The etiology of RA remains unknown, although both genetic and environmental factors likely are involved.⁹ Theories on the pathogenesis of RA postulate an inciting immunologic event in a genetically susceptible individual with subsequent inflammation in the joint resulting in synovial proliferation and joint destruction. The initial inciting immunologic event is unknown, but both immune complex disease and cellular immune events have been hypothesized.^10,11 Immunohistologic studies of the joint space have shown an early accumulation of T lymphocytes, which localize to the synovial tissue and initiate the inflammation that causes the clinical manifestations of RA.¹² Proliferation of synovial fibroblasts, synovial hypertrophy, and pannus formation occur.^9,12 In established RA there is an accumulation of polymorphonuclear leucocytes (PMNs) in the synovial fluid, suggesting recruitment of PMNs in later stages of the disease. These changes lead to erosion of bone at the joint margin, osteopenia at the joint margin, and in long-standing disease, joint destruction.

These immunologic processes cause the release of cytokines and metalloproteinases that perpetuates the joint destruction and leads to the production of serum RF.^9,12 RF is a polyclonal autoantibody directed against immunoglobulin G (IgG), which results in circulating immune complexes. It can be detected by several tests, including sheep red blood cell agglutination and enzyme-linked immunosorbent assay (ELISA). RF is a useful marker for the presence of RA and is present early in the disease course in 85% to 90% of patients with RA.^6,12 However, its contribution to the pathogenesis of the disease remains unclear, and the presence of RF is neither necessary nor sufficient for the diagnosis of RA.^6,12 High levels of RF have been associated with more severe clinical disease and poorer prognosis.^12,13 Anticitrullinated peptide (ACP) antibodies have also been reported in the serum of patients with RA.⁹ ACP antibody positivity has a high specificity (∼ 90%) for RA, has a sensitivity similar to RF, and levels can be detected before the start of clinical disease. Similar to RF, although these antibodies predict a more aggressive disease course, their participation in disease pathogenesis is unclear.⁹

There is a genetic predisposition to RA, with an association of the disease with the human leukocyte antigen (HLA) types, HLA-DR4 and HLA-DR1.¹⁴ Both HLA-DR4 and HLA-DR1 are thought to be involved in both the susceptibility to and the severity of RA.¹² In population studies, more than 90% of patients with RA have HLA-DR4 or HLA-DR1 or both.¹⁴ Polymerase chain reaction techniques have identified a specific sequence in the DRβ 1 gene that encodes an amino acid motif or shared epitope that has been found to occur in both HLA-DR4 and HLA-DR1 haplotypes.¹² This shared epitope has been hypothesized to serve as either a binding site for an antigenic peptide or as an autoantigen that activates T-cell inflammation.¹² Other genetic polymorphisms have also been implicated in RA susceptibility including polymorphisms in the genes for tumor necrosis factor α (TNF-α), PTPN22, and peptidyl arginase deiminases.⁹

In most patients with RA, the onset is insidious. However, in 10% to 20% of patients there may be an abrupt or explosive onset. The arthritis classically is described as an additive, symmetric, deforming polyarthritis. Typically, the small joints of the hands and feet are involved, although all joints may be affected. As with all inflammatory arthropathies, the disease is characterized by a gel phenomenon, that is, stiffness at rest improving with movement. Most patients complain of morning stiffness. X-ray studies of the affected joints show erosions of bone at the joint margin, which evolve into joint destruction with long-standing disease. Because of the damage to surrounding structures, joint laxity may develop; this process results in the characteristic ulnar deviation of the fingers.⁶

Extra-articular features are common in patients with RA.^{6,8,9,10,11,12,13,14,15,16} Generally, the number and severity of extra-articular complications increases with increasing disease duration and severity.⁶ The most common extra-articular lesion is the presence of rheumatoid nodules. These nodules occur in approximately 25% of patients with RA and are located primarily on extensor surfaces. On biopsy, they have a characteristic histologic picture with central fibrinoid necrosis surrounded by a palisade of elongated histiocyte-like cells. This core is enveloped by an outer zone of mononuclear inflammatory cells, primarily lymphocytes and plasma cells. Immunohistochemical analysis has demonstrated that the cells within the palisade layer stain for monocyte markers and that peripheral lymphocytes are predominantly T cells.¹⁷

