Chapter 26
Ocular Manifestations of the Rheumatic Diseases
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The rheumatic diseases are a heterogeneous collection of diseases that are multisystem in nature and immunologically mediated. They are loosely grouped into three general categories: the arthritides, the connective tissue diseases, and the vasculitides (Table 1). Behçet's disease has been classified variously but in this chapter is discussed with the vasculitides. The diagnosis of each of the rheumatic disorders is a clinical diagnosis. To ensure homogeneity in clinical research and assist in reporting in the literature, the American College of Rheumatology (ACR) has developed criteria for most of the rheumatic diseases. These criteria are for research purposes and cannot always be used in the care of every patient. However, they often provide a useful description of the clinical features of the disease.


Table 1. The Rheumatic Diseases

Rheumatoid arthritis
Seronegative (HLA-B27 associated) spondyloarthropathies
  Ankylosing spondylitis
  Reiter's syndrome
  Inflammatory bowel disease
  Psoriatic arthritis
Juvenile rheumatoid arthritis

Connective Tissue Diseases
  Systemic lupus erythematosus
  Polymyositis and dermatomyositis
  Sjögren's syndrome
  Relapsing polychondritis

  Polyarteritis nodosa
  Churg-Strauss syndrome
  Hypersensitivity vasculitis
  Henoch-Schönlein purpura
  Wegener's granulomatosis
  Lymphomatoid granulomatosis
  Giant cell arteritis (temporal arteritis)
  Takayasu's arteritis
  Behçet's disease


The clinical features of the rheumatic disorders are based on the anatomic pattern of disease. This situation is analogous to the definitions of ocular uveitis syndromes, in which the anatomic pattern of disease is used as characteristic criteria. Thus, rheumatoid arthritis generally is described as an additive, symmetric, deforming polyarthritis, while the seronegative spondyloarthropathies often are associated with a migratory, asymmetric oligoarthritis. Similarly, the different vasculitides are defined by the pattern of vascular involvement and the size of blood vessels commonly involved. As such, individual laboratory tests (e.g., rheumatoid factor [RF] or antinuclear antibody [ANA]) are supporting evidence in the diagnosis of the disease but do not define the disease.

The major ophthalmic manifestations of the rheumatic diseases include scleritis, Sjögren's syndrome, uveitis, retinal vascular disease, and neuroophthalmic lesions.1,2 Each of these is most characteristically associated with a few but not all of the rheumatic disorders. Hence, scleritis most often is seen with rheumatoid arthritis or with vasculitis. Acute anterior uveitis most often is seen with the seronegative spondyloarthropathies. Retinal vascular and neuroophthalmic lesions are seen with disorders that have either a vasoocclusive component, such as systemic lupus erythematosus or one of the vasculitides.

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Rheumatoid arthritis (RA) is the most common rheumatic disorder affecting an estimated 1% of the general population.3–7 The overall incidence of RA has remained fairly stable across geographic locations.6 Classically RA is described as an additive, symmetric, deforming polyarthritis. The diagnosis of RA is a clinical one, based on the features outlined below. The ACR criteria for the diagnosis of RA are outlined in Table 2.8


Table 2. American College of Rheumatology (ACR) Revised Criteria for the Diagnosis of Rheumatoid Arthritis

1. Morning stiffnessMorning stiffness in and around the joints lasting at least 1 hour before maximal improvement
2. Arthritis of three or more joint areasAt least three joint areas have simultaneously had soft tissue swelling or fluid (not bony overgrowth alone) observed by a physician. The 14 possible joint areas are right or left PIP, MCP, wrist, elbow, knee, ankle, and MTP joints.*
3. Arthritis of hand jointsAt least one joint area swollen as above in wrist, MCP, or PIP.
4. Symmetric arthritisSimultaneous involvement of the same joint areas (as in 2) on both sides of the body (hilateral involvement of PIPs, MCPs, or MTPs is acceptable without absolute symmetry).
5. Rheumatoid nodulesSubcutaneous nodules, over bony prominences, or exterior surfaces, or in juxtaarticular regions, observed by a physician.
6. Serum rheumatoid factorDemonstration of abnormal amounts of serum “rheumatoid factor” by any method that has been positive in less than 5% of normal control subjects.
7. Radiologic changes 

For classification purposes, a patient shall be said to have rheumatoid arthritis if he/she has satisfied at least 4 of the above 7 criteria. Criteria 1–4 must have been present for at least 6 weeks. Patients with 2 clinical diagnoses are excluded. Designation as “classic,” “definite,” or “probable” rheumatoid arthritis is not to be made.
*PIP, proximal interphalangeal joint; MCP, metacarpophalangeal joint; MTP, metatarsophalangeal joint; PA, posteroanterior (Arnett FC, Edworthy SM, Block DA, et al: The American Rheumanism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31:314, 1988. Copyright © 1988 Wiley-Liss. Reprined by permission of Wiley-Liss. Inc. a subsidiary of John Wiley & Sons lnc.)



The etiology of RA remains unknown, although both genetic and environmental factors likely are involved. 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.9,10 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.11 Proliferation of synovial fibroblasts, synovial hypertrophy, and pannus formation occur.11,12 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, osteoporosis at the joint margin, and in long-standing disease, joint destruction.

These immunologic processes cause the release of cytokines and metalloproteinases that perpetuate the joint destruction and leads to the production of serum RF.11,12 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 85-90% of patients with RA.7,11 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.7,11 High levels of RF have been associated with more severe clinical disease and poorer prognosis.11,13

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.11 In population studies, more than 90% of patients with RA have HLA-DR4, or HLA-DR1, or both.14 Studies of white Americans have shown a consistent association with HLA-DR4, with 70% of white patients with RA expressing the DR4 haplotype compared to 28% of patients with non-RA arthritis.15 Polymerase chain reaction techniques have identified a specific sequence in the DRβ1 gene that encodes an amino acid motif or shared epitope that has been found to occur in both HLA-DR4 and HLA-DR1 haplotypes.11 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.11


In the majority of 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.7

Extraarticular features are common in patients with RA.7,16 The most common extraarticular 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 pleural or within the lung. In the lung, the nodules may develop in clusters and cavitate, leading to bronchopleural fistula.7

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 the majority of patients are asymptomatic and left ventricular dysfunction because of the effusions is rare.7,18 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.7,16

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.7,16,19,20

Felty's syndrome consists of RA, splenomegaly, and leukopenia, and may represent up to 3% of patients with RA. Rheumatoid factor present in 98% of patients with Felty's 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.7,21


The goals of treatment for RA include the prevention and control of joint damage, prevention of loss of function, and pain reduction.22 Prior to the 1990s, the treatment of RA typically was approached in a stepwise fashion with nonsteroidal antiinflammatory drugs (NSAIDs) being the first line of therapy followed by institution of disease modifying antirheumatic drugs (DMARDs) in more severe or refractory cases.22 However, recent studies suggest that the destruction of the joints and loss of function occurs soon after the onset of synovitis.23,24 It is estimated that one half of the joint destruction that is seen over an 8-year period occurs in the first 2 years.25 Therefore, now a DMARD typically is instituted within the first 3 months of diagnosis of RA in addition to an NSAID.23 NSAID therapy includes salicylates, older nonselective cyclooxygenase (COX) inhibitors, and the newer COX-2 inhibitors. These NSAIDs are used to control pain and swelling and to improve the joint function but typically do not alter disease course or prevent joint destruction long term.22 Because joint destruction can occur within the first 2 years of the disease, early treatment with a DMARD or remittive agent is recommended.23 Remittive agents include hydroxychloroquine, sulfasalazine, methotrexate, etanercept, infliximab, leflunomide, and anakinra. Hydroxychloroquine and sulfasalazine are effective for milder disease.26–31 Hydroxychloroquine often is used first because of its relative lack of toxicity. Chloroquine is slightly more efficacious than hydroxychloroquine in the treatment of RA but also is more toxic; therefore, it is used infrequently.32 Methotrexate, an antimetabolite, typically is the first choice of remittive agents for more severe or advanced disease and has been found to be efficacious in the treatment of RA in multiple randomized clinical trials.33–36 Methotrexate was found to improve clinical signs and symptoms of RA, improve functional status, and slow radiographic disease progression. Leflunomide also has been found to be effective in controlling RA progression and in improving clinical and functional status both as monotherapy and in combination with methotrexate.37–39 Triple therapy with methotrexate, hydroxychloroquine, and sulfasalazine also has been shown to be effective in the treatment of RA, although simpler treatment regimens typically are used.40,41

Biologics are engineered agents designed to block cytokines or cytokine receptors. Biologic agents, including etanercept, infliximab, and anakinra have been found to be potent remittive agents in several randomized clinical trials.23,42–46 Etanercept is a recombinant tumor necrosis factor α (TNF-α) receptor Fc segment fusion protein and is effective in controlling progression of RA as initial monotherapy in early RA and as therapy for patients who have failed previous DMARD therapy.23,42,43 The typical dose of etanercept is 25 mg administered subcutaneously twice per week. Many patients taking etanercept improve more rapidly than those taking methotrexate, sometimes within 2 weeks after instituting etanercept.23,43 Etanercept also is effective in combination with methotrexate for controlling ongoing active RA in patients already taking methotrexate alone.43 Infliximab is a chimeric (mouse-human) anti-TNF-α monoclonal antibody and only is available as an intravenous preparation given either 3 to 5 mg every 4 weeks or 3 to 10 mg every eight weeks. Infliximab in combination with methotrexate has been used successfully to improve clinical and functional status in patients with RA who have failed methotrexate monotherapy.44,45 Anakinra, a recombinant human interleukin-1 receptor antagonist (IL-1Ra), also is approved for use in RA in a 100-mg daily dose given by subcutaneous injection.23 Anakinra inhibits the binding of the cytokines IL-1α and IL-1β to the IL-1 receptor, which prevents the activation of its target cells and subsequent synovial inflammation and joint destruction.23 Randomized clinical trials found anakinra to be superior to placebo in controlling clinical symptoms of RA.23 Another randomized clinical trial found that anakinra in combination with methotrexate was more effective in controlling RA progression than methotrexate alone.46

Immunosuppressive drugs, such as azathioprine,47,48 cyclosporine,49 or cyclophosphamide,48,50 also are efficacious in the treatment of RA but are used less frequently because of their toxicity. Occasionally they may be used in the treatment of rheumatoid vasculitis.22 Intramuscular and oral gold and d-penicillamine also are effective remittive agents but are used rarely because of more efficacious and better-tolerated newer drugs.22 Minocycline has been shown to be modestly effective in a randomized trial and is used for mild disease, although infrequently.51,52 Traditionally low-dose prednisone (5 mg every other day to 10 mg/d) was used to decrease stiffness and increase mobility. Although the newer remittive agents have decreased this practice, prednisone still is used.


The most common ocular manifestations of RA are keratoconjunctivitis sicca (secondary Sjögren's syndrome), scleritis, and rheumatoid corneal melts.2,53 Sjögren's syndrome originally was defined as dry eyes, dry mouth, and RA. It subsequently has become evident that Sjögren's syndrome can exist in association with a connective tissue disease, in which case it is termed secondary Sjögren's syndrome, or by itself with no definable associated connective tissue, in which case it is termed primary Sjögren's syndrome. In Sjögren's 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's syndrome.2

Scleritis (Fig. 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.2,54,55 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.56 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.56,57 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 and is seen in patients with long-standing RA. Any of the above types of scleritis may be seen in association with RA, although anterior scleritis is most common.2,56

Fig. 1. Scleritis in a patient with rheumatoid arthritis (Courtesy of David Knox, MD)

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.2,55,58 Of patients with scleritis, 10% to 33% have RA, and RA represents the most commonly seen rheumatic disease in patients with scleritis.53,56 In patients with RA, scleritis is associated with more severe systemic disease and with a greater frequency of extraarticular manifestations.53 Patients with RA are more likely to develop necrotizing scleritis than those patients with idiopathic scleritis.59 Necrotizing scleritis is more likely to be associated with systemic vasculitis and a poor systemic prognosis. In a retrospective study by Foster and colleagues, 29% of patients with RA and necrotizing scleritis or necrotizing keratitis died, typically because of complications of vascular disease.54

Rheumatoid corneal melts, also known as marginal corneal ulcers, may be either bland (not inflammatory) or necrotizing (peripheral ulcerative keratitis [PUK]) in nature. 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 high mortality rate, possibly because of an underlying rheumatoid vasculitis.2,54,55,59

Other uncommon features include Brown's syndrome,60–62 orbital myositis,63 and hydroxychloroquine retinal toxicity.64–71 Brown's syndrome has been described in a few patients with RA and is caused by a stenosing tenosynovitis of the superior oblique tendon.60–62 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.

