Posterior Uveitis and Collagen Vascular Diseases
SARCOIDOSIS-ASSOCIATED UVEITIS
Sapna Gangaputra
H. Nida Sen
Sarcoidosis is a multisystem granulomatous disorder that most commonly affects the lungs, skin, lymph nodes, eyes, central nervous system (CNS), reticuloendothelial system, the heart, and bones.
Epidemiology and Etiology
• Sarcoidosis occurs most commonly in African Americans and Caucasians of Northern European descent.
• The incidence and prevalence varies among different geographic regions and ethnic groups:
In the United States, the prevalence among African Americans is 35 to 82 in 100,000 persons, whereas in Caucasians, it is 8 to 11 in 100,000 persons.
In Scandinavia, the prevalence is 64 in 100,000 persons.
• Most common organs involved are the lungs (90% to 95%), followed by skin (15% to 20%), lymph nodes (15% to 40%), and eyes (12% to 20%).
• Systemic sarcoidosis typically affects young adults, whereas ocular sarcoidosis appears to have a bimodal presentation, with peaks at 20 to 30 years and 50 to 60 years.
• Ophthalmic involvement occurs in up to 50% of patients with systemic sarcoidosis, but most series suggest that the rate is around 25%.
• Sarcoidosis-associated uveitis occurs in 1% to 3% of pediatric and 10% of adult uveitis cases.
Ocular involvement is more common among women compared to men, and in African Americans compared to Caucasians.
Patients typically have a bilateral (98%), granulomatous anterior uveitis. This is the presenting sign of sarcoidosis in 10% to 20% of patients.
The most common site of intraocular involvement is anterior uveitis (two-thirds of patients).
The most common site of extraocular involvement is the lacrimal gland.
• Although the etiology is unknown, sarcoidosis is believed to be immune mediated. Both a genetic predisposition (familial aggregation, HLA-B8, and HLA-DRB1) and environmental factors (environmental allergens and infectious agents) have been suggested.
Symptoms
• Blurry vision, floaters • Redness, photophobia, ocular discomfort
• Respiratory symptoms (shortness of breath) and constitutional symptoms (fever, fatigue, night sweats, and weight loss)
Signs
• In 2006, the first International Workshop on Ocular Sarcoidosis developed criteria for the diagnosis of ocular sarcoidosis, which include seven ocular signs considered suggestive of ocular sarcoidosis (Table 7-1).
Mutton-fat (granulomatous) keratic precipitates (KPs), anterior chamber cells and flare, and iris or angle nodules (granulomas). Busacca nodules are in the iris stroma, and Koeppe nodules are on the pupillary margin (Figs. 7-1, 7-2, 7-3, 7-4, 7-5, 7-6 and 7-7).
The KPs may also be nongranulomatous.
Nodules on the trabecular meshwork and/or tent-shaped peripheral anterior synechiae
Vitreous cells, vitreous haze, snowballs sometimes with a “string of pearls” appearance, and snowbanks
Multifocal, cream-colored, peripheral chorioretinal lesions (Dalen-Fuchs nodules), either active or atrophic
Retinal vasculitis, perivenous sheathing (candle wax drippings, also known as taches de bougie), and/or a retinal macroaneurysm in an inflamed eye
Optic disc or choroidal granulomas
Bilaterality
• Other ophthalmic findings include:
Lacrimal gland enlargement
Subconjunctival granulomas
Optic neuritis
Heerfordt syndrome (uveoparotid fever): anterior uveitis, parotid gland enlargement, facial palsy, and fever
Retinal neovascularization, sometimes with a sea fan appearance
• The major systemic signs include:
Respiratory dysfunction
Skin macules and papules, including erythema nodosum and lupus pernio
Cranial nerve palsies
Ataxia and cognitive dysfunction
Cardiomyopathy and arrhythmias
Differential Diagnosis
• Vogt-Koyanagi-Harada (VKH) syndrome
• Sympathetic ophthalmia
• Multifocal choroiditis
• Primary intraocular lymphoma (retinal lymphoma)
• Tuberculosis
• Syphilis
• Lyme disease
• Blau syndrome and juvenile idiopathic arthritis in children
Diagnostic Evaluation
• Definitive diagnosis requires tissue biopsy showing noncaseating granulomas. The granulomas appear as whorls of epithelioid cells surrounding multinucleated Langhans giant cells. Conjunctival biopsies are only performed in the presence of conjunctival granulomas.