Pulmonary lesions that may occur include pleural disease, pulmonary effusions, pleural or pulmonary nodules, arteritis with resultant pulmonary hypertension, and interstitial fibrosis. Pleuritis develops in 20% of patients with RA and may occur concurrently with the initial arthritic symptoms. Pulmonary effusions may be large enough to cause dyspnea. Rheumatoid nodules may develop in the pleura or within the lung. In the lung, the nodules may develop in clusters and cavitate, leading to bronchopleural fistula.⁶

Cardiac involvement includes pericarditis, which may be detected in as many as 50% of patients with RA at autopsy. Pericardial effusion secondary to pericarditis may be seen on echocardiogram in up to 31% of patients with RA, although most patients are asymptomatic and left ventricular dysfunction because of the effusions is rare.^6,18 Cardiac conduction defects as a consequence of rheumatoid nodules present in the conducting system can occur. Rheumatoid nodules also have been detected on heart valves.^6,16

Rheumatoid vasculitis occurs in less than 1% of patients with RA and typically is seen in patients with severe arthritis and high RF titers. It presents as a polyneuropathy, particularly with lower extremity anesthesia or hypesthesia, poorly healing leg ulcers, or as palpable purpura. Digital gangrene and occasionally visceral ischemia also may be manifestations of rheumatoid vasculitis.^6,16,19,20

Felty syndrome consists of RA, splenomegaly, and leukopenia and may represent up to 3% of patients with RA.²¹ Rheumatoid factor is present in 98% of patients with Felty syndrome, and titers typically are high. The pathogenesis of the leukopenia is unknown, but possible mechanisms include accelerated removal of leukocytes and suppression of granulopoiesis. Chronic leg ulcers with recurrent infections and hyperpigmentation of the skin also are characteristic features.^6,22

The most common ocular manifestations of RA are keratoconjunctivitis sicca (secondary Sjögren syndrome), scleritis, and rheumatoid corneal melts.^2,47 Sjögren syndrome originally was defined as dry eyes, dry mouth, and RA. It subsequently has become evident that Sjögren syndrome can exist in association with a connective tissue disease, in which case it is termed secondary Sjögren syndrome, or by itself with no definable associated connective tissue, in which case it is termed primary Sjögren syndrome. In Sjögren syndrome, there is a lymphocytic infiltration of the lacrimal and salivary glands resulting in glandular destruction and dysfunction. This process ultimately results in a characteristic loss of tearing and saliva. Approximately 11% to 13% of patients with RA have secondary Sjögren syndrome.²

Scleritis (Fig. 26-1) is the second most common ocular manifestation of RA, affecting an estimated 1% to 6% of patients with RA and 14% of patients with rheumatoid vasculitis.^2,48,49 Scleral inflammation can be classified as episcleritis or scleritis. Episcleritis presents with discomfort rather than pain, more superficial ocular inflammation, less frequent and severe ocular complications, and typically a less frequent association with systemic disease.⁵⁰ Conversely, scleritis often is characterized by pain, presents with deeper inflammation and edema in the sclera, often has ocular complications, which may be severe, and in approximately one half of the cases, is associated with systemic disease.^50,51 Episcleritis may be self-limited and spontaneously remitting, whereas scleritis typically requires therapy. Scleritis may be classified as anterior, posterior, or necrotizing. Anterior scleritis is subdivided into diffuse and nodular types. Scleromalacia perforans is a separate category, in which there is an insidious but destructive scleral process; it is seen in patients with long-standing RA. Any of the previously named types of scleritis may be seen in association with RA, although anterior scleritis is most common.^2,50

Although estimates of the frequency of scleritis in patients with RA have been as high as 6%, large series have shown that approximately 1% of patients with RA have scleral disease.^2,49,52 Of patients with scleritis, 10% to 33% have RA, and RA represents the most commonly seen rheumatic disease in patients with scleritis.^47,50 In patients with RA, scleritis is associated with more severe systemic disease and with a greater frequency of extra-articular manifestations.⁴⁷ Patients with RA are more likely to develop necrotizing scleritis than those patients with idiopathic scleritis.⁵³ Necrotizing scleritis is more likely to be associated with systemic vasculitis and a poor systemic prognosis. In a retrospective study by Foster et al,⁴⁸ 29% of patients with RA and necrotizing scleritis or necrotizing keratitis died, typically because of complications of vascular disease.