Patients with RA on hydroxychloroquine or chloroquine often are referred for ophthalmic evaluation and follow-up in order to monitor the patient for drug toxicity. Hydroxychloroquine is used much more frequently than chloroquine because it has less toxicity than chloroquine.66 Both drugs have ocular toxicity as their dose-limiting side effect.64–71 They are accumulated in pigmented tissues, such as the retinal pigment epithelium, and may produce a bull's eye pigmentary retinopathy. This retinopathy is thought to be reversible if discovered early,69 but irreversible, despite discontinuation of the drug, when allowed to progress. Because of this toxicity, patients taking hydroxycloroquine are referred for screening ophthalmic examinations in order to detect the early signs of toxicity. It is recommended that all patients in whom hydroxychloroquine is to be instituted receive a baseline ophthalmic examination including visual acuity, dilated fundus examination, Amsler grid testing, and visual field testing with the Humphrey automated perimetry 10-2 test. Color testing and fundus photography also are suggested at the baseline examination. The timing of follow-up examinations to screen for signs of toxicity is controversial. The frequency of retinopathy is less than 5% when doses less than 6.5 mg/kg per day (less than 400 mg/d) of hydroxychloroquine are used.67 It appears that patients can be treated with large cumulative doses of hydroxychloroquine without evidence of toxicity when daily doses at this level are used.68 However, the risk for patients taking less than 6.5 mg/kg per day of hydroxychloroquine remains greater than zero over long-term follow-up.69 Cost-effectiveness analyses have suggested that a baseline ophthalmic examination followed by annual follow-up ophthalmic examination may be the most cost-effective approach.70 However, one study in which rheumatologists and ophthalmologists were surveyed revealed that the majority recommended monitoring every 6 months for hydroxychloroquine toxicity.71 Therefore, our practice has been to follow patients who are taking hydroxychloroquine at a dose of 400 mg daily every 6 months and to follow those patients taking 200 mg daily annually.

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The seronegative spondyloarthropathies include ankylosing spondylitis (AS), Reiter's syndrome, arthritis with inflammatory bowel disease, and psoriatic arthritis. Historically, these disorders were called seronegative because they lacked rheumatoid factor, which distinguished them from RA, in which patients were said to be seropositive. The seronegative spondyloarthropathies are better termed the HLA-B27–associated spondyloarthropathies, because of their statistical association with the gene HLA-B27. In addition, these disorders are linked by several clinical features and sometimes are difficult to differentiate in the earlier stages of the disease. Clinical findings include a predilection for axial skeletal involvement, extraarticular features, enthesopathy (inflammation of the insertion of tendons), and an asymmetric, migratory oligoarthritis.72 The most common ocular manifestation of the seronegative spondyloarthropathies is a nongranulomatous, recurrent, acute anterior uveitis. Acute anterior uveitis shares with the spondyloarthropathies an association with the gene HLA-B27; approximately 50% of patients with acute anterior uveitis possess HLA-B27,73–75 and if the uveitis is unilateral and recurrent, up to 71% of patients will be HLA-B27 positive.75 Approximately 50% of patients with HLA-B27–associated acute anterior uveitis have a seronegative spondyloarthropathy.75,76


The seronegative spondyloarthropathies (Table 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-B27.77–83 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%,2,77,78


Table 3. The Seronegative (HLA-B27 Associated) Spondyloarthropathies

DisorderFrequency HLA-B27 (%)Frequency Uveitis (%)
Ankylosing spondylitis9025
Reiter's syndrome70–8020–40
Inflammatory bowel disease62–12
 With sacroiliitis50–7050
Psoriatic arthritis18–227
 With sacroilitis50–60 

(Adapted from Jabs DA: The rheumatic diseases. In Ryan S (ed): The Retina. Vol II. pp. 457–480. Copyright 1989, with permission from Elsevier Science.)


The best insight into a possible environmental trigger for these disorders is provided by reactive arthritis and epidemic Reiter's syndrome. Reactive arthritis and epidemic Reiter's syndrome occur 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. Reactive arthritis is distinguished from epidemic Reiter's syndrome by the other extraarticular features present in Reiter's syndrome. In reactive arthritis and epidemic Reiter's syndrome, the presence of HLA-B27 again is associated strongly with the development of disease.72,84

The exact molecular mechanisms by which HLA-B27 predisposes to disease are unknown. Theories include molecular mimicry,72,85 and the possibility that HLA-B27 is associated with a defective class I antigen-mediated cellular response.83 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.83,85 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.83,86

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AS is characterized by involvement of the axial skeleton and bony fusion (ankylosis).87 The estimated prevalence of AS is 0.1% to 0.2% of the general population, and is 2% in HLA-B27–positive patients.83 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.88,89 Between 10% and 30% of HLA-B27–positive first-degree relatives of AS patients will develop the disease.90

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.83,93 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 are 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.72,87,92


The treatment of AS relies on the judicious use of NSAIDs and a program of physical therapy and exercise. The more potent NSAIDs, indomethacin and phenylbutazone, appear to be more effective in the treatment of spondylitis than many of the others. Although phenylbutazone is effective for the treatments of spondylitis, it has been associated with the occurrence of aplastic ankylosis, which has limited the use of this drug. Antiinflammatory medications do not reverse and generally do not prevent the ultimate spinal ankylosis. However, they relieve symptoms and allow the patient to participate in an exercise program. The program of physical therapy and exercise allows the patient to maximize the mobility of the spine and to allow spinal fusion to occur in a posture most advantageous to the patient.72,87 Methotrexate and infliximab have been reported to be effective in the management of more severe disease.72,93–95


The primary ocular manifestation of AS is a nongranulomatous, recurrent, acute, anterior uveitis.76,87,90 Generally, one eye is affected at a time, although both eyes may suffer attacks.76,90 Occasionally anterior chamber inflammation may be severe enough to produce hypopyon, fibrin deposition, and posterior synechiae (Fig. 2).87,92 An estimated 25% to 40% of patients with AS suffer an attack of uveitis at some time during the course of their disease.83,87,90 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.90,92,96,97 Rarely, a spillover vitritis is seen in patients with acute anterior uveitis and AS, but it is substantially less frequent than the typical iridocyclitis.99

Fig. 2. Fibrin clot and posterior synechiae in a patient with acute, anterior uveitis and ankylosing spondylitis.

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Reiter's syndrome originally was characterized by the classic triad of arthritis, urethritis, and conjunctivitis. In 1981, the American Rheumatism Association expanded this original set of criteria to: (1) the presence of a peripheral arthritis with a duration of greater than or equal to 1 month and (2) an associated urethritis, cervicitis, or diarrhea.100 The increased scope of the disease encompasses reactive arthritis in which a sterile arthritis ensues after the infection has resolved.100 Typically it is rare for a patient to present with the classic triad originally described. Historically, Reiter's syndrome existed in two forms: epidemic and endemic. Epidemic Reiter's syndrome occurs after an infectious gastroenteritis; the ensuing arthritis occurs after the gastroenteritis has resolved, and it is a sterile arthritis. Although a triggering agent can be identified for epidemic Reiter's syndrome, none as yet has been identified for endemic Reiter's syndrome. Because patients with Reiter's syndrome often developed urethritis and presented to venereal disease clinics, it initially was believed that endemic Reiter's syndrome was because of Chlamydia, but studies have not demonstrated a higher prevalence of chlamydial infection in patients with Reiter's syndrome than in controls, and the role of Chlamydia remains debated.72,100

The arthritis of Reiter's syndrome 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. Systemic symptoms including fever and weight loss also may occur. The disease tends to follow an episodic and relapsing course.100–102 The arthritis may be recurrent in 15% to 50% of patients.100 Another 15% to 30% of patients will develop chronic arthritis over 10 to 20 years of follow-up.100,101


Conjunctivitis was one 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's 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 Reiter's syndrome over long-term follow-up.83,90,103 Some studies of patients with acute anterior uveitis suggest that Reiter's syndrome is more frequently seen in patients with acute anterior uveitis than is AS,75,98 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 Reiter's syndrome and is found more commonly with Reiter's syndrome than with AS. Rarely other forms of posterior ocular involvement such as multifocal choroiditis have been reported in Reiter's syndrome.104,105 Rarely, patients may develop a keratitis with punctate epithelial lesions, progressing to a central loss of the corneal epithelium and subepithelial infiltrates.106–108

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Inflammatory bowel disease (IBD) consists of two distinct diseases: ulcerative colitis and Crohn's disease. Ulcerative colitis is an inflammatory disorder of the colonic mucosa. Crohn's disease, also known as regional enteritis, granulomatous ileocolitis, or granulomatous colitis, is a focal granulomatous disease involving any area of the gastrointestinal tract.


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.109,110 Arthritis occurs in approximately 22% of patients with IBD. Two distinct variants of enteropathic arthritis are seen. One form is a large-joint, lower-extremity, nondeforming oligoarthritis. The activity of this enteropathic arthritis parallels that of the bowel disease. The frequency of this type of enteropathic arthritis is approximately 15% in Crohn's disease and 10% in ulcerative colitis.111 The second form of arthritis associated with IBD is an HLA-B27–associated axial-sacroiliac spondylitis, which is seen in approximately 20% of patients with Crohn's disease and in 10% to 15% of patients with ulcerative colitis.111 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.112 Between 50% and 70% of patients with spondylitis and IBD are HLA-B27 positive.111 Of the HLA-B27–positive patients with IBD, 50% will develop acute anterior uveitis.109 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.83,111,113


Treatment of the IBD is individualized and dependent on the extent and severity of the disease. Typically treating the underlying bowel disease improves the joint disease. Localized proctitis often may be treated with corticosteroid enemas. More extensive bowel disease may require systemic corticosteroid therapy. Generally, nonsteroidal therapy with sulfasalazine is used first in an effort to minimize steroid complications and often is used to decrease the does of corticosteroids needed. Severe corticosteroid-dependent IBD also can be treated with corticosteroid-sparing agents, such as azathioprine or methotrexate.111,113 Infliximab has been shown to induce remissions in Crohn's disease and is effective in the treatment of Crohn's-related fistulas.114 However, infliximab appears to be ineffective in treatment of ulcerative colitis.111 Because of the risk of colonic malignancy with long-standing ulcerative colitis, a colectomy sometimes is performed. After colectomy the mucocutaneous manifestations and the enteropathic arthritis may resolve.111


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.90,110,113,115 The ocular manifestations include anterior uveitis, scleritis, and keratitis. Anterior uveitis is the most common ocular manifestation.115–118 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.90,119,120 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.121–123 It has been suggested that these retinal vascular lesions are caused by a thrombic diathesis seen in some patients with IBD.121 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. 3).117,118 Rarely, keratitis118,124 and Brown's syndrome125 may be seen in association with IBD.

Fig. 3. Scleritis in a patient with inflammatory bowel disease. A. Active scleritis. B. Healed scleritis after treatment of the inflammatory bowel disease.