• Systemic evaluation and imaging studies: chest radiograph and/or high-resolution chest computed tomography (CT) to identify hilar lymphadenopathy; gallium scan
(not recommended for routine screening); pulmonary function tests (reduction in diffusing capacity); bronchoalveolar lavage (elevated CD4/CD8 ratio); biopsy of the involved tissue; and/or brain magnetic resonance imaging (MRI) if neurosarcoidosis is suspected.
(not recommended for routine screening); pulmonary function tests (reduction in diffusing capacity); bronchoalveolar lavage (elevated CD4/CD8 ratio); biopsy of the involved tissue; and/or brain magnetic resonance imaging (MRI) if neurosarcoidosis is suspected.
TABLE 7-1. Diagnostic Criteria for Ocular Sarcoidosis from the International Workshop on Ocular Sarcoidosis | ||||||||||||||
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• Laboratory testing: Angiotensin-converting enzyme is elevated in 75% of patients, lysozyme, hypercalcemia, hypercalciuria, anemia, elevated erythrocyte sedimentation rate (ESR)/C-reactive protein (CRP), anergy, elevated alkaline phosphatase.
• When screening for ocular sarcoidosis among patients with active uveitis, the combination of an elevated serum angiotensin-converting enzyme level and chest radiographic findings typical for sarcoidosis increases the sensitivity up to 79%.
• Fluorescein angiography can reveal retinal vascular leakage, early blockage and late staining of choroidal granulomas, retinal pigment epithelial (RPE) window defects, and cystoid macular edema (CME).
• None of the above is specific or diagnostic by itself; therefore, it is a clinical diagnosis, which is supported by imaging and laboratory testing. Tissue biopsy is required for definitive diagnosis.
Treatment
• Corticosteroids are the mainstay of therapy for both ocular and systemic sarcoidosis, and intravenous pulse steroids may be needed in some very severe cases.
• Sarcoidosis is often responsive to steroids; however, chronic uveitis often requires
immunomodulatory therapy. Methotrexate, cyclosporine, mycophenolate mofetil, and infliximab have all been used successfully in ocular sarcoidosis.
immunomodulatory therapy. Methotrexate, cyclosporine, mycophenolate mofetil, and infliximab have all been used successfully in ocular sarcoidosis.
• Local treatment with topical drops, periocular steroids, and intraocular steroid implants can also be considered in select cases.
Prognosis
• The prognosis is good if treated early.
• African Americans tend to have more acute and severe disease, whereas Caucasians tend to have chronic, asymptomatic disease.
• Chronic posterior or panuveitis, glaucoma, CME, older age at presentation, and delay in presentation to a sarcoid/uveitis subspecialist may confer a poor visual prognosis.
• Ocular complications can include glaucoma, cataract, CME, optic disc edema, occlusive vasculopathy, retinal or optic disc neovascularization, vitreous hemorrhage, and retinal detachment.
 FIGURE 7-1. Sarcoidosis. A. There are large, granulomatous-appearing (mutton-fat) keratic precipitates in this patient with sarcoidosis. B. Busacca nodules in the iris stroma are typically associated with diseases causing granulomatous uveitis, such as sarcoidosis. |
REFERENCES
Baughman RP, Teirstein AS, Judson MA, et al. Case control etiologic study of sarcoidosis (ACCESS) research group. Clinical characteristics of patients in a case control study of sarcoidosis. Am J Respir Crit Care Med. 2001;164(10 Pt 1):1885-1889.
Groen F, van Laar JA, Rothova A. Chest radiographic screening for sarcoidosis in the diagnosis of patients with active uveitis. Ann Am Thorac Soc. 2017;14(6):912-918.