Rheumatoid corneal melts, also known as marginal corneal ulcers, may be either bland (not inflammatory) or necrotizing (peripheral ulcerative keratitis [PUK]) in nature. These melts have been described as occurring spontaneously or after ocular surgical procedures.⁵⁴ Noninflammatory marginal keratitis often can be treated with local measures. Necrotizing keratitis requires aggressive medical therapy with systemic corticosteroids and often immunosuppressive drugs. Patients with PUK and RA have a high mortality rate, possibly because of an underlying rheumatoid vasculitis.^2,48,49,53

Other uncommon features include Brown syndrome,^55,56 orbital myositis,⁵⁷ and hydroxychloroquine retinal toxicity.^58,59 Brown syndrome has been described in a few patients with RA and is caused by a stenosing tenosynovitis of the superior oblique tendon.^55,56 Rare cases of a retinal microangiopathy with cotton-wool spots have been reported,² but these probably are the result of an associated rheumatoid vasculitis.

The seronegative spondyloarthropathies (Table 26-3) are thought to be multifactorial in nature and triggered by an environmental insult in a genetically predisposed person. This genetic predisposition is evidenced by the strong association with HLA-B27.^{61,65,66,67,68,69} AS has the strongest association in that more than 90% of white patients with AS are HLA-B27 positive, whereas the general population frequency of HLA-B27 is approximately 8%.^2,61,65

The best insight into a possible environmental trigger for these disorders is provided by epidemic reactive arthritis. Epidemic reactive arthritis occurs after an infectious gastroenteritis with a limited number of organisms, including Shigella, Salmonella, and Yersinia. The subsequent arthritis occurs well after the infectious gastroenteritis has resolved and is a sterile arthritis. The arthritis appears to represent an immunologic response to the infectious organism, which triggers the arthritis in a susceptible person. In reactive arthritis, the presence of HLA-B27 again is associated strongly with the development of disease.^60,70

The exact molecular mechanisms by which HLA-B27 predisposes to disease are unknown. Theories include molecular mimicry^60,71 and the possibility that HLA-B27 is associated with a defective class I antigen-mediated cellular response.⁶⁹ The molecular mimicry hypothesis suggests that there is a similarity at the molecular level between the HLA-B27 molecule and the inciting organisms, allowing for the triggering of an immune response and the subsequent development of clinical disease.^69,71 The process is felt to be analogous to rheumatic fever or acute poststreptococcal glomerulonephritis, where the immune response to a cross-reactive antigen results in a subsequent immune-mediated disease. Alternatively it has been suggested that the HLA-B27 molecule may be a defective molecule associated with an aberrant cytotoxic T-cell response.^69,72

AS is characterized by involvement of the axial skeleton and bony fusion (ankylosis).⁷³ The estimated prevalence of AS is 0.1% to 0.2% of the general population and is 2% in HLA-B27–positive patients.⁶⁹ Young adult males are affected most frequently, with a male-to-female ratio of approximately 3:1. Earlier studies suggested a much higher male-to-female ratio, but it subsequently has become evident that women may have mild or atypical forms of the disease.^74,75 Between 10% and 30% of HLA-B27–positive first-degree relatives of AS patients will develop the disease.⁷⁶

The characteristic symptom of AS is chronic low back pain, which improves with exercise. The symptoms may be mistaken by patients as a strain-related injury, and the diagnosis may be delayed by several years.^69,77 As with other inflammatory arthropathies, the disease is associated with morning stiffness. The inflammation results in fusion of the axial skeleton (spinal ankylosis) and sacroiliitis. Physical examination reveals restricted motion of the spine and may reveal tenderness over the sacroiliac joints. Radiographic examination of the spine and sacroiliac joints is important in the diagnosis of the disease. The demonstration of sacroiliitis on radiographic examination of the sacroiliac joints is almost a sine qua non for the diagnosis of spondylitis. The end stage of this process is a completely fused and immobilized spine, also known as a bamboo or poker spine. In addition to the spinal arthritis, patients may also develop an arthritis of the shoulders and hips, limited chest expansion, restrictive lung disease, apical pulmonary fibrosis, aortic insufficiency because of arteritis, and heart block.^60,73,78