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Psoriatic arthritis is a syndrome defined by the presence of psoriasis and an associated seronegative inflammatory arthritis.126 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.126,127 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.126 Nail changes are present in 90% of patients with psoriatic arthritis as compared to 41% of patients with psoriasis but without arthritis.128 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 multilans 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.72,126


Conjunctivitis occurs in approximately 20% to 33% of patients with psoriatic arthritis, iritis in 4% to 7%, and scleral disease in 2%.90,126,127,129 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's syndrome also has been reported in patients with psoriatic arthropathy.130

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Juvenile rheumatoid arthritis (JRA), also known as juvenile chronic arthritis (JCA) or juvenile idiopathic arthritis (JIA), is defined as an arthritis of greater than 3 months' duration with onset at less that 16 years of age.131 Other causes of arthritis in children, such as leukemia, must be excluded. The traditional classification of JRA depends on the pattern of presentation of the arthritis and has been classified as polyarticular, oligoarticular, and systemic disease. Polyarticular JRA is defined as presentation with five or more joints involved, and is seen in 30% of children presenting with JRA. Oligoarticular JRA involves four or less joints, and comprises 60% of children with JRA. Systemic disease is the disorder originally described by Still, affects 10% of children with JRA, and has prominent systemic features with a variable arthritis.132


The incidence and prevalence of JRA have been estimated as 10 to 20 cases per 100,000 population per year and 65 to 148 cases per 100,000 population, respectively.133–135 Five distinct subgroups of JRA have been described. The systemic variant of JRA also is known as Still's disease. The male to female ratio is approximately 1:1 and the onset of disease is generally at less 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.132 Ocular disease generally is not associated with this variant.131

Two types of oligoarticular JRA have been described. ANA-positive oligoarticular disease typically is 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 1:5. The arthritis is an oligoarticular, large-joint, lower-extremity arthritis that tends to spontaneously remit and not leave significant articular deformities. More than 80% of these patients have a positive ANA test. This subgroup of patients is associated with HLA-DR5, DR6, DR8, DQ1, and DQ2.136–138 A chronic anterior uveitis is the characteristic ocular feature of this group.131,139–141

A second type of oligoarticular disease 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 5:1. The arthritis is a large-joint, lower-extremity oligoarthritis. Sacroiliitis is common, and these children tend to progress to AS over time. Ninety 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.131,142,143

Two types of polyarticular disease have been described. In older children, older than 10 years of age, an RF-positive (seropositive), rheumatoid-like polyarthritis may develop. Girls are affected more commonly than boys. 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 associated with HLA-DR4, the HLA antigen seen in adult RA. Ocular disease in uncommon in this subgroup.131,132,142

A second type of polyarticular disease has been defined.132,144 The children are older and tend to present with an additive, symmetric, deforming polyarthritis. However, patients are RF-negative but are HLA-B27–positive. Sacroiliitis and spondylitis are common, and a characteristic fusion of the posterior spines of the C2 and C3 vertebrae in the cervical spine can be seen. Micrognathia occurs in approximately 25%. The ocular lesion seen tends to be a recurrent acute iridocyclitis and occurs in 25% of patients.144


The goal of treatment for JRA is to control the clinical symptoms of the disease and to limit joint deformity using the most conservative and safest therapy available.132 Initial therapy typically begins with either aspirin or NSAIDs, such as ibuprofen or naproxen. The NSAID dose is dependent on the child's age and weight. Because of the potential association between aspirin use and Reye's syndrome, any aspirin or NSAID should be discontinued in a sick child who potentially has influenza or varicella. Systemic corticosteroids generally are avoided, except in severe systemic disease, because of the potential for growth retardation with long-term use. If the patient fails to respond to NSAIDs alone, methotrexate typically is used because it is well-tolerated, has been shown to be effective in the treatment of JRA in a randomized clinical trial, and there is extensive experience with the drug over long-term follow-up.145–147 Methotrexate also has been found to be effective in the treatment of JRA-associated uveitis.148–150 Other immunosuppressive drug therapies, including cyclosporine and azathioprine, have been used to treat JRA that is refractory to treatment with methotrexate.132 Etanercept also has been shown to be effective in the treatment of polyarticular JRA in a multicenter randomized clinical trial.151


Approximately 12% to 17% of children with any type of JRA have uveitis.152–154 A population-based study performed in Finland reported the mean annual incidence and prevalence rates for JRA-associated uveitis as 0.2 and 2.4 cases per 100,000 population, respectively.155 The ocular manifestations of JRA 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%.132,139,156–159 Although traditionally it has been thought that these cases occur primarily in girls, a recent retrospective study of 90 children with JRA found no gender difference in the risk of developing uveitis.152 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.160 Two thirds of patients have bilateral disease, and in patients with unilateral disease, the majority will develop uveitis in the fellow eye within 1 year of presentation.132 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. Secondary glaucoma occurs in 10% to 20% of patients with JRA-associated uveitis and is a poor prognostic finding.154,156,157,161 Posterior synechiae are common. 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.154,156–158,162–164 One study from Finland reported on 426 incident cases of JRA 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,157,165 more recent case series have suggested that intraocular lenses can be placed in these patients with good visual outcome.166,167

Treatment for the uveitis associated with JRA 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 one to two 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.148–150 Systemic corticosteroids are given in the 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 in order to avoid side effects such as growth retardation.

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Familial juvenile systemic granulomatosis, also known as Jabs syndrome, Blau syndrome, and autosomal dominant granulomatous disease of childhood, is an uncommon genetic disease with polyarthritis and uveitis that often is misdiagnosed as JRA or sarcoidosis.168–172 The disease is inherited in an autosomal dominant fashion, and the joint disease is a granulomatous, deforming, nonerosive polysynovitis. Other more variable features of the syndrome include rash, cranial nerve palsies, and vasculopathy.168–172 The syndrome is caused by mutations in the CARD15 gene, which is involved in apoptosis and is preferentially expressed on monocytes.173 The CARD15 gene also has been linked to Crohn's disease, but the mutations for the two disorders are in different segments of the gene.173

Children with this syndrome often are misdiagnosed as having either JRA or sarcoidosis. Familial juvenile systemic granulomatosis may be distinguished from JRA by the presence of polyarthritis on presentation, the absence of ANA, and the pattern of inheritance. Although patients with familial juvenile systemic granulomatosis may have a chronic anterior uveitis similar to JRA, these patients also may have multifocal choroiditis, which is not seen in patients with JRA.172 Patients with JRA who have chronic uveitis tend to have oligoarticular arthritis and positive ANA antibodies. Familial juvenile systemic granulomatosis differs from sarcoidosis by the pattern of arthritis, the absence of pulmonary involvement and adenopathy, and the inheritance pattern.172 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 are common.

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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 Fcγ receptors IIA and IIIA located on chromosome 1 all suggest a genetic predisposition.174,175 Pathogenetically SLE is characterized by B-cell hyperactivity, polyclonal B-cell activation, hypergammaglobulinemia, autoantibody formation, and abnormal T-cells.174 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).174 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.176–178 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- and T-cells causing further inflammation and tissue damage.174


The incidence of SLE has been estimated as 2 to 9 cases per 100,000 population per year.179 SLE is a multisystem disease that may affect almost any organ system.179–184 Because of the multisystem nature of the disease, criteria for the diagnosis have been established and are outlined in Table 4.185 To establish a diagnosis of SLE, four or more criteria must be met. SLE is a clinical diagnosis, and no single laboratory test defines the disease. These criteria are for use in clinical investigations and may not always be applicable in patient management.


Table 4. The 1982 Revised Criteria for the Diagnosis of Systemic Lupus Erythematosus


  1. Malar rash
  2. Discoid lupus
  3. Photosensitivity
  4. Oral ulcers
  5. Arthritis
  6. Serositis (pleuritis, pericarditis)
  7. Renal disorder (proteinuria, nephritis)
  8. Neurologic disorder (seizures, psychosis)
  9. Hematologic disorder (hemolytic anemia, leukopenia, lymphopenia or thrombocytopenial)
  10. Immunologic disorder (positive LE cell preparation, anti-DNA test, anti-Sm or false-positive test for syphilis)
  11. Antinuclear antibody

*Persons shall be said to have SLE if he or she has 4 or more of the 11 criteria. (Reprinted from Jabs DA: The rheumatic diseases. In Ryan S (ed): The Retina, Vol II. pp. 457–480. Copyright 1989, with permission from Elsevier Science.)


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 flush. 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.179–183

Raynaud's 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.179–183 Involvement of the central nervous system (CNS) by lupus occurs in 35% of patients with SLE.183,184 Peripheral nervous system involvement with a peripheral neuropathy and cranial nerve palsy is less common. CNS lupus may present as seizures, an organic brain syndrome, or psychosis.184 Transverse myelitis is an uncommon manifestation, occurring in only 4% of patients with SLE but often is seen in association with optic neuritis.

Eighty to 85% of patients with SLE have articular disease at some point during the course of their SLE. 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.179–183

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.179–183

The lupus anticoagulant may be found in 28% to 34% of patients with SLE.186–191 The lupus anticoagulant is a member of a family of antiphospholipid antibodies, which also includes the anticardiolipin antibodies. These antibodies are found in combination with clinical features including arterial or venous thrombosis and pregnancy morbidity in patients with antiphospholipid antibody syndrome (APS), which may be a primary disease unassociated with other autoimmune diseases or may be secondary to SLE. Approximately 15% of patients with SLE have APS.192–195 The APS is associated with occlusive disease, which can lead to tissue ischemia and end-organ damage, and with thrombotic disorders, such as deep vein thrombophlebitis and strokes.186–195 The mechanism by which antiphospholipid antibodies cause thrombosis is not known, but two possible explanations are induction of platelet aggregation by the antibody and inhibition of prostacyclin production by the vascular endothelium. Both of these mechanisms could cause vessel occlusion.195


Because SLE is a multisystem disease with highly variable features in different patients, treatment is directed at the specific symptoms in any given patient. Nonsteroidal antiinflammatory agents or low-dose prednisone are used for treatment of the arthritis and serositis.196 Hydroxychloroquine often is used for the treatment of the skin disease or as a corticosteroid-sparing agent for mild skin disease, although it may require 3 to 6 months of therapy before a complete response is noted.196–198 High-dose corticosteroids, including pulse intravenous (IV) corticosteroids, often are necessary for end-organ or life-threatening disease, such as severe hematologic abnormalities (i.e., hemolytic anemia, severe thrombocytopenia), lupus nephritis, or CNS lupus.196 In patients with rapidly progressive renal disease, pneumonitis, systemic vasculitis, or CNS lupus, IV pulse corticosteroids have been used successfully with clinical improvement within days.199–201 Long-term therapy after pulse corticosteroids is required.

Cytotoxic drugs have proven to be effective in the treatment of patients with severe lupus nephritis. Monthly IV cyclophosphamide at a dose of 0.5 to 1.0 g/m2 was found to cause remission of renal disease over a 5-year period in 85% of patients if given in combination with IV methylprednisolone, compared to 62% of patients treated with IV cyclophosphamide only, and 29% of patients treated with intravenous methylprednisolone only.202 Daily oral cyclophosphamide 1 to 2 mg/kg per day or azathioprine 1 to 2 mg/kg per day have been used alone or in combination with oral corticosteroids to control life-threatening active lupus nephritis.196,203 However, because pulse intravenous cyclophosphamide causes less side effects than oral cyclophosphamide, pulse intravenous cyclophosphamide typically is the preferred treatment for lupus nephritis. For severe, refractory disease, bone marrow immunoablation with or without autologous stem cell transplantation has been successful in inducing remission in a small number of patients over 1 to 2 years of follow-up.204 Anticoagulation therapy is instituted in patients with SLE and APS. Although aspirin or low-dose heparin are used commonly, it has been suggested that warfarin (Coumadin, Bristol-Myers Squibb) is the only intervention that significantly lowers clotting risk in these patients.205,206


The major ocular manifestations of SLE can be classified into five general categories: (1) involvement of the skin of the eyelids with cutaneous disease; (2) secondary Sjögren's syndrome; (3) retinal vascular lesions; (4) neuroophthalmic lesions; and (5) scleritis.2 Eyelid disease is most often discoid lupus erythematosus involving the margins of the lids.207 Secondary Sjögren's syndrome occurs in approximately 20% of patients with SLE and is indistinguishable from the sicca complex seen in patients with other rheumatic disorders.183

Retinal vascular lesions are the most common form of intraocular involvement in patients with SLE. The retinopathy most frequently consists of cotton-wool spots (Fig. 4) with or without intraretinal hemorrhages.208–210 The frequency of this finding varies depending on the patient population studied and the activity of the disease. One study209 found that only 3% of ambulatory outpatients had cotton-wool spots, while two separate studies180,210 found that 28% to 29% of hospitalized patients with active SLE had retinal vascular findings. This retinopathy occurs independently of hypertension and is thought to be related to the underlying microangiopathy of SLE. The histopathology of CNS lupus is that of a microangiopathic disease with small vessel vasoocclusion, a process presumed to be similar to that in the retina.211,212 Studies of autopsy material of patients with SLE have demonstrated immune reactants, primarily immunoglobulin and complement in the ocular vessel walls, and it has been suggested that these are the cause of the microangiopathy.213 Fluorescein angiographic studies have suggested that mild background retinopathy with microaneurysms and telangiectatic vessels may be relatively common.210

Fig. 4. Cotton-wool spots along the superotemporal arcade in a patient with active systemic lupus erythematosus.

