerosis.

Non-SS KCS is mostly found in postmenopausal women, in women who are pregnant, in women who are taking oral contraceptives, or in women who are on hormone replacement therapy (especially estrogen only pills). The common denominator here is a decrease in androgens, either from reduced ovarian function in the postmenopausal female or from increased levels of the sex hormone binding globulin in pregnancy and birth control pill use. Androgens are believed to be trophic for the lacrimal and meibomian glands. They also exert potent anti-inflammatory activity through the production of transforming growth factor beta (TGF-beta), suppressing lymphocytic infiltration.

Lipocalins (previously known as tear-specific prealbumin), which are present in the mucous layer, are inducible lipid-binding proteins produced by the lacrimal glands that lower the surface tension of normal tears. This provides stability to the tear film and also explains the increase in surface tension that is seen in dry eye syndromes characterized by lacrimal gland deficiency. Lipocalin deficiency can lead to the precipitation in the tear film, forming the characteristic mucous strands seen in patients with dry eye symptomatology.

The glycocalyx of the corneal epithelium contains the transmembrane mucins (glycosylated glycoproteins present in the glycocalyx) MUC1, MUC4, and MUC16. These membrane mucins interact with soluble, secreted, gel-forming mucins produced by the goblet cells (MUC5AC) and also with others like MUC2. The lacrimal gland also secretes MUC7 into the tear film.

These soluble mucins move about freely in the tear film (a process facilitated by blinking and electrostatic repulsion from the negatively charged transmembrane mucins), functioning as clean-up proteins (picking up dirt, debris, and pathogens), holding fluids because of their hydrophilic nature, and harboring defense molecules produced by the lacrimal gland. Transmembrane mucins prevent pathogen adherence (and entrance) and provide a smooth lubricating surface, allowing lid epithelia to glide over corneal epithelia with minimal friction during blinking and other eye movements. Recently, it has been suggested that the mucins are mixed throughout the aqueous layer of tears (owing to their hydrophilic nature) and, being soluble, move freely within this layer.

Mucin deficiency (caused by damage to the goblet cells or the epithelial glycocalyx), as seen in Stevens-Johnson syndrome or after a chemical burn, leads to poor wetting of the corneal surface with subsequent desiccation and epithelial damage, even in the presence of adequate aqueous tear production.

Pathophysiology

A genetic predisposition in SS associated KCS exists as evident by the high prevalence of human leukocyte antigen B8 (HLA-B8) haplotype in these patients. This condition leads to a chronic inflammatory state, with the production of autoantibodies, including antinuclear antibody (ANA), rheumatoid factor, fodrin (a cytoskeletal protein), the muscarinic M3 receptor, or SS-specific antibodies (eg, anti-RO [SS-A], anti-LA [SS-B]), inflammatory cytokine release, and focal lymphocytic infiltration (ie, mainly CD4⁺ T cells but also B cells) of the lacrimal and salivary gland, with glandular degeneration and induction of apoptosis in the conjunctiva and lacrimal glands. This results in dysfunction of the lacrimal gland, with reduced tear production, and loss of response to nerve stimulation and less reflex tearing. Active T lymphocytic infiltrate in the conjunctiva also has been reported in non-SS associated KCS.

Both androgen and estrogen receptors are located in the lacrimal and meibomian glands. SS is more common in postmenopausal women. At menopause, a decrease in circulating sex hormones (ie, estrogen, androgen) occurs, possibly affecting the functional and secretory aspect of the lacrimal gland. Forty years ago, initial interest in this area centered on estrogen and/or progesterone deficiency to explain the link between KCS and menopause. However, recent research has focused on androgens, specifically testosterone, and/or metabolized androgens.

It has been shown that in meibomian gland dysfunction, a deficiency in androgens results in loss of the lipid layer, specifically triglycerides, cholesterol, monounsaturated essential fatty acids (eg, oleic acid), and polar lipids (eg, phosphatidylethanolamine, sphingomyelin). The loss of polar lipids (present at the aqueous-tear interface) exacerbates the evaporative tear loss, and the decrease in unsaturated fatty acids raises the melting point of meibum, leading to thicker, more viscous secretions that obstruct ductules and cause stagnation of secretions. Patients on antiandrogenic therapy for prostate disease also have increased viscosity of meibum, decreased tear break-up time, and increased tear film debris, all indicative of a deficient or abnormal tear film.