The primary ocular manifestation of AS is a nongranulomatous, recurrent, acute, unilateral or unilateral alternating anterior uveitis.^64,76 Generally, one eye is affected at a time, although both eyes may suffer attacks.^64,76 Occasionally anterior chamber inflammation may be severe enough to produce hypopyon, fibrin deposition, and posterior synechiae (Fig. 26-2).⁷⁸ An estimated 25% to 40% of patients with AS suffer an attack of uveitis at some time during the course of their disease, with eye inflammation occasionally preceding the systemic diagnosis.^69,76,79 Studies of patients with acute anterior uveitis have reported that AS is present as the underlying systemic disease in 18% to 34% of these patients.^76,78,80,81 Rarely, a spillover vitritis is seen in patients with acute anterior uveitis and AS, but it is substantially less frequent than the typical iridocyclitis.⁸² Scleritis has rarely been reported in patients with HLA-B27–associated disease.⁸³

Reiter syndrome was originally characterized by the classic triad of arthritis, urethritis, and conjunctivitis. Typically, it is rare for a patient to present with the classic triad originally described. As such, the term Reiter syndrome has been replaced with the entities undifferentiated spondyloarthritis and reactive arthritis. Undifferentiated spondyloarthritis refers to patients with inflammatory spinal pain and/or synovitis but without evidence of AS.⁸⁴ Enthesitis (i.e., inflammation at the site of an insertion of a ligament, tendon, or fascia to bone) is another common finding. The clinical course of undifferentiated spondyloarthritis varies per individual, with some experiencing disease remission, some progressing to AS, and some continuing with undifferentiated inflammation. As in AS, first-line treatment is with NSAIDs, with methotrexate and TNF inhibitors reserved for more severe cases.⁸⁴

Reactive arthritis refers to patients who develop an inflammatory arthritis after an infection, with symptoms typically starting 1 to 4 weeks after an episode of gastroenteritis or urethritis.⁸⁴ The microbials associated with reactive arthritis include the enteric bacteria Salmonella, Shigella, Yersinia, Campylobacter, Clostridium difficile, and Chlamydia (whose various species can cause urethritis and upper respiratory infections).⁸⁴ The arthritis of reactive arthritis is migratory, asymmetric, episodic oligoarthritis affecting primarily the large joints at the lower extremities, such as the knees or ankles. Other articular features include heel pain, sausage digits caused by interphalangeal arthritis of the toes and/or fingers, and sacroiliitis. Mucocutaneous lesions include urethritis in men and cervicitis in women, circinate balanitis, painless oral ulcers, keratoderma blennorrhagica, and dystrophic nail lesions.^84,85 Systemic symptoms including fever and weight loss also may occur. The disease tends to follow an episodic and relapsing course.^84,85,86 The arthritis may be recurrent in 15% to 50% of patients.⁸⁴ Another 15% to 30% of patients will develop chronic arthritis over 10 to 20 years of follow-up.^84,86

Conjunctivitis was part of the original triad described by Reiter and is one of the hallmarks of the disease. It tends to be a feature of early disease, particularly of the initial attack, and may be missed if patients are seen only during subsequent attacks. Depending on the source of the reported series, and on the diagnostic criteria used, the frequency of conjunctivitis in patients with Reiter syndrome has varied from 33% to 100%. The more serious ocular manifestation is recurrent, acute, nongranulomatous anterior uveitis. It occurs in approximately 5% to 20% of patients with the initial attack but may occur in as many as 50% of patients with reactive arthritis over long-term follow-up.^69,76,87 Some studies of patients with acute anterior uveitis suggest that reactive arthritis is more frequently seen in patients with acute anterior uveitis than is AS,^63,88 although this finding may be the result of a referral bias or of geographic variations in the prevalence of these disorders. As with AS, occasionally a spillover vitritis has been described in reactive arthritis and is found more commonly with reactive arthritis than with AS. Rarely other forms of posterior ocular involvement such as multifocal choroiditis and panuveitis have been reported.^89,90 Optic disc edema in the setting of an anterior uveitis has also been described.² Rarely, patients may develop a keratitis with punctate epithelial lesions, progressing to a central loss of the corneal epithelium and subepithelial infiltrates.^91,92,93