The finding of retinal vascular changes in patients with SLE correlates with the activity of the disease.214 The relationship of cotton-wool spots alone to CNS lupus has been debated, but to date no relationship has been established. Most experts feel that the finding of cotton-wool spots does not indicate the presence of CNS lupus. A much less frequent, severe retinal vasoocclusive disease has been described and does appear to be associated with CNS lupus, in particular, diffuse CNS dysfunction, such as an organic brain syndrome.214–223 This more severe retinal vasoocclusive disease may present as a central retinal artery occlusion, central retinal vein occlusion, branch artery occlusion, or most frequently, a diffuse retinal vasoocclusive process (Fig. 5), sometimes called retinal vasculitis. Although this last process sometimes has been called retinal vasculitis, the exact pathogenesis may not be true vasculitis. Cases of severe retinal vasoocclusive disease in SLE in association with the lupus anticoagulant also have been reported, and the retinal disease in these cases is presumed to be secondary to this autoantibody (Fig. 6).190,191 The prognosis for vision with this diffuse retinal vascular disease is poor and retinal neovascularization commonly develops. Panretinal photocoagulation may be of value in the treatment of the neovascularization of severe lupus retinopathy. Approximately 50% of eyes affected with this severe vaso-occlusive disease become blind. Although visual loss is common in those patients with severe retinal disease, in the more common mild retinopathy visual loss is unusual.223

Fig. 5. A. Fundus photograph and B. fluorescein angiogram, demonstrating diffuse vaso-occlusive disease in a patient with systemic lupus erythematosus. Fluorescein angiogram shows extensive nonperfusion of the retina. (Jabs DA, Fine SL, Hochberg MC, et al: Severe retinal vaso-occlusive disease in systemic lupus erythematosus. Arch Ophthalmol 1104:558, 1986. Copyrighted 1986, American Medical Association. Reprinted with permission.)

Fig. 6. A. Fundus photograph and B. fluorescein angiogram demonstrating diffuse vaso-occlusive disease in a patient with systemic lupus erythematosus. This is peripheral nonperfusion of the retina. The patient had anticardiolipin antibodies. (Jabs DA, Fine SL, Hochberg MC, et al: Severe retinal vaso-occlusive disease in systemic lupus erythematosus. Arch Ophthalmol 104:558, 1986. Copyrighted 1986, American Medical Association. Reprinted with permission.)

Even less common than retinopathy is lupus choroidopathy, of which only a few cases have been reported to date.214,224–226 Early autopsy studies demonstrated the frequent presence of mononuclear inflammatory cells in the choroid of patients with untreated SLE.208 The clinical changes seen in patients with lupus choroidopathy include serous elevation of the retina, most often of the neurosensory retina, serous elevations of the retinal pigment epithelium, and combined elevations of both (Fig. 7). These clinical findings are associated with systemic vascular disease, either hypertension because of lupus nephritis or systemic vasculitis.226 Treatment of the underlying disease, with systemic corticosteroids and immunosuppressive agents if needed, and control of any hypertension can resolve these serous retinal detachments.

Fig. 7. A. Fundus photograph and B. and C. fluorescein angiogram of a patient with choroidopathy and systemic lupus erythematosus. The fluorescein angiogram demonstrates multiple “smokestack” areas of fluorescein leakage. (Jabs DA, Hanneken A, Schachat AP, et al: Choroidopathy in systemic lupus erythematosus. Arch Ophthalmol 106:230, 1988. Copyright 1986, American Medical Association. Reprinted with permission.)

Neuroophthalmic involvement in SLE includes cranial nerve palsies, lupus optic neuropathy, and central retrochiasmal disorders of vision.227–237 The central disorders include hallucinations and visual field loss.232,237 The optic nerve lesion most often seen in SLE is reported as retrobulbar optic neuritis. However, other optic nerve lesions can be seen, including anterior optic neuritis with optic disc edema, ischemic optic neuropathy, and a slowly progressive visual loss from lupus optic neuropathy.227–236 Autopsy studies have suggested that a microangiopathic process may be the pathogenesis of lupus optic neuropathy. Focal demyelination can be seen, but more severe lesions with axonal damage and even optic nerve infarcts have been demonstrated.227–229,231 One case demonstrated both demyelination and loss of axons with foci of total destruction of the optic nerve.229 This finding suggests that the same process may cause milder, reversible lesions and more severe irreversible infarct-like lesions. Transverse myelitis is seen in over 50% of patients with lupus optic neuropathy as compared with its overall frequency of 4% in patients with SLE.236 The frequency of clinical optic neuropathy in SLE patients has been estimated at 1% to 2% of patients with SLE.182–184

Scleritis occurs less commonly in patients with SLE. In one retrospective study of 97 patients with scleritis, 4% had SLE.56 Any type of scleritis may be seen, but anterior scleritis appears most commonly. Therapy that controls the underlying SLE typically controls the scleritis.2,56

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Scleroderma is a systemic connective tissue disease of unknown etiology characterized by fibrous and degenerative changes in the skin and the viscera. The hallmark of scleroderma is the skin change, which consists of a thickening, tightening, and induration of the skin. It caused by fibrous replacement of the dermis of the skin, with subsequent loss of mobility and contracture. In addition, vascular insufficiency and vasospasm are present.238–240 Localized forms of scleroderma, such as linear scleroderma and morphea, also exist.238


The etiology of scleroderma is unknown. The most characteristic feature of scleroderma is the increased collagen content in the skin and visceral organs.241 Some investigators studying fibroblasts from patients with scleroderma in vitro have demonstrated increased collagen production.242 The second characteristic feature is the vascular disease, including Raynaud's phenomenon and diffuse microvasculopathy, which typically is present at the first recognizable stages of the disease.241 Although no hypotheses of pathogenesis have been proved, several have been proposed, including a primary vascular disorder, an abnormality of fibroblast function (i.e., a collagen production abnormality), and a primary immunologic disorder. However, it is thought that the abnormality of fibroblast function, which causes the accumulation of collagen and extracellular matrix, is secondary to either a primary vascular or immunologic process.241 The vascular theory suggests that the primary lesion is a vascular abnormality, which subsequently triggers a fibroblastic response and the abnormal collagen deposition. The fibroblastic response to this initial vascular insult further aggravates the problem by the intimal proliferation seen in blood vessels and the increase in dermal collagen in the skin.238,243 Several investigators have found that the sera from patients with scleroderma are cytotoxic for endothelial cells, and abnormalities of platelet aggregation and platelet activation have been detected in patients with scleroderma.244–246 However, it is unknown whether these changes are primary or are secondary to platelet activation because platelets pass through damaged blood vessels. The demonstration of a scleroderma-associated antigen that is released under the conditions of hypoxemia-reperfusion (i.e., Raynaud's phenomenon) suggests that the initial insult in scleroderma could be vascular.247

Because of the presence of a mononuclear inflammatory cell infiltrate in the dermis of patients with scleroderma,248 an immunologic process has been proposed. The infiltrating lymphocytes in the dermis of patients with scleroderma consist largely of CD4+ T cells.249In vitro studies have demonstrated that lymphocytes from these patients can produce cytokines, which will augment collagen production by fibroblasts.238 Furthermore, dermal antigens have been shown to stimulate lymphocytes from scleroderma patients to produce a variety of cytokines. Patients with scleroderma also have polyclonal hypergammaglobulinemia, and autoantibodies, such as ANA, are seen in greater than 90% of patients with scleroderma. These features suggest an immune-mediated or autoimmune process.


Scleroderma characteristically affects middle-aged women with a peak age of onset of 30 to 50 years of age. The incidence has been calculated at 18 to 20 cases per million population per year.250,251 It is estimated that there are 75,000 to 100,000 cases of scleroderma in the United States.238 Scleroderma is defined by the skin changes, which consist of thickening, tightening, induration, and hidebound changes, resulting in a loss of mobility and contracture. The disease characteristically begins peripherally and involves the fingers and hands, with a subsequent centripetal spread up the arms to involve the face and body. Early in the disease, an edematous phase of the skin changes may exist, but later-stage disease consists of contracture and shiny, taut, hidebound skin. Telangiectasia and calcinosis are common. Early in the disease process, skin biopsy specimens demonstrate a mononuclear inflammatory cell infiltrate. In later-stage disease there is a subcutaneous fibrosis with thinning of the skin, loss of the epidermis, and an absence of epidermal appendages.238–240

Approximately 90% of patients with scleroderma have Raynaud's phenomenon, which is the initial complaint in approximately 70% of patients.238 Raynaud's phenomenon consists of pallor, cyanosis, suffusion, and tingling that occur in an abrupt and phasic manner after a known exposure. Most often this exposure is cold but other precipitating factors, including emotion, have been described. Raynaud's phenomenon is the result of an exaggerated vasospasm and subsequent vasodilation in response to the cold challenge. Microvascular abnormalities may be detected in the digital arteries and in the nail bed capillaries of patients with scleroderma.252 Severe narrowing of this vasculature is seen in greater than 75% of patients.238 Raynaud's phenomenon may be more systemic in nature, and similar vasospastic events have been detected in the cardiac, pulmonary, and renal vasculature in scleroderma patients after cold exposure.253,254 Histologically, the blood vessels often show intimal proliferation (in patients with severe vascular disease), which may be associated with fibrinoid necrosis. As a consequence of Raynaud's phenomenon and vascular insufficiency, digital ulcers may develop.238

Gastrointestinal involvement may occur in more than 75% of patients with scleroderma. The esophagus is involved most frequently and shows dysmotility, gastroesophageal reflux and stricture formation. Small bowel involvement is less frequent and presents with decreased motility, bacterial overgrowth, and malabsorption. Large bowel involvement produces widemouth diverticula.238

Pulmonary disease is found in 75% to 90% of patients at autopsy but is less frequently detected clinically. As the management of scleroderma-associated renal crisis has improved, pulmonary disease has become the leading cause of mortality.238 Patients develop pulmonary fibrosis and may have exertional dyspnea, decreased lung capacity, and a restrictive lung disease. Pulmonary hypertension and right-sided heart failure may develop as a consequence of this process.238,243,255 Cardiac disease may be detected in approximately one third of patients because of fibrotic involvement of the cardiac conduction system, and resulting in conduction abnormalities and arrhythmias.256

Renal disease is a major cause of mortality and often is associated with the onset of malignant hypertension and a rapid progression to renal failure.257,258 Scleroderma renal crisis or scleroderma kidney was almost uniformly fatal until the late 1970s; however, aggressive antihypertensive therapy can successfully reverse scleroderma renal crisis.259–261

Musculoskeletal lesions include polyarthralgias, tendon friction rubs, infrequently polyarthritis, and occasionally myositis. Myositis may occur as an overlap syndrome, sometimes termed sclerodermatomyositis.238–240 A peripheral neuropathy because of entrapment caused by the fibrotic process impinging on the nerve has been seen. Trigeminal neuralgia is the most common example of this neuropathy.262

There is a spectrum of disease ranging from the more mild CREST variant to severe diffuse scleroderma. The CREST variant was named for its features of calcinosis, Raynaud's phenomenon, esophageal disease, sclerodactyly, and telangiectasia. This syndrome is more benign than diffuse scleroderma and more slowly progressive. In patients with the CREST syndrome, visceral involvement is less common than in diffuse scleroderma. The CREST syndrome is associated with anticentromere antibodies in 50% to 96% of patients, which are a marker for this variant.263–266 Patients with diffuse scleroderma, also known as progressive systematic sclerosis, have a more rapidly progressive skin disease with more severe and progressive visceral involvement. These patients have a poorer prognosis than those with the CREST variant.

Overlap syndromes occur between scleroderma and other connective tissue diseases. The best known overlap syndrome is mixed connective tissue disease, which has features of SLE, systemic sclerosis, and myositis.267 It was characterized by antibodies to ribonuclear protein (RNP). It originally was suggested that there was a corticosteroid-responsive nature to many of the clinical features. Long-term follow-up studies have suggested that mixed connective tissue disease generally evolves into systemic sclerosis.268


No specific treatment has been determined definitely to be efficacious in altering the progression of scleroderma, and traditionally treatment has been directed toward management of the complications and symptomatic relief. Corticosteroids are ineffective in the treatment of scleroderma itself, but occasionally may be used for treatment of the inflammatory stage of interstitial lung disease in scleroderma or of the associated myositis in patients with an overlap syndrome.238,269 Immunosuppressive agents, including chlorambucil, azathioprine, and 5-fluorouracil, have not shown any consistent value in the treatment of scleroderma.238

Scleroderma renal crisis, which previously was a fatal complication, often can be controlled by aggressive treatment of the hypertension and dialysis for renal failure. Control of the hypertension involves the use of multiple antihypertensive agents including angiotensin converting enzyme blockade.259–261 Raynaud's phenomenon most often is treated with calcium channel antagonists, such as nifedipine. These agents are effective in symptomatic relief and reducing the number of attacks of the Raynaud's phenomenon. Calcium channel antagonists are more effective in patients with idiopathic Raynaud's phenomenon than in those with scleroderma, possibly reflecting the fixed vascular changes caused by luminal narrowing in patients with scleroderma.270,271


The eye is frequently involved in patients with scleroderma.272,273 Most often, this involvement consists of scleroderma of the eyelids, resulting in tightness of the lids and blepharophimosis. Lid involvement occurs in 30% to 65% of patients with scleroderma. Despite the frequent involvement of the eyelids, corneal exposure is fortunately uncommon. Conjunctival vascular abnormalities, including telangiectasia and vascular sludging, often occur. Estimates of this finding have run as high as 71%. These changes in the conjunctival vasculature may be analogous to those seen in the nailfold capillary bed.