Herbort CP, Rao NA, Mochizuki M; members of Scientific Committee of First International Workshop on Ocular Sarcoidosis. International criteria for the diagnosis of ocular sarcoidosis: results of the first International Workshop on Ocular Sarcoidosis (IWOS). Ocul Immunol Inflamm. 2009;17(3):160-169.
Lobo A, Barton K, Minassian D, du Bois RM, Lightman S. Visual loss in sarcoid-related uveitis. Clin Experiment Ophthalmol. 2003;31(4):310-316.
Pasadhika S, Rosenbaum JT. Ocular sarcoidosis. Clin Chest Med. 2015;36(4):669-683.
 FIGURE 7-2. Sarcoidosis. A. This patient with severe sarcoidosis has posterior uveitis with granulomas and intense exudates surrounding the vessels. Note the asymmetric involvement between the right and left eyes. The fluorescein angiogram of the left eye (lower right) demonstrates leakage and staining in the late frames. B. Exudates surrounding the vessels, also known as “candle wax drippings” or “taches de bougie,” are seen inferiorly. |
 FIGURE 7-3. Sarcoidosis. “Candle wax drippings” along the major arcade vessels. (Courtesy of Sunir Garg, MD.) |
 FIGURE 7-4. Sarcoidosis. Sarcoidosis patient with intermediate uveitis with snowballs and retinal vascular sheathing inferiorly (magnified), as well as retinal vasculitis with leakage on fluorescein angiogram. Note that the extent of retinal vascular leakage is significantly more impressive than expected based on the fundus exam. |
 FIGURE 7-5. Sarcoidosis. There are multiple skin nodules due to sarcoidosis in an African American patient with liver and ocular sarcoidosis. The inferior periorbital skin, the nose, elbow, and perioral skin are involved. |
 FIGURE 7-6. Sarcoidosis. There are the typical punched-out chorioretinal lesions in a 65-year-old Caucasian patient with ocular sarcoidosis. These lesions are believed to be representative of atrophic Dalen-Fuchs nodules. |
 FIGURE 7-7. Sarcoidosis. Optic nerve granuloma in the right eye of a 42-year-old African American patient with sarcoidosis. |
SYMPATHETIC OPHTHALMIA
Rishi R. Doshi
S. R. Rathinam
Emmett T. Cunningham Jr.
Sympathetic ophthalmia is a bilateral granulomatous panuveitis that occurs when ocular surgery or ocular trauma to one eye (the exciting eye) incites inflammation both in the traumatized eye and in the fellow (sympathizing) eye.
Etiology and Epidemiology
• It has an estimated incidence of 0.03 in 100,000; the incidence is higher after vitreoretinal surgery (1 in 1152 procedures) compared to other ocular surgeries; and surgery has surpassed trauma as the most common inciting event.
• Previously sequestered ocular antigens from the uvea, retina, or choroidal melanocytes stimulate an autoimmune response.
• Historically, men and children were more commonly affected because of higher rates of trauma, but currently, it occurs equally in both men and women with an increased incidence in elderly patients because of higher rates of surgery.
• It may occur after endophthalmitis, with an incidence from 1% to 11%.
• 80% of cases occur within 3 months of surgery/trauma and 90% occur within 1 year, but it has been reported to occur anytime between 1 week and 66 years after injury.
• There is an increased prevalence in patients with HLA-DR4 and HLA-A11.
Symptoms
• Patients often have a prodrome of tearing, photophobia, and blurry vision (loss of accommodation), which may progress to severe vision loss, pain, floaters, and photopsias in both eyes.
Signs
• Both eyes have inflammation with:
Anterior uveitis (55%); granulomatous KPs, iris thickening and synechiae, low or high intraocular pressure (from ciliary body shutdown or angle closure), vitritis (47%); disc edema (20%); serous retinal detachment (12%); choroiditis (8%); and macular edema (5%) (Figs. 7-8, 7-9, 7-10, 7-11 and 7-12)
Dalen-Fuchs nodules are yellow-white midequatorial RPE lesions composed of epithelioid cells and histiocytes (30% to 70%).
Late findings may include sunset glow fundus, optic atrophy, choroidal neovascularization, and phthisis.
Systemic findings may include cerebrospinal fluid pleocytosis, hearing disturbances, alopecia, poliosis, and vitiligo (but these are much more typical of VKH).