Various proinflammatory cytokines that may cause cellular destruction, including interleukin 1 (IL-1), interleukin 6 (IL-6), interleukin 8 (IL-8), TGF-beta, TNF-alpha, and RANTES, are altered in patients with KCS. IL-1 beta and TNF-alpha, which are present in the tears of patients with KCS, cause the release of opioids that bind to opioid receptors on neural membranes and inhibit neurotransmitter release through NF-K b production. IL-2 also binds to the delta opioid receptor and inhibits cAMP production and neuronal function. This loss of neuronal function diminishes normal neuronal tone, leading to sensory isolation of the lacrimal gland and eventual atrophy.

Proinflammatory neurotransmitters, such as substance P and calcitonin gene related peptide (CGRP), are released, which recruit and activate local lymphocytes. Substance P also acts via the NF-AT and NF-K b signaling pathway leading to ICAM-1 and VCAM-1 expression, adhesions molecules that promote lymphocyte homing and chemotaxis to sites of inflammation. Cyclosporin A is an NK-1 and NK-2 receptor inhibitor that can downregulate these signaling molecules and is a novel addition to the therapeutic armamentarium for dry eye, being used to treat both aqueous tear deficiency and meibomian gland dysfunction. It has been shown to improve the goblet cell counts and to reduce the numbers of inflammatory cells and cytokines in the conjunctiva.

These cytokines, in addition to inhibiting neural function, may also convert androgens into estrogens, resulting in meibomian gland dysfunction, as discussed above. An increased rate of apoptosis is also seen in conjunctival and lacrimal acinar cells, perhaps due to the cytokine cascade. Elevated levels of tissue-degrading enzymes called matrix metalloproteinases (MMPs) are also present in the epithelial cells.

Mucin synthesizing genes, designated MUC1-MUC17, representing both transmembrane and goblet-cell secreted, soluble mucins, have been isolated, and their role in hydration and stability of the tear film are being investigated in patients with dry eye syndrome. Particularly significant is MUC5AC, expressed by stratified squamous cells of the conjunctiva and whose product is the predominant component of the mucous layer of tears. A defect in this and other mucin genes may be a factor in dry eye syndrome development. In addition to dry eye, other conditions, such as ocular cicatricial pemphigoid, Stevens-Johnson syndrome, and vitamin A deficiency, which lead to drying or keratinization of the ocular epithelium, eventually lead to goblet cell loss. Both classes of mucins are decreased in these diseases, and, on a molecular level, mucin gene expression, translation, and posttranslational processing are altered.

Normal production of tear proteins, such as lysozyme, lactoferrin, lipocalin, and phospholipase A2, is decreased in KCS.

Frequency

United States

Dry eye is a very common disorder affecting a significant percentage (approximately 10-30%) of the population, especially those older than 40 years.

In the United States, an estimated 3.23 million women and 1.68 million men, a total of 4.91 million people, aged 50 years and older are affected.

International

The frequency of dry eye in other countries closely parallels that of the United States.

Mortality/Morbidity

Dry eye may be complicated by sterile or infectious corneal ulceration, particularly in patients with SS. Ulcers are typically oval or circular, less than 3 mm in diameter, and located in the central or paracentral cornea. Occasionally, corneal perforation may occur. In rare cases, sterile or infectious corneal ulceration in dry eye syndrome can cause blindness. Other complications include punctate epithelial defects (PEDs), corneal neovascularization, and corneal scarring.

Race

The frequency and the clinical diagnosis of dry eye are greater in the Hispanic and Asian populations than in the Caucasian population.

Sex

Dry eye may be slightly more common in women. KCS associated with SS (a type of dry eye) is believed to affect 1-2% of the population, and 90% of those affected are women.