Keratoconjunctivitis sicca with a Sjögren's-like picture has been described.274,275 Minor salivary gland biopsy studies have suggested that two different pathogenetic mechanisms may be present. Some patients appear to have inflammation of the glands, similar to Sjögren's syndrome, while others appear to have a glandular fibrosis. Early studies suggested a correlation between these two variants and the variants of scleroderma, with CREST patients having salivary gland inflammation and diffuse systemic sclerosis patients having minor salivary gland fibrosis.274 Subsequent studies have suggested that this association is not as clear-cut.275

Other reported lesions have included periorbital edema occurring as part of the early edematous phase of scleroderma,276 cranial nerve palsies,277 scleral pits,278 restrictive ophthalmopathy,279 and extraocular muscle myositis occurring in a patient with sclerodermatomyositis.280 All these lesions are uncommon and have been described only as case reports. There are occasional reports of retinal vascular lesions in patients with scleroderma but without scleroderma renal disease. They are uncommon and occur in less than 5% of patients. Such cases include retinal hemorrhage, branch retinal vein occlusion, and central retinal vein occlusion.272,273,281 More common has been the retinopathy of malignant hypertension seen in patients with scleroderma renal crisis. The clinical findings include cotton-wool spots, intraretinal hemorrhages, and optic disc edema. Both clinical and histologic studies have demonstrated that the process in patients with scleroderma is identical to that seen in patients with idiopathic malignant hypertension.2,282–285

In contrast to the infrequent findings of retinopathy in patients with scleroderma, small case series of fluorescein angiographic studies have suggested more frequent abnormalities of the choroidal vasculature in patients with systemic sclerosis, including patchy and irregular perfusion of the choroid and variable hyperfluorescence of the retinal pigment epithelium in one third to one half of the patients. The lesions were clinically silent, and ophthalmoscopy results were normal. These angiographic abnormalities were interpreted as damage to the retinal pigment epithelium caused by vascular lesions in the choroid.286–289

In summary, retinal complications are uncommon in patients with scleroderma unless hypertension is present. Occasionally, retinal vascular disease may herald the onset of malignant hypertension and a medical emergency for the scleroderma patient. Choroidal vascular changes may be more common but are clinically silent.

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Polymyositis and dermatomyositis are inflammatory diseases of skeletal muscles characterized by pain and weakness in the involved muscle groups. In the typical case, weakness begins insidiously and involves the proximal muscle groups, particularly those of the shoulders and hips. Dermatomyositis is distinguished from polymyositis by the presence of cutaneous lesions. The skin lesions of dermatomyositis include an erythematosus to violaceous rash, which may affect the eyelids (heliotrope rash), cheeks, nose, chest, and extensor surfaces, and a rash over the knuckles of the fingers, known as Gottron's papules.290–292


The etiology of the myositis is unknown. The pathogenesis appears to be an immune-mediated attack against the skeletal muscle fibers triggered by environmental factors in a susceptible individual.290 Muscle biopsy specimens may show vascular deposits of immunoglobulin and complement. These vascular deposits represent immune complexes that produce vascular damage.293,294 The presence of vasculopathy in patients without a defined inflammatory vasculitis may explain the occasional occurrence of retinopathy and small vessel vasoocclusion in patients with dermatomyositis. Other pathologic changes in muscle suggest cellular immune mechanisms, with lymphocyte proliferation in response to skeletal muscle antigens reported by some investigators.294,295

Immunogenetic studies have suggested a genetic predisposition in both childhood and adult polymyositis and dermatomyositis. The strongest associations exist for the HLA-B8, DR3, and DR52 antigens.296,297 The association with HLA-DR3 and B8 are especially high in white patients with an antibody to a saline extractable nuclear antigen, Jo-1.290 Anti-Jo-1 antibody is one of several myositis-specific autoantibodies identified in a small subset of patients with idiopathic myositis. The presence of this antibody has been associated with an increased prevalence of interstitial pulmonary fibrosis, arthritis, and Raynaud's phenomenon.290,298,299


The estimated incidence of myositis in the United States is 5 new cases per million population per year and reports have ranged from 0.5 to 8.4 new cases per million population per year.300 Women are affected more often than men in adult myositis. The age of onset is bimodal, affecting children ages 10 to 15 years and adults ages 45 to 60 years most frequently.290 In the typical case, symmetric, proximal muscle weakness begins insidiously either in the lower or the upper extremities. The patient slowly becomes aware of difficulty in running, climbing stairs, and ultimately in getting out of a chair. The gait then becomes clumsy, and the patient has difficulty in arising without assistance. Systemic symptoms including malaise and weight loss are frequently present. On examination, a symmetric, proximal upper limb and lower limb weakness is found in almost every patient. Cutaneous lesions are found in patients with dermatomyositis but not in those with primary idiopathic polymyositis.290

Laboratory abnormalities include an elevated erythrocyte sedimentation rate and elevated skeletal muscle enzymes. The muscle enzymes found to be abnormal include creatinine phosphokinase (CPK), aldolase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactic dehydrogenase (LDH). Although the pattern of abnormal enzymes varies from individual to individual, the CPK is most frequently abnormal. Electrmyographic abnormalities are present in more than 90% of patients with myositis and consist of an increase in insertional activity of muscle, fibrillation potentials, and positive sharp waves at rest. Motor unit action potentials show myopathic changes with decreased amplitude and duration and an increase in the proportion of polyphasic potentials. Bizarre, high-frequency, repetitive discharges also are seen.290

Muscle biopsy specimens reveal the degeneration of muscle fibers with occasional areas of regeneration. Interstitial muscle necrosis is present in approximately 60% of biopsy specimens, and interstitial fibrosis in another 20%. Inflammatory infiltrates of muscle are present in 75% of muscle biopsy specimens. The inflammatory infiltrate consists primarily of mononuclear inflammatory cells with lymphocytes and plasma cells. Vasculitis often is seen in childhood dermatomyositis.290

Polymyositis and dermatomyositis have been classified into five groups as outlined in Table 5.301,302 Malignancy occurs in 13% of adults with dermatomyositis. Patients with malignancy are likely to be over 45 years of age and have dermatomyositis. The tumors present occur at typical cancer sites and are generally diagnosed either concurrently or within 1 year of the diagnosis of myositis.303,304 Vasculitis is frequent in patients with childhood dermatomyositis. Inflammatory myositis associated with a connective tissue disease is most often seen with either SLE, primary Sjögren's syndrome, or scleroderma.


Table 5. Classification of Idiopathic Inflammatory Myopathies

Primary idiopathic polymyositis
Primary idiopathic dermatomyositis
Dermatomyositis (or polymyositis)
Childhood dermatomyositis (or polymyositis)
Polymyositis or dermatomyositis associated with collagen vascular disease (overlap group)



Corticosteroids are the mainstay of treatment for myositis. Ninety percent of patients improve on corticosteroid therapy alone, and 50% to 75% have complete remission.305 Corticosteroid therapy typically is begun at a dosage of 1 mg/kg per day (60 to 80 mg daily) and continued until the muscle enzymes have normalized. Once the myositis is controlled, the corticosteroid doses are tapered, utilizing continued monitoring of the skeletal muscle enzymes. When corticosteroids fail or when corticosteroid-related complications become unacceptable, immunosuppressive agents such as methotrexate or azathioprine have been used as steroid-sparing agents in the treatment of myositis.290,306–309 Hydroxychloroquine has been used effectively for the skin lesions in patients with dermatomyositis but has no effect on the myositis.310 Case series have suggested that pulse intravenous cyclophosphamide and cyclosporine also may be useful in controlling the myositis, particularly in children.290


The most common ocular manifestation of patients with dermatomyositis is the heliotrope rash affecting the eyelids. Occasionally ophthalmoplegia caused by to involvement of the extraocular muscles by myositis may be seen.311 Cotton-wool spots occasionally have been seen in association with polymyositis and dermatomyositis.312–317 The majority of these reports are in children with dermatomyositis, and this association may be the result of the vasculitis commonly seen in these children.312–317 However, a microangiopathy also has been reported in an occasional dermatomyositis patient without demonstrable systemic vasculitis.317 The retinal vasculopathy may be caused by the presence of inflammatory mediators in the microvasculature.

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Sjögren's syndrome originally was described as a triad of dry eyes, dry mouth, and RA. It subsequently has become apparent that Sjögren's syndrome may coexist with a variety of other connective tissue diseases (secondary Sjögren's syndrome), or without a defined connective tissue disease (primary Sjögren's syndrome). Secondary Sjögren's syndrome is seen most often in association with RA, SLE, or scleroderma.318–322 Primary Sjögren's syndrome is associated withHLA-DR3, while secondary Sjögren's with RA is associated with HLA-DR4, the HLA type associated with RA itself.322


The cause of the dry eyes and dry mouth in patients with Sjögren's syndrome is a mononuclear inflammatory infiltrate in the lacrimal and salivary gland resulting in glandular destruction and dysfunction. Multiple studies have demonstrated that the minor salivary gland biopsy is a useful tool for documenting the presence of this inflammatory infiltrate.322–324 Immunohistologic studies of minor salivary gland biopsy specimens have demonstrated that the majority of cells in this infiltrate are CD4+ T cells, with lesser numbers of CD8+ T cells and B cells.325,326 Lacrimal gland biopsy specimens have shown a higher percentage of B cells.327 This difference in the relative proportion of B cells in minor salivary gland biopsy and lacrimal gland biopsy specimens may reflect intrinsic differences in the glands or different sampling in an evolving process.328


Although several criteria for the diagnosis of Sjögren's syndrome have been proposed, none have been widely accepted as yet. Most investigators use some variation of a system in which two of the following three elements are present: (1) keratoconjunctivitis sicca; (2) evidence of salivary gland dysfunction, such as an abnormal minor salivary gland biopsy or abnormal salivary flow study; and (3) presence of a defined rheumatic disease, such as RA, SLE, or scleroderma.319 Secondary Sjögren's syndrome is diagnosed when a defined connective tissue disease is present, and primary Sjögren's syndrome when no defined connective tissue disease is present. There appears to be a subgroup of patients with primary Sjögren's syndrome who have an aggressive systemic illness associated with serologic abnormalities, cutaneous vasculitis, CNS disease, and hematologic abnormalities.329–331

Patients with Sjögren's syndrome frequently have multiple autoantibodies including ANA, RF, and antibodies to the two Sjögren's syndrome antigens, Ro (SSA) and La (SSB). Studies using immunodiffusion as the technique for detecting anti-Ro and anti-La have demonstrated antibodies to these antigens in approximately 50% and 30% of patients with Sjögren's syndrome, respectively.318–322 Antibody studies using ELISA techniques have shown antibodies to Ro in 96% of patients and to La in 87% of patients with Sjögren's syndrome.332


Keratoconjunctivitis sicca is the ocular hallmark of Sjögren's syndrome. This disorder is most often documented by an abnormal Schirmer's test demonstrating decreased tear production and damage to the ocular surface using rose bengal staining. Treatment of keratoconjunctivitis sicca consists of the frequent instillation of tear substitutes. These drops may need to be given hourly, and sometimes patients need them even more frequently. The use of bland ointments for nighttime lubrication may also be necessary. More severe cases require punctal occlusion in order to reduce the frequency of instillation of tears. Punctal plugs often are used as a temporary measure to see if permanent punctal occlusion will be of benefit. Topical cyclosporine also may benefit patients with severe dry eye because of Sjögren's syndrome. A small, randomized, double-masked, placebo-controlled clinical trial demonstrated that patients treated with topical cyclosporine 2% had improved tear film break-up times and decreased rose bengal staining of the corneal surface.333

Occasionally, patients with RA and secondary Sjögren's syndrome may develop a corneal melting disorder. Patients in that subgroup of primary Sjögren's syndrome with systemic autoimmune features may develop CNS lesions mimicking multiple sclerosis.331 Ischemic optic neuropathy has been described and is presumed to be a consequence of CNS vasculitis.329,330 A small case series of patients with anterior and intermediate uveitis and primary Sjögren's syndrome also has been reported.334

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Relapsing polychondritis is a rare disease characterized by recurrent, widespread, and potentially destructive inflammation of cartilage, the cardiovascular system, and the special sense organs, particularly the eyes and ears.335 It appears to be the result of an immunologic attack on cartilage itself. The etiology is unknown, but the pathogenesis appears to be an immunologic reaction to type II collagen. Type II collagen is widespread in cartilage and is present in the eye. Autoantibodies, and cellular immune reactions to type II collagen have been demonstrated in patients with relapsing polychondritis.335,336 In one case series,336 the autoantibody titer correlated with the clinical course and severity of the disease.