Differential Diagnosis
• VKH (no history of penetrating trauma or surgery)
• Tuberculosis
• Sarcoidosis
• Syphilis
• Intraocular lymphoma
Diagnostic Evaluation
• On fluorescein angiography, patients have multiple pinpoint areas of hyperfluorescence with late leakage, choroidal lesions that block early and stain late, and late disc staining.
• Optical coherence tomography can show multifocal serous retinal detachments.
• B-scan ultrasonography demonstrates choroidal thickening and serous retinal detachments.
• Histopathology characteristically demonstrates a diffuse granulomatous non-necrotizing panuveitis with thickening of choroid and early sparing of choriocapillaris.
Treatment
• First-line therapy is high-dose oral corticosteroids (1 to 2 mg/kg/day), with a slow taper.
• Topical corticosteroids and cycloplegic/mydriatic agents can help alleviate some of the more acute symptoms.
• Corticosteroid-sparing immunosuppressive agents are typically required because most patients need long-term treatment.
• A fluocinolone acetonide implant (Retisert) may be useful in select cases.
• Enucleation of the exciting eye within 2 weeks of the inciting event may decrease the risk of sympathetic ophthalmia; once sympathetic ophthalmia occurs, enucleation should be considered only in a blind, painful eye.
Prognosis
• It is a vision-threatening disease, with only slightly more than half of treated patients retaining visual acuity ≥20/40. One-fourth of patients have vision worse than 20/200.
 FIGURE 7-8. Sympathetic ophthalmia. Phthisis bulbi following a ruptured globe in a patient with sympathetic ophthalmia. |
• Complications include cataract and glaucoma.
• Predictors of a poor outcome include a traumatic etiology, active, uncontrolled intraocular inflammation, and an exudative retinal detachment.
• Long-term visual loss may result from chorioretinal scars, chronic macular edema, and choroidal neovascularization.
REFERENCES
Castiblanco CP, Adelman RA. Sympathetic ophthalmia. Graefes Arch Clin Exp Ophthalmol. 2009;247:289-302.
Galor A, Davis JL, Flynn HW, et al. Sympathetic ophthalmia: incidence of ocular complications and vision loss in the sympathizing eye. Am J Ophthalmol. 2009;148:704-710.
Mahajan S, Invernizzi A, Agrawal R, Biswas J, Rao NA, Gupta V. Multimodal imaging in sympathetic ophthalmia. Ocul Immunol Inflamm. 2016;14:1-8.
Payal AR, Foster CS. Long-term drug-free remission and visual outcomes in sympathetic ophthalmia. Ocul Immunol Inflamm. 2016; 25:1-6.
Rathinam SR, Rao NA. Sympathetic ophthalmia following
postoperative bacterial endophthalmitis: a clinicopathologic study. Am J Ophthalmol. 2006;141(3):498-507.