Clinical

History

Ocular irritation of dry sensation, burning, itching, pain, foreign body sensation, photophobia, and blurred vision are common in patients with dry eye. These symptoms are often exacerbated in smoky or dry environments, by indoor heating, or by excessive reading or computer use. These symptoms are quantified objectively in the Ocular Surface Disease Index (OSDI) questionnaire, which lists 12 symptoms and grades each on a scale of 1-4.

In KCS, symptoms tend to be worse toward the end of the day, with prolonged use of the eyes, or with exposure to extreme environmental conditions. Patients with meibomian gland dysfunction may complain of redness of the eyelids and conjunctiva, but, in these patients, the symptoms are worse on awakening in the morning.

Paradoxically, some patients with dry eye syndrome complain of too much tearing. When evidence of dry eye syndrome exists, this symptom often is explained by excessive reflex tearing due to severe corneal surface disease from the dryness.

Certain systemic medications also decrease tear production, such as antihistamines, beta-blockers, and oral contraceptives.

Past medical history may be significant for coexisting connective tissue disease, rheumatoid arthritis, or thyroid abnormalities. A thorough review of systems should be obtained, asking specifically about dry mouth.

Physical

Signs of a dry eye include the following:

• Bulbar conjunctival vascular dilation
• Decreased tear meniscus
• Irregular corneal surface
• Decreased tear break-up time
• Punctate epithelial keratopathy
• Corneal filaments
• Increased debris in the tear film
• Conjunctival pleating
• Superficial punctuate keratitis, with positive fluorescein staining
• Mucous discharge
• Corneal ulcers in severe cases

Symptoms often do not correlate with signs.

In severe cases, there may be an epithelial defect or a sterile corneal infiltrate or ulcer. Secondary infectious keratitis also can develop. Both sterile and infectious corneal perforations can occur.

Causes

The International Dry Eye WorkShop (DEWS) recently developed a 3-part classification of dry eye, based on etiology, mechanisms, and disease stage.¹

The classification system, which is updated as an etiopathogenic classification by the DEWS Subcommittees, formulated by the National Eye Institute (NEI)/Industry Dry Eye Workshop Report in 1995, distinguishes 2 main categories (or causes) of dry eye states, as follows: an aqueous deficiency state and an evaporative state.

• Deficient aqueous production
  • Sjogren syndrome dry eye
    • Primary
    • Secondary
  • Non-Sjogren syndrome dry eye
    • Lacrimal gland deficiency
    • Lacrimal gland duct obstruction
    • Reflex hyposecretion
    • Systemic drugs
• Evaporative
  • Intrinsic causes
    • Meibomian gland dysfunction
    • Disorders of lid aperture
    • Low blink rate
    • Drug action (eg, Accutane)
  • Extrinsic causes
    • Vitamin A deficiency
    • Topical drugs and preservatives
    • Contact lens wear
    • Ocular surface disease (eg, allergy)

Deficient aqueous production can be further classified as follows:

• Non-Sjögren syndrome
  • Primary lacrimal gland deficiencies
    • Idiopathic
    • Age-related dry eye
    • Congenital alacrima (eg, Riley-Day syndrome)
    • Familial dysautonomia
  • Secondary lacrimal gland deficiencies
    • Lacrimal gland infiltration
    • Sarcoidosis
    • Lymphoma
    • AIDS
    • Graft vs host disease
    • Amyloidosis
    • Hemochromatosis
    • Lacrimal gland infectious diseases
    • HIV diffuse infiltrative lymphadenopathy syndrome
    • Trachoma
    • Systemic vitamin A deficiency (xerophthalmia) – Malnutrition, fat-free diets, intestinal malabsorption from inflammatory bowel disease, bowel resection, or chronic alcoholism
    • Lacrimal gland ablation
    • Lacrimal gland denervation
  • Lacrimal obstructive disease
    • Trachoma
    • Ocular cicatricial pemphigoid
    • Erythema multiforme and Stevens-Johnson syndrome
    • Chemical and thermal burns
    • Endocrine imbalance
    • Postradiation fibrosis
  • Medications – Antihistamines, beta-blockers, phenothiazines, atropine, oral contraceptives, anxiolytics, antiparkinsonian agents, diuretics, anticholinergics, antiarrhythmics, topical preservatives in eye drops, topical anesthetics, and isotretinoin
  • Reflex hyposecretion – Reflex sensory block and reflex motor block
    • Neurotrophic keratitis - Fifth nerve/ganglion section/injection/compression
    • Corneal surgery - Limbal incision (eg, extracapsular cataract extraction), keratoplasty, refractive surgery (eg, PRK, LASIK, RK)
    • Infective - Herpes simplex keratitis, herpes zoster ophthalmicus
    • Topical agents - Topical anesthesia
    • Systemic medications – Beta blockers, atropine-like drugs
    • Chronic contact lens wear
    • Diabetes
    • Aging
    • Trichloroethylene toxicity
    • Cranial nerve VII (CN VII) damage
    • Multiple neuromatosis
• Sjögren syndrome
  • Primary (no associated connective tissue disease [CTD])
  • Secondary (associated CTD)
    • Rheumatoid arthritis
    • Systemic lupus erythematosus
    • Progressive systemic sclerosis (scleredema)
    • Primary biliary cirrhosis
    • Interstitial nephritis
    • Polymyositis and dermatomyositis
    • Polyarteritis nodosa
    • Hashimoto thyroiditis
    • Lymphocytic interstitial pneumonitis
    • Idiopathic thrombocytopenic purpura
    • Hypergammaglobulinemia
    • Waldenstrom macroglobulinemia
    • Wegener granulomatosis

Evaporative loss can be further classified as follows:

• Intrinsic causes
  • Meibomian gland disease
    • Reduced number - Congenital deficiency, acquired meibomian gland dysfunction
    • Replacement - Distichiasis, distichiasis lymphedema syndrome, metaplasia
    • Meibomian gland dysfunction
      • Hypersecretory - Meibomian seborrhea
      • Hyposecretory - Retinoid therapy
      • Obstructive – Simple, primary or secondary to local disease (eg, anterior blepharitis), systemic disease (eg, acne rosacea, seborrheic dermatitis, atopy, ichthyosis, psoriasis), syndromes (eg, anhidrotic ectodermal dysplasia, ectrodactyly syndrome, Turner syndrome), and systemic toxicity (eg, 13-cis retinoic acid, polychlorinated biphenyls); or cicatricial, primary or secondary to local disease (eg, chemical burns, trachoma, pemphigoid, erythema multiforme, acne rosacea, VKC, AKC)
  • Low blink rate
    • Physiological phenomenon, such as during performance of tasks that require concentration (eg, working at a computer or a microscope)
    • Extrapyramidal disorder, such as Parkinson disease (decreasing dopaminergic neuron pool)
  • Disorders of eyelid aperture and eyelid/globe congruity
    • Exposure (eg, craniostenosis, proptosis, exophthalmos, high myopia)
    • Lid palsy
    • Ectropion
    • Lid coloboma
  • Drug action (eg, Accutane)
• Extrinsic causes
  • Vitamin A deficiency
    • Development disorder of goblet cells
    • Lacrimal acinar damage
  • Topical drugs and preservatives (surface epithelial cell damage)
  • Contact lens wear
  • Ocular surface disease (eg, allergy)

A classification of dry eye on the basis of mechanisms includes tear hyperosmolarity and tear film instability.

For a classification of dry eye on the basis of severity, the Delphi Panel Report was adopted and modified as a third component of the DEWS.¹ See Table.

Table. Dry Eye Severity levels^1,2

Open table in new window

[ CLOSE WINDOW ]

Table

Dry Eye Severity level	1	2	3	4 (Must have signs and symptoms.)
Discomfort, severity & frequency	Mild and/or episodic; occurs under environmental stress	Moderate episodic or chronic, stress or no stress	Severe frequent or constant without stress	Severe and/or disabling and constant
Visual symptoms	None or episodic mild fatigue	Annoying and/or activity-limiting episodic	Annoying, chronic and/or constant, limiting activity	Constant and/or possibly disabling
Conjunctival injection	None to mild	None to mild	+/–	+/++
Conjunctival staining	None to mild	Variable	Moderate to marked	Marked
Corneal staining (severity/location)	None to mild	Variable	Marked central	Severe punctate erosions
Corneal/tear signs	None to mild	Mild debris, decreased meniscus	Filamentary keratitis, mucus clumping, increased tear debris	Filamentary keratitis, mucus clumping, increased tear debris, ulceration
Lid/meibomian glands	MGD variably present	MGD variably present	Frequent	Trichiasis, keratinization, symblepharon
TFBUT (sec)	Variable	≤10	≤5	Immediate
Schirmer score (mm/5 min)	Variable	≤10	≤5	≤2