The clinical features of IBD are diarrhea and abdominal pain. Diarrhea may or may not be bloody. Extraintestinal manifestations of IBD include dermatitis, mucous membrane disease, ocular inflammation, and arthritis. Skin disorders occur in 6.5% to 15% of patients with IBD and include erythema nodosum and pyoderma gangrenosum.^94,95 Arthritis occurs in up to 25% of patients with IBD.⁹⁶ One form of arthritis associated with IBD is an HLA-B27–associated axial-sacroiliac spondylitis, which is seen in approximately 20% of patients with Crohn disease and in 10% to 15% of patients with ulcerative colitis.⁹⁶ In one series of 103 patients with IBD, arthritis occurred in 39% of patients, and of the patients with arthritis, 90% met the criteria for spondyloarthropathy.⁹⁷ Between 50% and 70% of patients with spondylitis and IBD are HLA-B27 positive.⁹⁶ Of the HLA-B27–positive patients with IBD, 50% will develop acute anterior uveitis.⁹⁴ The activity of this spondylitis is unrelated to that of the bowel disease, and in 18% to 20% of patients, the spondylitis will be asymptomatic.^69,96,98 Another form of arthritis seen in patients with IBD involves the peripheral joints and is seen in 5% to 15% of patients.⁹⁶ Type 1 disease is a large-joint, lower-extremity, nondeforming oligoarthritis that tends to have an acute onset and resolves within 6 weeks. Type 2 disease is an arthritis involving more than five joints and tends to have a more chronic course. There tends to be a correlation between peripheral arthritis and gut activity in UC but not in Crohn disease.⁹⁶

Ocular inflammation has been reported to occur in up to 13% of patients with IBD but typically occurs in approximately 2% to 6% of patients.^76,84,98 The ocular manifestations include anterior uveitis, scleritis, and keratitis. Anterior uveitis is the most common ocular manifestation.^100,101,102 More often it presents as a nongranulomatous, recurrent, acute anterior uveitis. This type of uveitis is seen in association with spondylitis and HLA-B27. Chronic and bilateral uveitis also occurs occasionally and may be seen more frequently in women with IBD.^76,103,104 There have been occasional case reports of retinal vascular disease, including retinal artery occlusion and retinal vasculitis, and ischemic optic neuropathy in patients with IBD.^105,106,107 It has been suggested that these retinal vascular lesions are caused by a thrombic diathesis seen in some patients with IBD.¹⁰⁵ All types of scleritis have been associated with IBD including anterior scleritis, necrotizing scleritis, and posterior scleritis. The scleral inflammation may parallel the activity of the underlying bowel disease (Fig. 26-3).^101,102 Rarely, keratitis^102,108 and Brown syndrome¹⁰⁹ may be seen in association with IBD.

Psoriatic arthritis is a syndrome defined by the presence of psoriasis and an associated seronegative inflammatory arthritis.¹¹⁰ Psoriasis is a common cutaneous disorder, affecting 1% to 3% of the population and is characterized by erythematosus, well-demarcated macular lesions with silvery scales. It characteristically occurs on extensor surfaces, particularly the elbows and scalp, but also the chest or back. Approximately 10% to 20% of patients with psoriasis have arthritis.^110,111 The skin disease generally precedes the onset of the arthritis by several years, but the arthritis precedes the onset of skin disease in 15% of patients with psoriatic arthritis.¹¹⁰ Nail changes are present in 90% of patients with psoriatic arthritis as compared to 41% of patients with psoriasis but without arthritis.¹¹² The nail changes include pitting, transverse ridges, crumbling, and onycholysis.