The most common clinical features are outlined in Table 6. They include auricular inflammation, polyarthritis, and nasal cartilage inflammation. Laryngotracheal-bronchial disease occurs in approximately one-half of the patients with relapsing polychondritis and may lead to death from laryngeal collapse. Involvement of the internal ear, cardiovascular system, and skin are less common. Relapsing polychondritis may be seen as an overlap syndrome with other systemic connective tissue autoimmune diseases such as RA.335 Systemic vasculitis occurs in 17% of patients with relapsing polychondritis and may help to account for the occasional retinal vasculitis reported.335,337–341


Table 6. Clinical Features of Relapsing Polychondritis

FindingFrequency (%)
Auricular inflammation85–95
Nasal cartilage inflammation64–66
Ocular inflammation54–59
Laryngotracheal-bronchial disease42–49
Cardiovascular disease24–28
Systemic vasculitis11
Cutaneous disease16

(Adapted from Jabs DA: The rheumatic diseases. In Ryan S (ed): The Retina. Vol II, pp. 457–480. Copyright 1989, with permission from Elsevier Science.)


Joint involvement in relapsing polychondritis is a migratory, asymmetric, episodic, nondeforming polyarthritis. Costochondritis is a classic feature. Cardiovascular lesions include aortic insufficiency caused by progressive dilation of the aortic ring and ascending aorta. Skin lesions most often are caused by a cutaneous vasculitis, and include palpable purpura and livedo reticularis. Auricular chondritis and nasal chondritis are the features that most often suggest the diagnosis. Most laboratory tests are nonspecific; however, antibodies to native and denatured type II collagen are found in approximately 50% of patients. Titers of this antibody may correlate with disease activity. On biopsy of cartilaginous structures such as the ear, there is a loss of the basophilic staining of the cartilage matrix and perichondral inflammation. Eventually there is destruction of the cartilage and replacement of it by fibrous tissue.335–340,342


Dapsone and corticosteroids have been the mainstay of treatment for relapsing polychondritis.335,343–345 Dapsone at doses of 50 to 200 mg/d often is used first and seems to be particularly effective in mild disease without cardiac or respiratory involvement.335,343,344 For patients whose disease is refractory to dapsone, systemic corticosteroids (e.g., 0.5 to 1 mg/kg per day of prednisone) may be needed. Pulse intravenous methylprednisolone has been used successfully in patients with airway compromise.335 Immunosuppressive agents including azathioprine, cyclosporine, and methotrexate have been useful in corticosteroid-resistant cases.335,346–349 In patients with ocular disease, indomethacin may be used to try to treat anterior scleritis, but systemic corticosteroids often are needed. Necrotizing scleritis or posterior scleritis requires systemic corticosteroids.


Ocular manifestations are frequent in relapsing polychondritis and occur in 50% to 54% of reported patients.335,349–356 The most common ocular manifestations are conjunctivitis, episcleritis, scleritis, and uveitis. In patients with associated vasculitis, optic nerve involvement and cranial nerve palsies may be seen. Scleral involvement is the most common ocular manifestation of relapsing polychondritis and occurs in 35% to 41% of patients.335,349 Although diffuse anterior scleritis is seen most frequently, all types of scleral inflammation including recurrent episcleritis, necrotizing scleritis, and posterior scleritis have been reported. Uveitis occurs in approximately 17% to 25% of patients and most often is either an anterior uveitis (iridocyclitis) or a sclerouveitis. Keratitis, including marginal corneal ulceration, has been seen in 10% to 15% of patients with relapsing polychondritis. One series reported retinopathy in 10% of their patients with relapsing polychondritis, consisting of a few cotton-wool spots and intraretinal hemorrhages.351 Branch retinal vein occlusion and central retinal vein occlusion were also reported. Ischemic optic neuropathy has been reported and appears to be because of an associated systemic vasculitis.

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The systemic vasculitides are primary vasculitic disorders in which no underlying disease is found, and are listed in Table 7. Each of the different vasculitides is characterized by its clinical pattern of vessel involvement and the histopathologic features of the vasculitis.357–360 The classification system for the systemic vasculitides was modified in 1994 by the Chapel Hill Consensus Conference, and categorizes the vasculitides by the size of the vessels involved: large-, medium-, or small-sized blood vessels.361 The ocular manifestations of the systemic vasculitides generally fall into two general categories: scleritis, and vasculitis-mediated damage to the retina, optic nerve, or cranial nerves.2 Although any of these eye lesions may occur with any of the vasculitides, the frequency of ocular involvement and the pattern of ocular involvement in dependent on the size and pattern of blood vessels involved by a given type of vasculitis. Thus, ocular manifestations are relatively uncommon in polyarteritis nodosa (PAN), which generally involves vessels of the viscera, but are very common in Wegener's granulomatosis, which frequently involves the vessels of the head and neck.


Table 7. Classification of the Vasculitides

Large vessel
  Giant cell arteritis (temporal arteritis)
  Takayasu's arteritis
  Cogan's syndrome

Medium vessel
  Polyarteritis nodosa

Small vessel
  Churg-Strauss syndrome
  Wegener's granulomatosis
  Behçet's disease
  Henoch-Schönlein purpura
  Hypersensitivity vasculitis
  Lymphomatoid granulomatosis



The etiology of most vasculitides is unknown. The pathogenesis of vasculitis is complex with genetic, infectious, and environmental factors triggering autoantibody- and immune complex-mediated injury to endothelial cells of blood vessels, leading to inflammation of vessel walls, thrombosis, and tissue ischemia and necrosis. Studies of HLA antigens have found associations between HLA-DRβ1 and giant cell arteritis,362 HLA-DR2 and Takayasu's arteritis in Japanese populations,363 and HLA-B51 with Behçet's disease.364,365 Infectious agents are thought to induce vasculitis by molecular mimicry, in which either antibodies or T cells cross-react with self-antigens that are similar to the infectious antigen.366,367 Possible infectious agents have been considered as inciting agents in the etiology of Wegener's granulomatosis, PAN, and giant cell arteritis but none have been proven.367 Antineutrophil cytoplasmatic antibodies (ANCA) have been found to activate neutrophils, which damage vessel endothelial cells and enhance the release of cytokines that promote further inflammation in ANCA-associated vasculitides such as Wegener's granulomatosis.367 Examples of an immune complex-mediated vasculitis have been reported in hepatitis B-associated PAN,368–371 and in hepatitis C-associated essential mixed cryoglobulinemia.367 Approximately 10% of patients with PAN are hepatitis B-antigen–positive. Circulating immune complexes composed of hepatitis B antigen and antibodies to the hepatitis B antigen have been found in vessel walls early in the disease process.371 It is thought that the hepatitis B antigen containing circulating immune complexes deposited in the vessel wall provides the initial immunologic insult leading to the subsequent occurrence of vasculitis. In essential mixed cryoglobulinemia, an estimated 85% to 95% of patients have circulating antibodies to hepatitis C virus.372–374 The serum cryoglobulins consist of immune complexes containing polyclonal IgG antibodies to hepatitis C viral RNA. In one prospective study, 54% of patients with hepatitis C and chronic liver disease had serum cryoglobulins.374

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Giant cell arteritis (GCA), also known as temporal arteritis, is a disease of patients age 50 years or older.375 All size vessels may be affected, although the temporal arteries are involved most frequently. The vasculitis is granulomatous in nature with a variable number of giant cells present. Occasionally the infiltrate may show only lymphocytes and plasma cells without evident giant cells.360

Clinical Features

GCA has been described in all races, although whites most often are affected. It is particularly common in northern climates, such as Scandinavia, Great Britain, and the northern United States, and is the most common systemic vasculitis in Western countries.375–378 Autopsy studies have estimated the frequency of GCA at 1.1% of the population.379 Diagnostic criteria were established by the ACR in 1990 for GCA and have been found to be highly sensitive and specific for the diagnosis of GCA when used in research studies involving patients with vasculitis.380 The criteria require finding three of more of the following signs or symptoms: age greater than 50 years; new-onset headache; tenderness over the temporal artery or a pulseless temporal artery; erythrocyte sedimentation rate (ESR) greater than 50 mm/hr using the Westergren technique; arteritis with a mononuclear infiltrate or multinucleated giant cells on biopsy; and granuloma formation380–383 (Table 8). Polymyalgia rheumatica refers to a symptom complex of proximal muscle pain and stiffness, and may present as a disease entity itself, or in association with GCA.384 Approximately 40% to 50% of patients with polymyalgia rheumatica will have GCA.385 Jaw claudication, with pain on chewing, often is associated with the positive temporal artery biopsy.382


Table 8. Clinical Features of Giant Cell Arteritis

SymptomsFrequency (%) (range)SignsFrequency (%) (range)
Headache60 (36–100)Temporal artery tenderness55 (28–91)
Polymyalgia rheumatica47 (20–86)Nodular artery35 (8–48)  
Jaw claudication36 (4–67)Pulseless artery51 (23–72)
Anonexia36 (15–69) Scalp tenderness57 (28–97)
Malaise29 (12–97)Fever48 (71–98)
Extremity claudication 8 (3–43)Weight loss45 (16–76)
Depression25 (4–46)Blindness36 (7–66)
Facial neuralgia21 (2–41)  
Blurred vision16 (6–23)  
Vertigo12 (3–20)  
Amaurosis fugax12 (2–19)  
Diplopia12 (2–43)  

(Adapted from Goodman BW: Temporal arteritis, Am J Med 67: 839, 1979. Copyright 1979, with permission from Exerpta Medica Inc.)


More than 90% of patients with GCA have an elevated ESR. Keltner386 has stated that only 2% of patients have a normal ESR, but rates of normal ESR in patients with polymyalgia rheumatica and suspected GCA have been reported as high as 6% to 22%.387–388 Some care must be taken in interpreting the ESR, because the method used must be known. Markedly elevated ESRs are obtained with the Westergren method, and in patients with GCA, the Westergren method yields a median ESR of 96 mm/hr, with a range of 50 to 132 mm/hr. Similarly, studies stating that the normal ESR in elderly patients can be as high as 40 mm/hr have used the Westergren method. The Wintrobe method, which uses a close-ended tube, produces a mean ESR in patients with GCA of 51 mm/hr, with a range of 38 to 59 mm/hr.388–394 C-reactive protein (CRP) has been suggested as a good marker because it is a more sensitive marker of the acute phase response, and a normal CRP has been reported in only 1% of patients with suspected or confirmed GCA.387,388

Temporal artery biopsy is the gold standard for making the diagnosis of GCA. The pathologic features in a temporal artery biopsy include occlusion of the vessel lumen with either thrombus formation or subintimal edema and cellular proliferation. There is fragmentation of the internal elastic lamina and a patchy degeneration of smooth muscle cells. Granulomatous inflammation may affect all portions of the vessel wall. Temporal artery biopsies occasionally may be negative on one side and positive on the second side. Two studies have suggested that the frequency of false-negative unilateral biopsies is 4% to 5%, but one study reported the rate of false-negative biopsies as high as 15%. These false-negative unilateral biopsies are caused by the presence of “skip areas” in temporal artery biopsy specimens.387,395–401


The treatment of GCA typically consists of systemic corticosteroids. The initial dose of prednisone for patients with GCA generally is 1 mg/kg per day (60 to 80 mg daily). Symptoms may respond promptly within several days. Treatment with daily oral corticosteroids is prophylactic for loss of vision.375,402,403 Treatment generally is instituted at the initial high dose and then slowly tapered, utilizing the clinical symptoms to monitor the disease. Alternate-day steroids are ineffective in the initial treatment of GCA.402 Some studies have suggested that GCA is a self-limited disease and will resolve itself after a period of 1 to 2 years. However, most patients require treatment with corticosteroids for 2 to 3 years. Other steroid-sparing agents, such as methotrexate, azathioprine, cyclosporine, and cyclophosphamide, as well as hydroxychloroquine and dapsone have been tried in the treatment of GCA with mixed results. Methotrexate has been the most extensively and rigorously studied. However, the data from randomized placebo-controlled clinical trials have not consistently supported its use.387,404,405

Ocular Manifestations

The most frequent ocular manifestation of GCA is ischemic optic neuropathy (ION). ION is caused by involvement of the posterior ciliary arteries supplying the optic nerve and clinically may be either anterior or retrobulbar. Overall, visual loss from ischemic optic neuropathy has been reported to occur in 36% of patients. Early series reported 50% to 70% of patients with visual loss, but in more recent series this has been reduced to 13%.406,407 This reduction in visual loss is thought to represent earlier recognition of the disease and institution of corticosteroid therapy.386,408–411 The characteristic clinical features of ION are a painless, sudden loss of vision, loss of color vision, and the characteristic altitudinal visual field defect. The visual field loss sometimes may be a Bjerrum-type scotoma rather than a complete altitudinal loss. Anterior ION is diagnosed when optic disc edema is present, whereas retrobulbar ION is diagnosed when the initial appearance of the disc is normal.