Dry Eye Severity level	1	2	3	4 (Must have signs and symptoms.)
Discomfort, severity & frequency	Mild and/or episodic; occurs under environmental stress	Moderate episodic or chronic, stress or no stress	Severe frequent or constant without stress	Severe and/or disabling and constant
Visual symptoms	None or episodic mild fatigue	Annoying and/or activity-limiting episodic	Annoying, chronic and/or constant, limiting activity	Constant and/or possibly disabling
Conjunctival injection	None to mild	None to mild	+/–	+/++
Conjunctival staining	None to mild	Variable	Moderate to marked	Marked
Corneal staining (severity/location)	None to mild	Variable	Marked central	Severe punctate erosions
Corneal/tear signs	None to mild	Mild debris, decreased meniscus	Filamentary keratitis, mucus clumping, increased tear debris	Filamentary keratitis, mucus clumping, increased tear debris, ulceration
Lid/meibomian glands	MGD variably present	MGD variably present	Frequent	Trichiasis, keratinization, symblepharon
TFBUT (sec)	Variable	≤10	≤5	Immediate
Schirmer score (mm/5 min)	Variable	≤10	≤5	≤2

Scoliosis

Juvenile Rheumatoid Arthritis: Follow-up

Juvenile Rheumatoid Arthritis: Follow-up
Author: C Egla Rabinovich, MD, MPH, Associate Professor and Co-Division Chief, Department of Pediatrics, Division of Pediatric Rheumatology, Duke University Medical Center
Contributor Information and Disclosures
Updated: Apr 7, 2010

