DESCRIBE IN DETAIL SCLERAL MANIFESTATIONS IN RHEUMATIC DISEASES - CLASSIFICATION , CAUSES AND DISEASE PREVALENCE ?
A 1 INTRODUCTION
1 The term sclera is derived from a greek word " SCLEROS " meaning " HARD "
A ) sclera is an opaque , elastic and resilient tissue of the eye
B ) comprises to 90 % of the outer coat of eye
3 Failure to recognize the significance of temporal headaches indicative of temporal arteritis in patients with polymyalgia rheumatica may result in acute loss of vision with blindness.
4 In contrast, visual symptoms may only present when irreversible damage to the eye has occurred, as in the case of the insidious onset of intermediate uveitis in children with pauci-articular JCA with a positive ANA.
5 Abnormal connective tissue components such as collagen or fibrillin (in the case of Marfan’s syndrome) may lead to different forms of arthropathy and visual loss depending on the type of collagen in the tissues involved.
A ) For example, defective synthesis of type I collagen leads to osteoporosis and blue sclera in osteogenesis imperfecta.
B ) In the very rare condition of osteoporosis–pseudoglioma syndrome, where there is a mutation in the low-density lipoprotein receptor-related protein 5 (LRP5), there is an association between reduced bone mass, resulting in osteoporosis, and a defect in vitreal macrophage function with vitreal vessel regression, resulting in blindness .
C ) Patients with Stickler’s syndrome, who have a defect in the synthesis of type II A collagen, present with premature osteoarthritis requiring early joint replacement, and loss of vision due to defects in the synthesis of collagen in the vitreus, resulting in retinal detachment .
D ) Defects in the synthesis of type II B collagen results in arthrogryposis and keratoconus, in which visual loss is due to changes in physical properties of the cornea.
E ) Similarly, inflammatory disorders of the eye may be associated with different connective tissue disorders.
F ) There may be a strong association with particular genes but the phenotypic presentation may depend on the anatomical site of the ocular lesion.
1 - The classical example of this is the unilateral acute onset of anterior uveitis in patients with ankylosing spondylitis and other seronegative arthritides, associated with a high frequency of HLA B27.
2 - Each acute attack usually responds to local steroid drops and mydriatics and if promptly treated does not result in any residual damage to the eye.
3 - Genetic variations in proinflammatory mediators and their receptors appear to influence the susceptibility and severity of the inflammatory response within the eyes of patients prone to development of idiopathic acute anterior uveitis .
G ) Intermediate uveitis involves the anterior and posterior (pars plana) ciliary body, the former affected sometimes in patients with sarcoidosis, and the latter, presenting with pars planitis, may be associated with multiple sclerosis (MS).
H ) The posterior uveal tract may be involved in patients with a number of systemic diseases, including Behçet’s syndrome.
1 - This is a polygenic disease and although no clear pattern of inheritance has been established, the most closely associated risk factor is HLA B5.
2 - It is of interest that chromosome 6 contains the HLA B5 locus and in close proximity to it are several other genes related to inflammation, including tumour necrosis factor (TNF).
3 - The TNF inhibitor infliximab has demonstrated great promise in the treatment of Behçet’s disease.
4 - In Behçet’s syndrome there is not only an inflammatory process but also a thrombotic risk, possibly related to the presence of factor V Leiden.
5 - 44% of patients with retinal occlusive disease have the factor V Leiden mutation .
I ) The Vogt–Koyanagi–Harada (VKH) syndrome is a multisystem disease characterized by acute bilateral panuveitis.
1 - Patients may present with a polyarthritis but the organs that contain melanocytes are targets of inflammation, resulting in areas of depigmentation in the skin and eyebrows (poliosis).
2 - Involvement of the central nervous system with sterile meningitis and the inner ears may also be affected.
3 - Involvement of the uveal tract results in retinal detachment.
4 - VKH is considered to be an autoinflammatory disease against melanocyte antigens .