Amaurosis fugax has been reported in 2% to 19% of patients with giant cell arteritis. Amaurosis fugax is felt to be a preischemic optic neuropathy symptom and an indication for immediate corticosteroid therapy in these patients.382 In one series, approximately 40% of patients with amaurosis fugax and GCA developed ION and another 15% developed central retinal artery occlusions.406

Retinal findings are less frequent and include central and branch retinal artery occlusions, cilioretinal artery occlusion, and ischemic retinopathy with cotton-wool spots and/or intraretinal hemorrhages.412,413 Diplopia as a result of ophthalmoplegia has been reported in approximately 12% of patients with GCA. The pattern of extraocular muscle involvement may fluctuate with time and often is not indicative of a particular cranial nerve paresis. Instead, these lesions are thought to represent ischemia of the extraocular muscles. Such patients are at high risk for the development of ION and require prompt corticosteroid therapy.382,414–417 Other reported ocular complications include the ocular ischemic syndrome,418 hypotony,419 choroidal ischemia,411 Horner's syndrome and other pupillary abnormalities, visual field defects, and cortical blindness.386,420 The high frequency of ocular disease in patients with GCA is because of the pattern of vascular involvement, with almost universal involvement of vessels of the head and neck.421

Although corticosteroid use in a patient who has developed ION is primarily for prophylaxis of involvement of the fellow eye, there have been case reports of the reversal of ischemic optic neuropathy with the immediate institution of high-dose pulse IV corticosteroid therapy.422,423 This form of therapy is the use of 1 g of methylprednisolone daily as an intravenous infusion for 1 to 3 days. A response has been reported when patients were treated within the first 24 hours of presentation. Although this aggressive form of therapy would seem to be appropriate in a patient with newly diagnosed ION and GCA, it may not be of benefit in many, or perhaps most, patients.


Takayasu's arteritis is a chronic, systemic, obliterative vasculitis that affects large arteries, particularly branches of the aorta. It occurs primarily in children and young women. The disease is rare in the Western world but common in Asia, where the estimated incidence rate is 2.6 cases per million people per year. Other names for Takayasu's arteritis include aortic arch arteritis, aortitis syndrome, and pulseless disease.424–427

The disease affects primarily the large elastic arteries and selected muscular arteries. The aorta, the aortic arch vessels, and other major branches of the aorta commonly are involved. The inflammatory lesion is a panarteritis in which active granulomatous inflammtion may coexist with sclerosing fibrosis, vessel narrowing, and thrombosis. Active inflammation has been documented in arterial vessels at autopsy in patients with clinically inactive disease. In 20% of patients, the lesions are aneurysmal. Weakened vascular walls may develop dissection, or an aneurysm may rupture.357,428

Clinical Features

Takayasu's arteritis is a disease of children and young adults. Almost all patients are younger than 40 years of age at onset of disease, and the peak onset of disease occurs between 10 and 24 years of age. Women are affected more often than men. Clinically, the disease course may be divided into pre-pulseless and late pulseless phases. Systemic features, such as fatigue, weight loss, or low-grade fever are seen in more than 50% of patients in the pre-pulseless phase. Alterations in circulation may be present in the acute pre-pulseless phase and include claudication of the upper and lower extremities, syncope, Raynaud's phenomenon, and angina. Progressive vascular insufficiency caused by large artery narrowing leads to the characteristic pulseless phase. Intermittant claudication of the extremities, hypertension, and bruits are common findings in the pulseless phase and are seen in 45%, 60%, and 80% of patients respectively in several large series. A blood pressure difference usually can be detected between the two arms. The disease is diagnosed based on characteristic clinical findings and confirmed using arteriography, which shows narrowing or occlusion of the aorta, its branches, or large arteries in the proximal upper or lower extremities. The vascular involvement is segmental, with smooth-walled, tapered, and focal narrowing.424–429


Takayasu's arteritis may be rapidly progressive and fatal. Treatment in the acute phase is critical and typically consists of systemic corticosteroids, which may successfully suppress the disease, relieve symptoms, and reverse absent pulses. The initial dose of prednisone generally is 1 mg/kg per day. Cyclophosphamide, methotrexate, cycolsporine, and mycophenolate mofetil have been used with some benefit in corticosteroid-resistant cases or in cases in which the corticosteroid could not be tapered to appropriately low maintenance doses. Surgical arterial reconstruction occasionally may be necessary.424,429

Ocular Manifestations

The most characteristic ocular findings of Takayasu's arteritis are hypertensive retinopathy and Takayasu's retinopathy. Takayasu's retinopathy may be categorized into four stages: stage 1 is dilation of small vessels; stage 2 is capillary microaneurysm formation; stage 3 is retinal arteriovenous (AV) anastomoses; and stage 4 is AV anastomoses with other ocular complications. In a series of 78 patients with Takayasu's arteritis, 30.8% of patients had hypertensive retinopathy and 13.5% had Takayasu's retinopathy.430 The AV anastomoses generally are seen around the disc in a wreath-like pattern and in the midperiphery, and are thought to be caused by ocular ischemia from narrowing of the carotid and vertebral arteries. These retinal changes are demonstrated best by fluorescein angiography. Long-standing and more severe ischemia may result in peripheral retinal nonperfusion, neovascularization, and consequent vitreous hemorrhage.431


Cogan's syndrome is defined as vestibuloauditory dysfunction accompanied by an interstitial keratitis and an arteritis similar to polyarteritis nodosa. The arteritis typically is a focal necrotizing inflammation that involves medium-sized muscular vessels and vessel bifurcations predominantly. Other systemic symptoms include arthralgias and myalgias, arthritis, and cardiovascular lesions such as aortic insufficiency.2,55

Ocular disease in Cogan's syndrome typically is that of a bilateral patchy interstitial keratitis, which later may develop into multiple, yellowish nodular lesions in the deep stroma of the cornea. Rarely scleritis or uveitis may complicate Cogan's syndrome. The vestibular and auditory disease in Cogan's syndrome typically responds to oral corticosteroids, which may prevent long-term hearing loss.55 The interstitial keratitis is treated with topical corticosteroids, such as 1% prednisolone acetate, at a dose of one drop every hour while awake until the disease is quiet. Once the keratitis is quiet, the corticosteroid drops may be tapered.

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Polyarteritis nodosa affects medium and small muscular arteries typically within the visceral and cutaneous blood vessels. The vasculitis is classified as necrotizing with a mixed inflammatory cell infiltrate. There tends to be a focal and segmental involvement of the vessels with the coexistence of both acute and healed vascular lesions. Characteristic histologic findings are microaneurysm formation and infarction.357–360,432

Clinical Features

The average age of onset of PAN is 40 to 50 years. Constitutional symptoms are seen in approximately 70% of patients with PAN. Renal involvement is common, affecting 40% of patients, and may be related either to the vasculitis or to glomerulonephritis. Hypertension may develop as a consequence of the renal disease and affects one third of patients. Gastrointestinal disease with infarction of the viscera also may occur, although infrequently. Neurologic disease is common in the peripheral nervous system, presenting with mononeuritis multiplex in 42% to 70% of patients with PAN. Involvement of the central nervous system is rare.357,359,427,433,434


Survival in untreated patients with PAN was poor, with the majority of patients dying within 1 to 2 years.432 The most common causes of death were renal failure, gastrointestinal infarction or hemorrhage, and cerebral vasculitis. High-dose oral corticosteroid therapy may quiet the disease and prolong survival. However, the long-term outcome of patients treated with corticosteroid therapy alone has been poor.435 Most patients with PAN are now treated with high-dose oral corticosteroids and immunosuppressive drugs, such as cyclophosphamide. This treatment regimen improves disease control and the long-term outcome. The initial dose of cyclophosphamide generally is 2 mg/kg per day. The corticosteroids are continued until the disease is controlled and then tapered over a period of 2 to 3 months. The cyclophosphamide is continued for a period of one year and then tapered and discontinued. Long-term remissions may be induced by this type of treatment.436,437 As an alternative, intravenous cyclophosphamide has been used at 10 to 15 mg/kg monthly and may be less toxic.438 Azathioprine, methotrexate, and mycophenolate mofetil appear to be effective for milder disease and have less side effects.427

Ocular Manifestations

Ocular involvement occurs in 10% to 20% of patients with PAN.433,439–456 Older series reporting ocular disease and PAN did not distinguish between PAN and other forms of vasculitis. In the older literature, many of the ocular lesions attributed to PAN were caused by Wegener's granulomatosis. The most common ocular manifestations of PAN are related to the vascular disease and include hypertensive retinopathy in patients with renal disease, retinopathy from the vasculitis itself, and retinal arterial occlusive disease, including central retinal artery occlusion. Occasionally central lesions resulting in visual loss (e.g., visual field deficits), cranial nerve palsies, scleritis, and marginal corneal ulceration are seen. Any type of scleritis can occur, although the anterior and necrotizing types are more common than posterior scleritis. Choroidal ischemia with serous detachments of the retina has also been reported.

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Churg-Strauss syndrome, also known as Churg-Strauss angiitis or allergic granulomatosis, was described by Churg and Strauss in 1951 and is characterized by necrotizing vasculitis, eosinophilic infiltrate, and extravascular granulomas. The vasculitis affects small arteries and veins, often arterioles and venules. Vessels involved include those of the upper and lower respiratory tract, the viscera, heart, and skin. The vasculitis may be necrotizing or granulomatous, and the inflammatory infiltrate is mixed in cell type. Eosinophils are prominent. Biopsy specimens often show extravascular necrotizing granulomas with prominent eosinophils.357,360,457–461

Clinical Features

In Churg-Strauss syndrome there is an allergic diathesis of unknown etiology. Nearly 70% of patients have allergic rhinitis, which may precede the vasculitis by several years. Lung disease, particularly asthma, is the sine qua non for the diagnosis of Churg-Strauss syndrome. Pulmonary infiltrates may be present and are migratory and transient. Pleural effusions also have been reported. Eosinophilia is present and generally is greater than 15,000 cells per microliter. A mononeuropathy or polyneuropathy attributed to the vasculitis is common. Cardiomyopathy, coronary arteritis, gastrointestinal, and renal disease also can occur, although infrequently.457–462


Treatment for Churg-Strauss syndrome typically is with high-dose oral corticosteroids either alone or in combination with oral cyclophosphamide. The 5-year survival rate is 79%. The presence of renal, gastrointestinal, or cardiac disease predicts poorer outcome and typically mandates more aggressive treatment.462

Ocular Manifestations

Ocular disease in Churg-Strauss syndrome is uncommon. Case reports have described uveitis, marginal corneal ulcers, scleritis, and neuroophthalmic lesions including cranial nerve palsies, papilledema, and optic neuropathy in association with the disease. Conjunctival granulomas also have been reported.458,46–466


Wegener's granulomatosis was originally described as a triad of necrotizing granulomatous lesions of the upper and lower respiratory tracts, focal necrotizing vasculitis, and glomerulitis.462,467–471 Subsequently, a limited form of Wegener's granulomatosis was described that consisted of the upper and lower airway granulomatous disease without involvement of the kidneys.472,473 Studies using renal biopsy have demonstrated that often there are subclinical renal lesions in patients with limited Wegener's granulomatosis.470

The vasculitis usually involves small arteries and veins, but occasionally larger blood vessels may be involved. It primarily affects the blood vessels of the upper and lower respiratory tract and the kidney, but infrequently the skin, heart, viscera, or brain also may be involved. The vasculitis may be necrotizing or granulomatous, and the inflammatory infiltrate mixed in nature. There is a geographic pattern of tissue necrosis.357

Clinical Features

The clinical features of Wegener's granulomatosis are outlined in Table 9. Men and women are affected equally by Wegener's granulomatosis, and the mean age of onset of the disease is 41 years. Sinus disease is the most characteristic feature clinically although biopsy specimens of sinus tissue may show only necrotic material without characteristic histologic features. Superinfection of the sinuses caused by the presence of necrotic material occurs commonly. Many patients have a history of improvement in their sinus disease with the use of antibiotics, which treat the superinfection and lessen the patients' symptoms. Pulmonary disease also is frequent and lung biopsy specimens often are diagnostic. Renal disease may be present on biopsy, even when it is not clinically evident. Early detection of renal disease is essential, as up to 85% of patients with Wegener's granulomatosis will develop renal disease during the course of the disease, and if left untreated, the mean survival time in a patient with Wegener's-associated renal disease is 5 months.364,467–470


Table 9. Clinical Features of Wegener's Granulomatosis

Organ SystemFrequency at Presentation (%)Frequency over Disease Course (%)
Upper Respiratory7090
   Paranasal sinuses6685
Nervous system<122–50

(Adapted from Jabs DA: The rheumatic diseases. In Ryan S (ed): The Retina. Vol II. pp. 457–480. Copyright 1989, with permission from Elsevier Science.)