 FIGURE 7-9. Sympathetic ophthalmia. B-scan ultrasound showing a chronic retinal detachment and choroidal thickening in a patient with sympathetic ophthalmia. |
 FIGURE 7-10. Sympathetic ophthalmia. Characteristic posterior segment findings in two patients who developed sympathetic ophthalmia weeks after uncomplicated pars plana vitrectomy. Color fundus photograph (A) and midphase fluorescein angiogram (B) from the same patient 2 months following vitrectomy showing a macular serous detachment with multiple, pinpoint areas of leakage through the retinal pigment epithelium. C. Color fundus photographs taken approximately 6 months following vitrectomy showing moderate vitreous inflammation and active chorioretinal infiltrates. D. Photograph of the same patient taken approximately 18 months following vitrectomy, after the patient’s inflammation had been controlled with high-dose systemic corticosteroids followed by noncorticosteroid immunosuppressive agents. Although histopathologically unverified, many would describe these infiltrates clinically as Dalen-Fuchs nodules. (Reproduced from Doshi RR, Arevalo JF, Flynn HW Jr, Cunningham ET Jr. Evaluating exaggerated, prolonged, or delayed postoperative intraocular inflammation. Am J Ophthalmol. 2010, with permission of Elsevier.) |
 FIGURE 7-11. Sympathetic ophthalmia. Bullous serous retinal detachment in a patient with sympathetic ophthalmia. |
 FIGURE 7-12. Sympathetic ophthalmia. A. This patient underwent ruptured globe repair following blunt trauma. B. Several months later, the patient returned complaining of photophobia and blurred vision in the previously healthy right eye. There is disc hyperemia, mild macular striations caused by subretinal fluid, and deep, choroidal yellow plaques characteristic of sympathetic ophthalmia. C. The fluorescein angiogram demonstrates disc hyperfluorescence and pinpoint leakage and staining from the areas of choroiditis. (Courtesy of Allen Chiang, MD, and Andre Witkin, MD.) |
VOGT-KOYANAGI-HARADA SYNDROME
Sapna Gangaputra
H. Nida Sen
Vogt-Koyanagi-Harada (VKH) syndrome is a bilateral granulomatous panuveitis with skin, meningeal, and auditory-vestibular involvement. It is an autoimmune inflammatory condition mediated by T cells that target melanocytes in individuals susceptible to the disease
Epidemiology and Etiology
• VKH has a predilection for pigmented races and is seen in patients from Asia, Middle East, and Latin America. It also occurs in persons with Native American ancestry. It is relatively rare in whites.
• It is most common in the second to fourth decade of life.
• There is a slight female preponderance.
• VKH has a genetic predisposition and has
been associated with HLA-DR4, HLA-DR53, and HLA-DRB1*0405.
• Unlike sympathetic ophthalmia, patients with VKH have no history of penetrating ocular trauma or surgery.
Signs
• An international committee on VKH nomenclature has revised the criteria for diagnosis as shown in Table 7-2.
This contribution to the work was done as part of the author’s official duties as NIH employees and is a work of the U.S. government.
Differential Diagnosis
• Sympathetic ophthalmia (these patients have a history of penetrating trauma)
• Bullous central serous chorioretinopathy (these patients have no inflammation)
• Posterior scleritis (eyes have scleral thickening on B-scan ultrasonography)
• Sarcoidosis
• Syphilis
• Lyme disease
• Ocular lymphoma
• Uveal metastasis
Diagnostic Evaluation
• Fluorescein angiography: Early in the angiogram, there are multiple pinpoint areas of hyperfluorescence at the level of the RPE which pool in the later frames. Late staining of the disc is often present (Figs. 7-15, 7-16, 7-17, 7-18, 7-19 and 7-20).
• B-scan ultrasonography: demonstrates nonspecific choroidal thickening and serous retinal detachments but can be helpful to rule out posterior scleritis and neoplastic disorders.
• Optical coherence tomography: On initial presentation, eyes may have increased choroidal thickness and serous retinal detachments. Patients can have orthogonal “septae” which are suggestive of VKH.
• Lumbar puncture: The majority of patients will have pleocytosis.
• Laboratory tests to rule out other diseases such as sarcoid and syphilis as needed.
Treatment
• These patients need prompt and aggressive systemic therapy. Systemic high-dose cortico-steroids (1 mg/kg up to 60 to 80 mg daily) are the first-line agent. Steroids are usually administered for 3 to 6 months with a slow taper.
• Corticosteroid-sparing immunosuppressive agents and biologic agents are initiated early in the treatment of VKH to prevent recurrences and to reduce steroid-related side effects.
TABLE 7-2. Diagnostic Criteria for VKH | ||||||
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Prognosis
• The prognosis is generally good with prompt and aggressive therapy.
• In addition to the development of cataracts and glaucoma, subretinal fibrosis and choroidal neovascular membranes may occur.
REFERENCES
Li M, Liu Q, Luo Y, et al. Enhanced depth SD-OCT images reveal characteristic choroidal changes in patients with Vogt-Koyanagi-Harada disease. Ophthalmic Surg Lasers Imaging Retina. 2016;47(11):1004-1012.
O’Keefe GA, Rao NA. Vogt-Koyanagi-Harada disease. Surv Ophthalmol. 2017;62(1):1-25.