Follow-up
Further Inpatient Care
Further inpatient care is required for persisting fevers of unknown origin or when children with known juvenile idiopathic arthritis (JIA) have severe exacerbation of disease. Admit for evaluation any child who loses the ability to walk for unknown reasons. Development of pericarditis in children with systemic juvenile idiopathic arthritis is usually an indication for admission.
Further Outpatient Care
Patients may have a gradually responsive disease (particularly those with pauciarticular juvenile idiopathic arthritis).
A small number of patients with pauciarticular juvenile idiopathic arthritis develop aggressive arthritis confined to a single joint; such patients may require more intensive medical treatment and physical therapy.
Some patients with polyarticular juvenile idiopathic arthritis demonstrate rapid response to treatment; however, most have prolonged courses, requiring frequent adjustments in medical and nonmedical therapy. Some have sufficient problems with activities of daily living, and they may benefit from courses of outpatient (and sometimes inpatient) rehabilitation.
Inpatient & Outpatient Medications
See Medication.
Transfer
Consider outpatient evaluation in a pediatric rheumatology center for all patients with known and suspected disease. Inpatient care for individuals with intercurrent illnesses may best be carried out at local hospitals; complications from juvenile idiopathic arthritis usually indicate transfer to a hospital with a pediatric rheumatology center.
Treatment of macrophage activation syndrome (MAS) is a medical emergency and should be done by physicians familiar with this complication.
Deterrence/Prevention
No prevention methods are known. The best means of deterrence is compliance with recommended treatment. As many as one half of patients may not comply with every detail of recommended treatment. Persisting noncompliance is a problem that increases risk of morbidity. Parents of such patients often admit noncompliance only to the child's primary care physician, rather than to a pediatric subspecialty team. The continued monitoring of compliance by the primary care physician, together with continuing communication between the pediatric subspecialist and primary physician, is an important part of the treatment of children with juvenile idiopathic arthritis and any chronic illness.
Complications
The following complications may occur:
• Systemic-onset juvenile idiopathic arthritis
o Pericarditis (patients often presenting with orthopnea and responsive to intravenous corticosteroid treatment)
o Hemolytic anemia
o Disseminated intravascular coagulopathy (DIC), often present at a low level of activity: The levels of D-dimer and fibrinogen may be elevated; their return to reference range levels is observed with successful treatment.
o MAS
 This is a rare, but important, complication, in which numbers of all 3 bloodlines become rapidly decreased. Hypofibrinogenemia, thrombocytopenia, and elevated aspartate aminotransferase levels are hallmarks.
 Hypotension, CNS disease, and marked hepatosplenomegaly may be noted as complications of a release of massive amounts of cytokines.
 Bone marrow aspiration may reveal histiocytic consumption of bone marrow precursors, which confirms the diagnosis and excludes malignancy. One does not need to see the histiocytic consumption for diagnosis of MAS.
 MAS often responds to cyclosporin A, and some case reports have detailed response to anakinra.
o Endarteritis resulting in circulatory compromise of the digits with threatened autoamputation
 This complication is even more rare than MAS.
 Central administration of prostaglandin E1 may be of potential benefit, similar to its use for patients with scleroderma and endarteritis.
• Pauciarticular juvenile idiopathic arthritis
o Knee flexion contractures: This complication requires splinting at night, in addition to medical treatment, to restore range of motion, allow recovery of muscle strength, and avoid subluxation of the joint. Intra-articular corticosteroid injection should be strongly considered.
o Uveitis
 Often asymptomatic, patients are typically young girls who have positive levels of antinuclear antibody (ANA).
 In such patients, evaluation using a slit-lamp examination by a pediatric ophthalmologist every 4 months can detect early disease.
 Treatment with topical corticosteroid medication and with mydriatic agents (to prevent closed-angle glaucoma) often can prevent progression of disease to development of calcium deposition in the lens (band keratopathy) and adhesions of the iris to the lens (posterior synechiae), in which an irregular pupillary margin develops.
 Such complications may herald a chronic active disease, in which vision is threatened; immunosuppressive agents, such as methotrexate or cyclosporin, may help to control chronic uveitis. Infliximab can be effective in some patients who are resistant to immunosuppressive agents.
o Leg length discrepancy (can result from neovascularization of growth plates of an affected knee)
 The problem may not be detected in patients with a knee flexion contracture until the contracture is corrected.
 Treatment consists of a shoe lift on the nonaffected side.
• Polyarticular juvenile idiopathic arthritis
o Skeletal abnormalities - Increased size of epiphyses, accelerated bone age, narrowed joint spaces, swan-neck and/or boutonniere deformities, and joint subluxation
o Cervical spine involvement
 Difficulty flexing the spine may create a problem for intubation prior to surgery; inform anesthesiologists of the patient's diagnosis. Screening cervical spine radiography (in both flexion and extension) may help screen for potential difficulties during induction of anesthesia.
 High-level subluxation is a potential complication.
Prognosis
Some studies suggest that many children with juvenile idiopathic arthritis can lead productive lives. However, other studies suggest many patients, particularly those with polyarticular disease, may have problems with active disease throughout adulthood, with sustained remission attained in a minority of patients. Early hip or wrist involvement, symmetric disease (even in pauciarticular patients), presence of rheumatoid factor, and prolonged active disease have been associated with poor long-term outcomes.
Children with systemic disease tend to have either complete responsiveness to medical therapy or development of a polyarticular course that tends to be refractive to medical treatment, with disease persisting into adulthood.
Most children with pauciarticular disease demonstrate eventual permanent remission; a small number progress to persisting polyarticular disease.
Patient Education
Educating the patient, family, and school personnel (eg, classroom teachers, physical education teachers, nurses) about juvenile idiopathic arthritis and its presentation, treatment, and potential effects is continually necessary. Members of the pediatric rheumatology team in pediatric rheumatology clinics are the best educators about juvenile idiopathic arthritis. Another important source of information is the American Juvenile Arthritis Organization, a council of the Arthritis Foundation.
For excellent patient education resources, visit eMedicine's Arthritis Center. Also, see eMedicine's patient education articles Juvenile Rheumatoid Arthritis and Understanding Rheumatoid Arthritis Medications.
Miscellaneous
Medicolegal Pitfalls
The major medicolegal pitfall lies in diagnosing juvenile idiopathic arthritis (JIA) when another problem exists (eg, infection, malignancy, orthopedic problem). Whenever possible, referral to a pediatric rheumatologist can help address this issue. Careful attention to presenting history and initial physical examination findings can lower the likelihood of such a pitfall. However, the chance of such a pitfall can never be eliminated completely.
At the time of diagnosis, inform parents and/or caregivers of the possible need to revise the diagnosis of juvenile idiopathic arthritis should new symptoms, physical findings, or unusual laboratory results develop.
Special Concerns
Chronic illness imposes burdens on families, who may vary in their abilities to cope. Social workers can help provide assessment and assist families in finding resources (including counseling). Remind parents and/or caregivers to bring all questions to the pediatric rheumatology team, who can often help. Any unusual symptom may signal a new complication of disease or adverse effect of medication. In the current health care environment, managed care can result in initial denial of services (eg, physical therapy), resulting in delays in treatment with subsequent morbidity. Advocacy by the primary care physician and pediatric rheumatologist can help point out the need for such services.