Psoriatic arthritis has been classified into five groups based on the clinical presentation of the arthritis. Classic psoriatic arthritis is manifested by involvement of the distal interphalangeal joints. Arthritis mutilans is a severely deforming, destructive, and usually widespread arthritis with ankylosis of joints and characteristic erosive joint changes seen radiographically. A symmetric, additive, deforming polyarthritis similar to RA can be seen. However, psoriatic arthritis usually is negative for RF. The most common presentations of psoriatic arthritis are monoarthritis or an asymmetric oligoarthritis, usually affecting the distal interphalangeal, proximal interphalangeal, or metatarsal interphalangeal joints. The fifth type of psoriatic arthritis is psoriatic spondylitis. Psoriatic spondylitis is an HLA-B27–associated disorder, and approximately 50% of patients with psoriatic spondylitis are HLA-B27 positive.^60,110 The course and severity of disease in psoriatic arthritis appears to be independent from the skin disease.¹¹⁰

Conjunctivitis occurs in approximately 20% to 33% of patients with psoriatic arthritis, iritis in 4% to 7%, and scleral disease in 2%.^{60,110,111,113} Patients with psoriatic spondylitis typically develop a nongranulomatous, recurrent, acute anterior uveitis, as is the case with other HLA-B27–associated arthropathies, but chronic uveitis also may occur. Brown syndrome also has been reported in patients with psoriatic arthropathy.¹¹⁴

The incidence and prevalence of JIA have been estimated as 10 to 20 cases per 100,000 population per year and 65 to 148 cases per 100,000 population, respectively.^117,118 Five distinct subgroups of JIA have been described. The systemic variant of JIA also is known as Still disease. The male-to-female ratio is approximately 1:1, and the onset of disease is generally at younger than 5 years of age. The arthritis has a variable relation to the onset of the systemic disease but is usually a polyarthritis. The systemic features include fever, a salmon-colored evanescent maculopapular rash, lymphadenopathy, hepatitis, splenomegaly, and serositis. An elevated erythrocyte sedimentation rate and leukocytosis are seen, but ANA and RF tests are negative in at least 90% of cases.¹¹⁶ Ocular disease generally is not associated with this variant.¹¹⁵

Two types of oligoarticular JIA have been described. Persistent oligoarthritis affects four or fewer joints through the disease course whereas extended oligoarthritis affects five or more joints after the first 6 months of the disease.¹¹⁶ Oligoarticular disease is typically seen in children younger than 5 years of age. The mean age of onset is 3 years. Girls are affected more often than boys with a male-to-female ratio of 1:4. The arthritis is an oligoarticular, large-joint, lower-extremity arthritis that tends to spontaneously remit and not leave significant articular deformities. Approximately 60% of these patients have a positive ANA test. Several loci of genetic susceptibility have been found in this subgroup of patients including ones involving the HLA alleles at class I (HLA A2) and class II (DRB1*0801, DRB1*1104. DRB1*1301).^116,119,120 A chronic anterior uveitis is the characteristic ocular feature of this group seen in 20% to 30% of children.^{115,121,122,123} A second type of oligoarticular disease (classified as enthesitis-related arthritis) is seen in older children, with a mean age of onset at 12 years. Boys are affected more often than girls, and the male-to-female ratio is approximately 7:1.¹¹⁶ The arthritis is a large-joint, lower-extremity oligoarthritis. Sacroiliitis is common, and these children tend to progress to AS over time. Enthesitis is also a common finding. Eighty percent of these children are HLA-B27 positive, and approximately 25% develop a nongranulomatous, recurrent, acute anterior uveitis. This variant shares the clinical and immunogenetic features of the seronegative spondyloarthropathies in adults, including the same type of uveitis.^115,124,125

Two types of polyarticular disease have been described. In children older than 10 years of age, an RF-positive (seropositive), rheumatoid-like polyarthritis may develop. Girls are affected more commonly than boys with a ratio of 9:1. The arthritis is an additive, symmetric, deforming polyarthritis similar to that of adult RA. The arthritis is persistent and results in long-term articular morbidity with joint erosions and deformity seen. This type of arthritis is strongly associated with HLA-DRB1*0401, the HLA antigen seen in adult RA. Ocular disease is uncommon in this subgroup.^115,116,124 A second type of polyarticular disease is one in which the RF factor is negative (the ANA is positive in approximately 40% of patients).¹¹⁶ The peak age of disease onset is between 6 and 7 years; the arthritis is variable and may be symmetric or asymmetric, and may involve small and large joints, the cervical spine, and the temporomandibular joint. The ocular finding tends to be chronic anterior uveitis and occurs in 10% of patients, most commonly in those patients with fewer affected joints.¹¹⁶