Rao NA, Gupta A, Dustin L, et al. Frequency of distinguishing clinical features in Vogt-Koyanagi-Harada disease. Ophthalmology. 2010;117(3):591-599, 599.e1.
Read RW, Holland GN, Rao NA, et al. Revised diagnostic criteria for Vogt-Koyanagi-Harada disease: report of an International Committee on Nomenclature. Am J Ophthalmol. 2001;131:647-652.
Yamaguchi Y, Otani T, Kishi S. Tomographic features of serous retinal detachment with multilobular dye pooling in acute Vogt-Koyanagi-Harada disease. Am J Ophthalmol. 2007;144(2):260-265. Epub 2007 May 29.
 FIGURE 7-13. Vitiligo. This African American patient with VKH had extensive areas of skin depigmentation (vitiligo). VKH, Vogt-Koyanagi-Harada. |
 FIGURE 7-14. Poliosis. A single white eyelash (poliosis) was found in this African American patient with VKH. VKH, Vogt-Koyanagi-Harada. |
 FIGURE 7-15. Vogt-Koyanagi-Harada (VKH) syndrome. Serous retinal detachments in early VKH. A. Multiple small serous detachments in the right macula of an AfricanAmerican male presenting with a 5-day history of blurred vision. B. Fundus autofluorescence showing alterations in the RPE. C. Fluorescein angiogram (FA) in the early arteriovenous phase revealing the classic finding of multiple areas of pinpoint leakage. D. The late phase of the FA demonstrating pooling of fluorescein in the multiple serous retinal detachments. RPE, retinal pigment epithelium. |
 FIGURE 7-16. Vogt-Koyanagi-Harada (VKH) syndrome. This is a 43-year-old woman from Central America. A. Color photograph demonstrating multiple serous retinal detachments. Deep yellow lesions consistent with choroiditis. B. FA showing multiple pinpoint areas of leakage with pooling of dye in the areas of serous retinal detachment. There is also staining of the optic disc. FA, Fluorescein angiogram. (Courtesy of Sunir Garg, MD and MidAtlantic Retina, the Retina Service of Wills Eye Hospital.) |
 FIGURE 7-17. Vogt-Koyanagi-Harada (VKH) syndrome. Optical coherence tomography (OCT) demonstrating a serious retinal detachment with subretinal septae, a finding suggestive of VKH. (Courtesy of MidAtlantic Retina, The Retina Service of Wills Eye Hospital.) |
 FIGURE 7-18. Vogt-Koyanagi-Harada (VKH) syndrome. Sunset glow fundus in late VKH. The orange-red color of the fundus, caused by loss of choroidal melanocytes in this patient with Native American ancestry, can develop 2 to 6 months after disease onset. Changes in the RPE are also visible. RPE, retinal pigment epithelial. |
 FIGURE 7-19. Vogt-Koyanagi-Harada (VKH) syndrome. Subretinal fibrosis in late VKH. Note the extensive fibrosis and pigmentary changes in an advanced case of VKH with a history of poorly controlled uveitis. |
 FIGURE 7-20. Vogt-Koyanagi-Harada (VKH) syndrome. EDI OCT helps differentiate from acute CSCR because subretinal septa are only seen in VKH, and decrease in choroidal thickness has been noted in quiescent stages, with increase during recurrences. CSCR, central serous chorioretinopathy; EDI, enhanced depth imaging; OCT, optical coherence tomography. |
OCULAR COMPLICATIONS OF RHEUMATOID ARTHRITIS
Sunir J. Garg
Rheumatoid arthritis (RA) is a chronic autoimmune disease that predominantly affects the peripheral joints. Patients with RA can develop extra-articular systemic and ocular involvement.
Epidemiology and Etiology
• RA is distributed worldwide, with a prevalence between 0.3% and 1.5%.
• Women develop RA three times more often than men.
• The incidence increases with advancing age.
• Activated T cells and antigen-antibody complexes cause a microvasculitis that affects joint synovial tissues as well as extra-articular tissues. Immune complex deposition and activation of complement play a pivotal role in the pathophysiology of RA.