Acknowledgments
The authors and editors of eMedicine gratefully acknowledge Michael L Miller, MD, to the original writing and development of this article.

Juvenile Rheumatoid Arthritis: Treatment & Medication

Author: C Egla Rabinovich, MD, MPH, Associate Professor and Co-Division Chief, Department of Pediatrics, Division of Pediatric Rheumatology, Duke University Medical Center
Contributor Information and Disclosures

Updated: Apr 7, 2010

Treatment

Medical Care

Medical care of children with juvenile rheumatoid arthritis (JRA) must be provided in the context of a team-based approach, considering all aspects of their illness (eg, physical functioning in school, psychological adjustment to disease). Using medications in the absence of an appropriate physical therapy program and attention to problematic social issues of the family is not successful. Success of medications is monitored best with repeated physical examinations and history. Both the number of joints involved and the duration of morning stiffness should demonstrate continued decrease, with elimination reflecting success.

Surgical Care

Surgery is not usually needed; however, some children with persisting pauciarticular juvenile rheumatoid arthritis, despite medical treatment, may benefit from intra-articular steroid injection. Such injections may also be effective in treating temporomandibular arthritis in children with polyarticular juvenile rheumatoid arthritis. Usually, delay joint replacement (often of the hips, in patients with polyarticular juvenile rheumatoid arthritis) until bone growth has completed, which is reflected by epiphyseal closure. The consistent effective use of medical treatment has consigned synovectomy to a rarely used intervention. Large leg length discrepancies may need surgical treatment.

Consultations

The subspecialty team includes the following:

• Pediatric rheumatologist (when available)
• Nurses (who help with education)
• Physical and occupational therapists: Nonmedical approaches (eg, physical and occupational therapy) are an important part of treatment. At presentation, arthritis may be so active as to preclude the use of an aggressive program of muscle strengthening. Nevertheless, the use of pain modalities during this period may permit the gradual introduction of an active program of exercises and stretching.
• Social workers: Social work evaluation helps to determine how well each family is coping with their child's disease in terms of emotional and financial resources. Social workers can offer invaluable guidance for helping children to maintain healthy relationships both within their families and at school. Transition programs for adolescents with arthritis can help prepare them for higher education and future vocations.

Pediatric ophthalmologists help provide slit-lamp examinations to exclude uveitis. Pediatric orthopedic surgeons can offer consultation when orthopedic diagnoses are being considered. The development of profound anemia or a drop in 2 or more cell lines may require the help of a pediatric hematologist. A pediatric gastroenterologist may help with hepatic abnormalities or symptoms suggesting inflammatory bowel disease.

Diet

No specific diet helps in the treatment of juvenile rheumatoid arthritis. However, because active juvenile rheumatoid arthritis has been associated with decreased osteoblastic activity and a risk of osteopenia, encourage the inclusion of at least 3 servings of calcium-rich foods each day. Consider behavioral intervention when poor calcium intake persists.