Approximately 12% to 17% of children with any type of JIA have uveitis.^134,135,136 A population-based study performed in Finland reported the mean annual incidence and prevalence rates for JIA-associated uveitis as 0.2 and 2.4 cases per 100,000 population, respectively.¹³⁷ The ocular manifestations of JIA are two different types of anterior uveitis. Acute anterior uveitis is seen in the HLA-B27–associated subgroups and is similar to that seen in adult HLA-B27–associated disease. Chronic anterior uveitis is seen primarily in the ANA-positive oligoarticular subgroup where frequencies have been reported to range from 20% to 56%.^{116,121,138,139,140} Although traditionally it has been thought that these cases occur primarily in girls, a recent retrospective study of 90 children with JIA found no gender difference in the risk of developing uveitis.¹³⁴ The chronic anterior uveitis tends to be asymptomatic or minimally symptomatic; therefore, it is recommended that these patients be evaluated every 3 months for screening in an effort to detect the uveitis early.¹⁴¹ Two thirds of patients have bilateral disease, and in patients with unilateral disease, most will develop uveitis in the fellow eye within 1 year of presentation.¹¹⁶ The chronic uveitis typically requires chronic therapy. Severe visual disability may develop. Band keratopathy and cataracts may be seen in up to one third of patients and are the most frequent causes of decreased vision.¹⁴² Secondary glaucoma occurs in 10% to 20% of patients with JIA-associated uveitis and is a poor prognostic finding.^{136,138,139,142,143} Posterior synechiae are common and have been shown to be associated with poorer visual acuity.^142,144 Other complications include macular edema in 8% to 10% of cases and phthisis in 4% to 10% of patients. Although blindness developed in 40% of patients reported in early series, more recent series have reported a better prognosis.^{140,145,146,147} One study from Finland reported on 426 incident cases of JIA diagnosed between 1989 and 1996, of whom 24% developed uveitis. In this series only 3% of those with uveitis were reported to have a best-corrected visual acuity of 20/60 or worse. The improved prognosis appears to be because of earlier detection, better treatment, and better surgical management of the complications. Although pars plana lensectomy with vitrectomy and aphakic correction traditionally had been considered the best method of cataract surgery in these patients,^138,148 more recent case series have suggested that intraocular lenses can be placed in these patients with good visual outcome.^148,149

Treatment for the uveitis associated with JIA depends on the type of uveitis. Acute anterior uveitis typically can be controlled with topical corticosteroid eye drops such as prednisolone acetate 1%. The medication is instituted at one drop every 1 to 2 hours while awake until the uveitis is controlled and then tapered slowly and discontinued. Milder forms of chronic uveitis also may be controlled with topical corticosteroids, although the medication may be required indefinitely to keep the uveitis quiet. The dose of topical corticosteroid is tapered to the lowest dose in which the uveitis remains quiet. In cases of more severe uveitis, methotrexate or cyclosporine may be used.^129,130,131 Immunosuppressive drug therapy has been shown to reduce the incidence of vision loss and ocular complications (i.e., hypotony and formation of epiretinal membrane) in patients with JIA uveitis.¹⁴⁴ Systemic corticosteroids are given in cases of severe, sight-threatening uveitis and are used in conjunction with a steroid-sparing agent such as methotrexate. The systemic corticosteroids are tapered and discontinued as quickly as possible r to avoid side effects such as growth retardation.