Symptoms
• A red eye due to episcleritis is common as is dry eye. As a result, patients may describe a foreign-body sensation and photophobia.
• Patients with scleritis complain of a deep, boring, periocular pain that radiates to the brow and temple.
Signs
• Ocular (Figs. 7-21, 7-22, 7-23, 7-24 and 7-25)
Keratoconjunctivitis sicca (dry eye): Rapid tear film breakup time and devitalized corneal epithelium are seen on staining. Schirmer testing demonstrates decreased tear production.
Sterile corneal infiltrates, as well as corneal edema, opacification, vascularization, and/or thinning with marginal furrowing, can occur.
Peripheral ulcerative keratitis (PUK) is a more aggressive form of perilimbal vasculitis.
Episcleritis is characterized by dilated episcleral vessels.
Patients with scleritis have a dilated superficial and deep episcleral vascular plexus that imparts a violaceous hue to the sclera. Unlike episcleritis, the dilated vessels lose their normal radial architecture.
Diffuse anterior scleritis is more common and has a better prognosis than other types of scleritis, including nodular scleritis, anterior necrotizing scleritis, necrotizing scleritis without inflammation (scleromalacia perforans), and posterior scleritis.
• Systemic
Patients initially develop fatigue, morning stiffness, and myalgias. The typical finding is polyarthritis that primarily affects the hands, feet, and cervical vertebrae.
Patients may also develop anemia, pericarditis, pleuritis, glomerulonephritis, neuropathy, and vasculitis of the skin (Fig. 7-26).
Differential Diagnosis
• Sjögren syndrome
• Enteropathic arthritis, including Crohn disease and reactive arthritis (Reiter syndrome)
• Psoriatic arthritis
• Systemic lupus erythematosus (SLE)
• Sarcoidosis
• Granulomatosis with polyangiitis (GPA) (Wegener granulomatosis)
• Dermatomyositis (DM)
• Polyarteritis nodosa (PAN)
Diagnostic Evaluation
• Specific markers: rheumatoid factor, antinuclear antibodies (ANA), antineutrophil cytoplasmic antibody (ANCA), anti-SS-A, anti-SS-B antibodies, and anti-cyclic citrullinated peptides antibodies
• Nonspecific markers: complete blood count, chest radiograph, ESR, CRP, liver function tests, kidney function tests
Treatment
• Systemic disease: Three major classes of drugs are used: nonsteroidal anti-inflammatory drugs (NSAIDs), disease-modifying antirheumatic drugs, and corticosteroids.
• Ocular disease
For cases of dry eye, artificial tear substitutes and lubricating ointments, topical steroids, or topical cyclosporin A 0.05-2% drops should be used. Temporary punctal plugs and/or permanent punctal occlusion with cautery or permanent tarsorrhaphy are also useful modalities for maintaining adequate ocular lubrication.
Keratitis: Topical and oral corticosteroids and topical 0.05-2% cyclosporin A drops may play a role in the treatment of RA-associated keratitis, particularly nonulcerative keratitis and infiltrative PUK. However, more severe cases may require systemic immunosuppression.
Scleritis: In mild cases, NSAIDS can be used along with, or instead of, low-dose oral steroids. Moderate-to-severe disease, including necrotizing scleritis and PUK, require systemic treatment. If patients cannot achieve disease remission with less than 10 mg of prednisone daily, steroid-sparing agents should be used. Antimetabolites (methotrexate, azathioprine, and mycophenolate mofetil), calcineurin inhibitors (cyclosporin and tacrolimus), and biologic agents (infliximab, adalimumab, and rituximab) have all been used with varying degrees of success. Although etanercept has good efficacy for the treatment of systemic RA, it is less efficacious for the treatment of the ocular disease than other biologic agents.
Nodular scleritis may be treated with injection of triamcinolone over the lesion, and some authors have reported success in treating certain types of anterior scleritis with periocular steroid injections.
Prognosis
If treated early, long-term remission can often be obtained. Acute exacerbations of the disease can be avoided with regular monitoring and titration of the dose of the immunosuppressive agent.
REFERENCES
Cao JH, Oray M, Cocho L, Foster CS. Rituximab in the Treatment of Refractory Noninfectious Scleritis. Am J Ophthalmol. 2016;164:22-28.