Before the use of immunosuppressive drugs for treatment, Wegener's granulomatosis was a fatal disease. Mean survival of untreated patients was 5 months, and the 1-year mortality was 82%.474 Corticosteroid therapy alone modestly improved survival to 12.5 months, but disease progression and relapses were common.475 Combination therapy with prednisone 1 mg/kg per day and oral cyclophosphamide 2 mg/kg per day improved the survival rate to greater than 80% at 5 years.462 Typically the corticosteroids are used until the disease is controlled and then subsequently tapered and discontinued. Treatment with oral cyclophosphamide is continued for 1 year after complete remission has been achieved, and then tapered and discontinued. The best results with this treatment regiment have been reported by the National Institutes of Health, where up to 90% of patients successfully achieved remission.467,468,470 In one study in which 158 patients with Wegener's granulomatosis were treated with combination prednisone and cyclophosphamide, 91% of patients had improvement in their disease and 75% had complete remission.476 Although some patients have relapsed after the discontinuation of therapy, a second remission often can be achieved. The complications of cyclophosphamide therapy include a dose-dependent and reversible leukopenia, hemorrhagic cystitis, and an increased risk of cancer, including a 33-fold increased risk of bladder cancer.474 Gonadal dysfunction, alopecia, and infection also may occur.470 In a randomized controlled trial of patients taking oral cyclophosphamide, 30% developed Pneumocystis carinii pneumonia.477 For this reason, P. carinii prophylaxis is recommended in patients taking daily oral cyclophosphamide. Although pulse IV cyclophosphamide therapy has fewer side effects than oral cyclophosphamide and has equal initial control of the disease, IV cyclophosphamide is less effective in inducing a remission than is daily oral cyclophosphamide. Other therapies for Wegener's granulomatosis have included methotrexate, which has been used typically for milder disease, and mycophenolate mofetil, which has been used successfully in some patients for remission maintenance. However, the results of clinical trials using these therapies are limited and inconsistent; therefore these are not recommended as treatment at this time.

Ocular Manifestations

Ocular disease occurs in 28% to 58% of patients with Wegener's granulomatosis during the course of the disease.470,478–482 Orbital involvement is common, ranging from 15% to 50% of patients, and in some series, is the most common form of ophthalmic involvement.470,480 Orbital disease often presents as an extension of the granulomatous inflammation from the sinus into the orbit (Fig. 8). This inflammation can lead to a compartment syndrome within the orbit, proptosis, orbital apex syndrome, compressive optic neuropathy, and subsequent irreversible vision loss. Orbital pseudotumor, separate from the sinus inflammation, also may be seen.483 Orbital cellulitis may occur as sinus superinfection extends into the orbit. Nasolacrimal duct obstruction and subsequent dacryocystitis occur in approximately 10% of patients and caused by involvement of the nasal mucosa.

Fig. 8. Orbital computed tomography (CT) scan demonstrating contiguous spread of sinus inflammation into both orbits in a patient with Wegener's granulomatosis.

Scleritis also is common in Wegener's granulomatosis, occurring in 16% to 38% of patients, and like orbital involvement, is either the first or second most frequent ocular feature, depending on the series.466,470 Scleritis may be of any type, particularly diffuse anterior or necrotizing scleritis (Fig. 9). Marginal corneal ulcers often are seen in association with the scleritis (necrotizing sclerokeratitis), and occasionally without scleritis.478–482,484 Posterior scleritis also has been reported.481

Fig. 9. Necrotizing scleritis in a patient with Wegener's granulomatosis.

Retinal vascular and optic nerve lesions occur in 10% to 18% of patients with ocular involvement from Wegener's granulomatosis. A retinopathy consisting of cotton-wool spots with or without intraretinal hemorrhages is more common, but retinal arterial occlusion has been reported as well. Ischemic optic neuropathy, optic disc vasculitis, and even a retinal vasculitis, have been reported. In patients with retinal vasculitis, neovascularization, vitreous hemorrhage, and rubeotic glaucoma may develop.450,478–482 Vision loss in Wegener's granulomatosis has been reported in approximately 8% of patients.476 Occasionally, the ocular disease in Wegener's granulomatosis will be active despite apparent control of the systemic disease. Although the ocular disease typically responds to treating the underlying disease, some patients, particularly those with severe orbital involvement, may require more aggressive therapy than that required to control other involved organs.55


Behçet's disease was initially described by Behçet in 1937 as a triad of oral ulcers, genital ulcers, and hypopyon uveitis. The disease is most common in the Middle East and Far East, particularly in Japan.485 In these populations, the disease is associated with the HLA-B51 antigen.365 It is believed that the HLA-B51 antigen may be associated with more severe disease.486,487 The pathogenesis of Behçet's disease remains unknown.

Clinical Features

The clinical features of Behçet's disease are outlined in Table 10.485,488–491 Oral ulcers are the most common clinical feature and essentially are required to make the diagnosis of Behçet's disease. The oral ulcers are painful, which distinguishes them from the painless ones of Reiter's syndrome, and range in size from 2 to 10 mm. They often come in crops. The genital ulcers have similar features but are diagnosed less often. Ocular disease, described in more detail below, occurs in 68% to 85% of patients. Skin involvement includes erythema nodosum, superficial thrombophlebitis, or pyoderma. Pathergy is the phenomenon in which a pustule occurs after the breaking of the skin by a needle, such as in blood drawing.488–491 The arthritis is an asymmetric, nondeforming, large joint polyarthritis, which frequently is corticosteroid responsive.492 Vascular lesions include migratory superficial thrombophlebitis, major vessel thrombosis, arterial aneurysms, and peripheral gangrene. The CNS lesions include brain stem syndrome, meningoencephalitis, or confusional states. Patients most often present with combinations of these three symptoms. CNS involvement by Behcet's disease is associated with an increased mortality.493–495


Table 10. Clinical Features of Behçet's Disease

FeatureFrequency (%)
Oral ulcers98–99
Genital ulcers80–87
Ocular disease68–85
Skin disease68–90
Central nervous system disease14–18

(Adapted from Jabs DA: The rheumatic diseases. In Ryan S (ed): The Retina, Vol II. pp. 457–480. Copyright 1989, with permission from Elsevier Science.)


Several different criteria have been proposed for the diagnosis of Behçet's disease. These include the Japanese criteria,496 the criteria of Mason and Barnes,488 the O'Duffy criteria,485 and in 1990, the criteria proposed by the International Study Group for Behçet's Disease,497 which were found to be 91% sensitive and 96% specific for the diagnosis of Behçet's disease. The International Study Group criteria are outlined in Table 11.


Table 11. The International Study Group Criteria for the Diagnosis of Bechet's Disease

Recurrent oral ulcerationMinor aphthous, major aphthous, or herpetiform ulceration observed by physician or patient, which recurred at least 3 times in one 12-month period
Plus 2 of: 
 Recurrent genital ulcerationAphthous ulceration or scanning, observed by physician or patient
 Eye lesionsAnterior uveitis, posterion uveitis, or cells in vitreous on slit lamp examination; or retinal vasculitis observed by an ophthalmologist
 Skin lesionsErythema nodosum observed by physician or patient, pseudofolliculitis or papulopustular lesions; or acneiform nodules observed by physician in postadolescent patients on corticosteroid treatment
 Positive pothergy testRead by physician at 24–48 hours

(Adapted from International Study Group for Behçet's Disease: Criteria for the diagnosis of Behçet's disease, Lancet 335 1078, 1990. Copyright 1990, with permission from Elsevier Science.)



Because of the poor results of corticosteroid therapy alone for ocular Behçet's, immunosuppressive drugs were tried in the early 1970s. Chlorambucil was used initially, typically at a dose of 0.1 to 0.2 mg/kg per day. Cyclophosphamide also is used at a dose of 1 to 2 mg/kg per day. As with other immunosuppressive drug therapy, the dosage generally is adjusted to keep the white blood cell count at approximately 3000 cells per microliter. Systemic corticosteroids, at an initial dose of 1 mg/kg per day of oral prednisone, are used in combination with an immunosuppressive agent to control the acute disease. Once the disease has been controlled, the corticosteroids are tapered and discontinued, and the immunosuppressive drug is continued for 12 to 18 months, then tapered and discontinued. Uncontrolled cases series of chlorambucil therapy for Behçet's disease have shown long-term, drug-free remissions after two years of treatment.498–500 Less published data are available using cyclophosphamide in the treatment of ocular Behçet's disease; however, some clinicians have found it equally effective as chlorambucil and easier to use. Side effects of the alkylating agents, cyclophosphamide and chlorambucil, include reversible cytopenias, sterility, and an increased risk of malignancy.498–506

Cyclosporine has been reported to be effective in the treatment of ocular Behçet's disease.507–509 A randomized clinical trial of 96 patients found that 50% of patients treated with cyclosporine at a dose of 10 mg/kg per day had a 75% to 100% reduction in the frequency and severity of attacks of their ocular disease.508 However, nearly 25% of patients treated with cyclosporine had no benefit in terms of the frequency and severity of ocular attacks. Cyclosporine's side effects include nephrotoxicity, which occurs in virtually all patients if high doses (10 mg/kg per day) are used510; therefore, lower doses of cyclosporine (5 mg/kg per day) than that used in the trial typically are used today. Furthermore, long-term, drug-free remissions generally are not seen with cyclosporine therapy, and discontinuation of cyclosporine typically is associated with a relapse of the disease.

Azathioprine also has been used in the treatment of Behçet's disease, and in a randomized clinical trial of 73 patients, was found to prevent contralateral eye involvement in patients with unilateral disease, and to prevent any eye involvement in those patients with Behçet's disease without ocular disease.511 However, as with cyclosporine, not all patients responded well, as 22% required additional therapy.511

Ocular Manifestations

The most common ocular manifestation of Behçet's disease is uveitis.512–514 Conjunctivitis, keratitis, and scleritis occasionally have been described in association with Behçet's disease but are uncommon. Neuroophthalmic lesions caused by vascular involvement by Behçet's disease have been described, including cranial nerve palsies, papilledema, and ischemic optic neuropathy.515

The most frequent ocular manifestation is anterior uveitis, which may present either with or without a hypopyon (Fig. 10). Although earlier series described hypopyon uveitis presenting in as many as 88% of patients, more recent series have described the frequency of hypopyon at only 9%. This decrease in the frequency of hypopyon likely represents earlier diagnosis and more aggressive therapy.512–514

Fig. 10. Hypopyon uveitis in a patient with Behçet's disease.

The characteristic posterior segment lesion of Behçet's disease is retinal vasculitis (Fig. 11). This retinal vasculitis may involve both veins and arteries, causing arterial occlusion and retinal necrosis. Occasionally, secondary neovascularization and retinal detachment develop.512–514,516 The retinal vasculitis in Behçet's disease is overwhelmingly bilateral; one series found that 81% of cases were bilateral at 1 year, and 93% were bilateral at 2 years.501 In their series, neovascularization developed in 17% of their patients.501 Focal necrotizing retinitis also has been described.

Fig. 11. Fundus photographs from a patient with Behçet's disease, demonstrating retinal vasculitis. A. Early macular lesion, and B. progressive disease 1 month later. (Reprinted from Jabs DA: The rheumatic diseases. In Ryan S (ed): The Retina, Vol II, pp. 457–480. Copyright 1989, with permission from Elsevier Science.)

The natural history of ocular Behçet's disease is poor. The majority of patients lose all or part of their vision within 5 years. In the natural history described by Mamo,517 74% of eyes had a final vision of 20/200 or worse. Of the 25 eyes that deteriorated to no light perception, vision declined to this level over an average period of 3.6 years. Although systemic corticosteroids may delay the progress of the ocular disease, they do not alter its ultimate outcome, hence, the use of immunosuppressive drugs for ocular Behçet's as described above.

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