Activity

Encourage patients to be as active as possible. Except in individuals with severe systemic disease, bed rest is not a part of the treatment. In fact, the more active the patient the better the long-term prognosis is. Children may experience increased pain during routine physical activities. As a result, these children must be allowed to self-limit their activities, particularly during physical education classes. A consistent physical therapy program, with attention to stretching exercises, pain modalities, joint protection, and home exercises, can help ensure that patients are as active as possible.

Medication

Classes of medications are suggested below, and specific drugs are covered in detail by category. See the therapeutic algorithm below

One set of suggested algorithms for the treatment of patients with juvenile arthritis. This should not be considered dogmatic because treatment is not standardized and remains empiric and, at times, controversial.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are used to treat all subtypes of juvenile rheumatoid arthritis (JRA). They may help with pain and decrease swelling. They are often used in conjunction with second-line agents. These medications are effective because of inhibition of prostaglandin synthesis. Naproxen is listed below as an example of an NSAID used in treatment; other NSAIDs commonly used include ibuprofen, tolmetin, diclofenac, and indomethacin. In addition, sulfasalazine is sometimes used as a second anti-inflammatory drug in some children with persisting pauciarticular and polyarticular disease. Its use may be considered as an intermediate step prior to adding a second-line drug such as methotrexate (MTX).

Aspirin is no longer the drug of first choice because of the increased frequency of gastric toxicity and hepatotoxicity when compared to other NSAID medications, along with its association with Reye syndrome. The discovery that cyclooxygenase (COX) in gastric and intestinal endothelium (ie, COX-1) is different in structure from that in leukocytes (ie, COX-2) has led to the development of anti-inflammatory drugs specific for COX-2. COX-2 inhibitors have been found to be effective in treatment of adults with rheumatoid arthritis. Studies of COX-2 inhibitors in persons with juvenile idiopathic arthritis are underway. Besides the benefit of greatly reducing gastric toxicity (although hepatotoxicity remains a possible adverse event), COX-2 inhibitors do not inhibit platelet aggregation. Thus, these agents may find a role in the treatment of inflammatory conditions in which a bleeding diathesis is a potential problem, such as in the postoperative setting.

NSAIDs alone are usually adequate for treatment of pauciarticular disease. However, an aggressive arthritis sometimes develops in this subtype, requiring the need to add a second-line drug. Various second-line drugs have been used in addition to first-line NSAIDs. Gold salt injections were used until approximately 15 years ago, when studies by the Pediatric Rheumatology Collaborative Study Group demonstrated the efficacy of oral (PO) MTX; these injections are not currently used for most children. Subsequent studies have demonstrated that some children with polyarticular arthritis unresponsive to PO MTX benefit from subcutaneous (SC) or intramuscular (IM) administration. The use of high-dose intravenous (IV) steroids as a therapeutic bridge in selected patients has been beneficial in some patients, particularly during an early period before MTX may have a full therapeutic effect.

Etanercept, a biologic agent administered SC twice weekly and containing a receptor to tumor necrosis factor (TNF) ligated to an Fc portion of immunoglobulin, has been found to be effective in controlling polyarticular arthritis not controlled by conventional medical treatment. Adalimumab is another anti-TNF agent now approved for use in juvenile idiopathic arthritis. These medications are for those children treated by pediatric rheumatology centers who are unresponsive to treatment including conventional second-line drugs.

Abatacept is a biological immune modulator with a delayed onset of action (4 mo) that may be useful in polyarticular disease.

Finally, the treatment of systemic juvenile idiopathic arthritis may require, in addition to treatment with NSAIDs, the careful use of either PO or high-dose pulse IV corticosteroids. Such treatment is best reserved for patients in whom definite arthritis has developed to avoid premature treatment in a patient who may prove to have a disease other than juvenile rheumatoid arthritis. Corticosteroids may be avoided with the use of anakinra, which is relatively new, inhibits interleukin (IL)-1 activity, and appears to have unique efficacy on the systemic signs and symptoms of systemic juvenile idiopathic arthritis. Rilonacept (anti-IL-1) may be an alternative treatment that is being studied, as is tocilizumab, which is anti-IL-6. Thalidomide has also been reported to be useful in these children.