Gangaputra S, Newcomb CW, Liesegang TL, et al, Systemic Immunosuppressive Therapy for Eye Diseases Cohort Study. Systemic immunosuppressive therapy for eye diseases cohort study. Methotrexate for ocular inflammatory diseases. Ophthalmology. 2009;116(11):2188-2198.
Schargus M, Wolf F, Tony HP, Meyer-Ter-Vehn T, Geerling G. Correlation between tear film osmolarity, dry eye disease, and rheumatoid arthritis. Cornea. 2014;33(12):1257-1261.
Watanabe R, Ishii T, Yoshida M, et al. Ulcerative keratitis in patients with rheumatoid arthritis in the modern biologic era: a series of eight cases and literature review. Int J Rheum Dis. 2017;20(2):225-230.
 FIGURE 7-21. Rheumatoid arthritis. Diffuse scleritis is characterized by deep, tortuous, dilated scleral vessels. There is also peripheral corneal melting with iris prolapse in this case. (Courtesy of S. R. Rathinam.) |
 FIGURE 7-22. Rheumatoid arthritis. There is peripheral ulcerative keratitis in a patient with active, previously undiagnosed rheumatoid arthritis. (Courtesy of S. R. Rathinam.) |
 FIGURE 7-23. Rheumatoid arthritis. There are several large, injected nodules as well as diffuse scleritis in this patient with nodular scleritis. Posterior synechiae and a cataract are present. (Courtesy of S. R. Rathinam.) |
 FIGURE 7-24. Rheumatoid arthritis. A. Significant scleral thinning with uveal prolapse. The lack of injection is typical of scleromalacia perforans. (Courtesy of Sunir J. Garg.) B. Significant scleral thinning with an inferior scleral melt. Compared with patients with necrotizing scleritis, patients with scleromalacia perforans have relatively little scleral redness and often have minimal to no discomfort. (Courtesy of S. R. Rathinam.) |
 FIGURE 7-25. Rheumatoid arthritis. A, B. Rheumatoid arthritis (RA) is a polyarthritis that affects the small joints of the hands and feet more frequently than larger joints. The synovial inflammation leads to joint destruction. These patients have the typical finger joint deformities seen in patients with RA. Prompt and aggressive therapy can dramatically reduce this debilitating aspect of RA. C. Similar joint destruction can also occur in the feet. (Courtesy of S. R. Rathinam.) |
 FIGURE 7-26. Rheumatoid arthritis. This patient has vasculitis of the skin, which can be seen in some patients with rheumatoid arthritis. (Courtesy of S. R. Rathinam.) |
BEHÇET DISEASE
H. Nida Sen
Behçet disease, or Adamantiades-Behçet disease, is a chronic, relapsing multisystem inflammatory disorder that is characterized by intraocular inflammation, oral and mucosal ulcerations, and skin lesions.
Epidemiology and Etiology
• It is more commonly seen in patients from the Mediterranean basin and Japan, along the route of the ancient “silk road.” It also occurs in persons with Native American ancestry.
In the United States, the prevalence is 8.6 in 100,000 persons, and is as high as 25 to 400 in 100,000 in Mediterranean countries. • Ocular involvement occurs in approximately 70% of patients with Behçet disease and is typically bilateral (>70%). Posterior/panuveitis is the most common form of uveitis in these patients.
Ocular disease can be the presenting symptom in 10% to 35% of patients and is characterized by recurrent, explosive exacerbations of intraocular inflammation.
• It typically affects young adults (mean age at onset is 25 to 35 years), but it may also occur in children.
• Men are slightly more affected than women.
• Behçet is a multifactorial disease: Genetic factors, environmental factors, infectious agents, and immunologic mechanisms all have been suggested.
Affected patients have a genetic predisposition, and it has been associated with HLA-B51. Recent large population studies confirmed this association and indicated HLA-B*15, HLA-B*27, HLA-B*57, and HLA–A*26 to be independent risk factors for Behçet disease, and HLA-B*49 and HLA–A*03 to be protective for Behçet disease.