5 - VKH, like rheumatoid arthritis, is associated with HLA DR4 but the implicated HLA DR4 subtypes differ for the two diseases.
6 - Evidence suggests that a defective Fas-mediated apoptosis response is found in lymphocytes of VKH and Behçet’s disease patients .
J ) Recently there has been great interest in an autosomal dominantly inherited triad of granulomatous inflammation in the uveal tract, skin and joints in a condition called familial juvenile systemic granulomatosis or Blau syndrome.
1 - Mutations in the Nod 2/Card 15 genes were reported to be associated with familial juvenile systemic granulomatosis in four families and different mutations of the same gene are associated with Crohn’s disease.
2 - Patients with Blau syndrome present with features consistent with Crohn’s disease.
3 - The Nod 2/Card 15 gene encodes an intracellular protein that is thought to be involved in sensing intracellular bacteria and participates in important signalling cascades leading to NF-κB activation and possibly apoptosis .
4 - Nod 2 proteins specifically detect the muramyl dipeptide component of peptidoglycan, a cell wall constituent of both Gram-positive and Gram-negative bacteria .
5 - It is suggested that Nod 2 may be expressed not only in the inflammatory cells migrating to tissues (i.e. monocytes, macrophages) but also in the tissues themselves, especially cell types that are involved in gatekeeper functions during the process of inflammation with respect to the intestinal epithelium and vascular endothelium .
K ) Rheumatoid arthritis is associated with scleritis, scleromalacia perforans and corneal melt.
1 - Traditionally it was assumed that the cornea was an immunologically privileged site due to paucity of blood vessels and lymphatics.
2 - However, it is now thought that immune cells may in fact pass between the eye and the systemic vascular and lymphatic circulations but, through a process of apoptosis, become inactivated.
3 - Griffith and colleagues demonstrated that the apoptosis-inducing cell membrane molecule Fas ligand is expressed on multiple ocular cells, including the corneal epithelium and endothelium.
4 - Inflammatory cells such as neutrophils and activated T cells are especially vulnerable to apoptosis induced by Fas ligand expressed on ocular cells.
5 - Approximately 50% of the corneal grafts from donor mouse strains that expressed functional Fas ligand on the corneal epithelium and endothelium, experienced long-term survival.
6 - By contrast, rejection occurred in 89–100% of the corneal grafts prepared from mutant mice that failed to express functional Fas ligand.
7 - Thus, Fas ligand creates a functional blockade of the efferent arm of the immune response.
8 - As far as the uveal tract is concerned, there are two animal models that may have relevance to uveitis seen in the human.
A ) Endotoxin-induced uveitis was described by Rosenbaum et al. , who showed that injection of lipopolysaccharide into the footpad of rats induced an acute anterior uveitis, the cellular infiltrate being mainly neutrophils.
B ) In experimental autoimmune uveoretinitis , retinal antigens were injected into rats.
C ) The inflammation occurred in the posterior uveal tract and the dominant cell type was a CD4 lymphocyte.
D ) The treatment of inflammatory eye disease is at present somewhat controversial. With respect to peripheral ulcerative keratitis (corneal melt), the treatment of choice would appear to be cyclophosphamide given intravenously, on the basis that this probably represents a form of vasculitis .
E ) The use of TNF-α-blocking therapy in the treatment of uveitis is at present a controversial area .
F ) In a recent trial of infliximab therapy in refractory uveitis, of 31 enrolled subjects 28 reached 10 weeks in the study.
G ) etanercept, in spite of its efficacy in treating arthritis, may actually induce attacks of uveitis in patients who have not previously experienced such episodes.
H ) In a retrospective study of 16 patients with a variety of inflammatory eye and joint diseases, there was a universal benefit from TNF inhibition for the joint disease, but only a 38% response rate for the associated uveitis or scleritis, and in five patients ocular inflammation began only after etanercept therapy was started .
I ) However, Rosenbaum reported that three randomized studies on the effect of etanercept for ankylosing spondylitis provided reassuring data.