The uveitis associated with familial juvenile systemic granulomatosis may be a chronic anterior uveitis or a chronic panuveitis with multifocal choroiditis. Patients may require aggressive medical therapy to control the uveitis, sometimes including immunosuppressive drugs. Ocular complications including cataract and macular edema are common.²

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease. Although the etiology of SLE is unknown, the association of SLE with HLA-DR2, HLA-DR3, and the association of lupus nephritis with Fcy receptors IIA and IIIA located on chromosome 1 all suggest a genetic predisposition.^156,157 Pathogenetically, SLE is characterized by B-cell hyperactivity, polyclonal B-cell activation, hypergammaglobulinemia, autoantibody formation, and abnormal T cells.¹⁵⁶ Autoantibodies seen in patients with SLE include ANA, antibodies to DNA, both single-stranded DNA (anti-ssDNA) and double-stranded or native DNA (anti-dsDNA), and antibodies to cytoplasmic components, such as anti-Sm, anti-Ro (SSA), and anti-La (SSB).¹⁵⁶ Studies have demonstrated multiple defects in T-cell signaling pathways in patients with SLE that are thought to lead to autoreactivity and hyperactivated T-cell lymphocytes.^158,159,160 SLE classically has been regarded as an immune complex disease, in which circulating immune complexes are deposited in tissue and incite an inflammatory response, which may lead to end organ damage. Immunoregulatory abnormalities in SLE lead to an inadequate clearing of immune complexes and further hyperactivation of both B cells and T cells, causing further inflammation and tissue damage.¹⁵⁶

The incidence of SLE has been estimated as 2 to 9 cases per 100,000 population per year.¹⁶¹ SLE is a multisystem disease that may affect almost any organ system.^{161,162,163,164,165,166} Because of the multisystem nature of the disease, criteria for the diagnosis have been established and are outlined in Table 26-4.¹⁶⁷ These criteria are for use in clinical investigations and may not always be applicable in patient management. SLE has a chronic course marked by periodic exacerbations of varying severity.¹⁶¹ Cutaneous disease occurs in approximately 85% of patients with SLE. The most classic manifestation is the characteristic butterfly rash across the nose and cheeks, also known as a malar rash. Other cutaneous lesions include discoid lupus erythematosus, vasculitic skin lesions such as cutaneous ulcers or splinter hemorrhages, purpuric skin lesions, alopecia, and livedo reticularis, a reticular purplish rash seen most commonly on the legs. Less common skin lesions include a maculopapular eruption, lupus profundus, bullous skin lesions, and urticarial skin lesions. Mucosal lesions occur in 30% to 40% of patients with SLE and characteristically are painless oral ulcers. Photosensitivity is a common feature of the skin lesions in SLE affecting up to 70% of patients, and patients may be exquisitely sun sensitive.^{161,162,163,164,166} The Raynaud phenomenon occurs in approximately 20% of patients with SLE. Cardiac disease includes pericarditis, occasionally myocarditis, and Libman-Sacks endocarditis. Libman-Sacks endocarditis was common in old autopsy series but now is unusual. Pleuropulmonary lesions include pleurisy and, less commonly, pneumonitis. Adenopathy and hepatosplenomegaly can be seen in 50% of patients with SLE.^{161,162,163,164,166} Involvement of the central nervous system (CNS) by lupus occurs in 35% of patients with SLE.^165,166 CNS lupus may present as seizures, an organic brain syndrome, or psychosis.¹⁶⁵ Transverse myelitis is an uncommon manifestation, occurring in only 4% of patients with SLE, but often is seen in association with optic neuritis. Peripheral nervous system involvement with a peripheral neuropathy and cranial nerve palsy is less common.

At some point during the course of their SLE, 80% to 85% of patients with SLE have articular disease. Articular involvement includes polyarthralgias and a nondeforming migratory polyarthritis. Cutaneous nodules, myalgias, and myositis are less common. Systemic features occur in more than 80% of patients with lupus and include fatigue, fever, and weight loss. Renal disease is present in approximately 50% of these patients. Lupus nephritis clinically presents as either proteinuria with a nephritic picture or as glomerulonephritis with active urinary sediment. Lupus nephritis is a major cause of morbidity and mortality in SLE.^{161,162,163,164,166} Patients with SLE often have a mild chronic anemia, known as anemia of chronic disease. However, they may also develop an autoimmune hemolytic anemia. Leukopenia, in particular lymphopenia, is a characteristic feature. Thrombocytopenia occurs in approximately one third of patients.^{161,162,163,164,166}