J ) However, more recently a report has indicated that in the context of juvenile chronic arthritis the use of etanercept was associated with an increase in relapse rates and first attacks of uveitis in children treated with it .
K ) A recent report of 18 patients treated with anti-TNF therapy using both infliximab and etanercept showed that 13 out of 15 patients treated with infliximab had either complete or partial control of ocular inflammation, whereas all seven patients treated with etanercept failed therapy and five of these were changed to infliximab therapy; four of these achieved either complete or partial response after initiation of infliximab treatment .
of TNF-α receptors
L ) This probably represents a neutrophil-mediated inflammatory process in comparison with the favourable effect of TNF inhibition in a T-cell mediated model of uveitis .
M ) The differential effects of infliximab versus etanercept may lie in the fact that infliximab induces cell lysis after binding to TNF-α and induces apoptosis of T lymphocytes , whereas etanercept neutralizes lymphotoxin-α.
N ) This may explain why infliximab and not etanercept is beneficial in the treatment of Crohn’s disease, but in the case of arthritis in JCA etanercept may be the drug of choice.
O ) In conclusion, we need to be aware of the association between rheumatic disorders and inflammatory eye disease, with particular reference to the site of the anatomical lesion of the eye, in terms of diagnosis and response to therapy.
1 - One particular example whereby the use of a TNF-blocking agent may be inappropriate would be in the treatment of pars planitis, which can be associated with MS.
2 - The treatment of MS with antibodies to TNF resulted in an increased rate of relapses of the underlying inflammatory disease .
3 - On the other hand, infliximab has been shown to be very effective in the treatment of cerebral and ophthalmic complications of Behçet’s disease in patients who relapse on corticosteroids and cyclosporin .
SCLERAL MANIFESTATIONS
1 SCLERITIS
A ) Scleritis is the inflammation in the episcleral and scleral tissues with injection in both superficial and deep episcleral vessels.
B ) It may involve the cornea, adjacent episclera and the uvea and thus can be vision-threatening.
C ) Scleritis is often associated with an underlying systemic disease in up to 50% of patients.
D ) Scleritis, or inflammation of the sclera, can present as a painful red eye with or without vision loss.
E ) The most common form, anterior scleritis, is defined as scleral inflammation anterior to the extraocular recti muscles.
F ) Posterior scleritis is defined as involvement of the sclera posterior to the insertion of the rectus muscles.
G ) Anterior scleritis, the most common form, can be subdivided into diffuse, nodular, or necrotizing forms.
H ) In the diffuse form, anterior scleral edema is present along with dilation of the deep episcleral vessels.
I ) The entire anterior sclera or just a portion may be involved. In nodular disease, a distinct nodule of scleral edema is present.
J ) The nodules may be single or multiple in appearance and are often tender to palpation.
K ) Necrotizing anterior scleritis is the most severe form of scleritis.
1 It is characterized by severe pain and extreme scleral tenderness.
2 Severe vasculitis as well as infarction and necrosis with exposure of the choroid may result.
3 A rare form of necrotizing anterior scleritis without pain can be called scleromalacia perforans. The sclera is notably white, avascular and thin. Both choroidal exposure and staphyloma formation may occur.
4 Posterior scleritis, although rare, can manifest as serous retinal detachment, choroidal folds, or both. There is often loss of vision as well as pain upon eye movement.
Etiology
1 There are many connective tissue disorders that are associated with scleral disease.
2 Rheumatoid arthritis is the most common.
3 It may also be infectious or surgically/trauma-induced.
4 There is no known HLA association.
Risk Factors
1 As scleritis is associated with systemic autoimmune diseases, it is more common in women.
2 It usually occurs in the fourth to sixth decades of life.
3 Men are more likely to have infectious scleritis than women.
4 Patients with a history of pterygium surgery with adjunctive mitomycin C administration or beta irradiation are at higher risk of infectious scleritis due to defects in the overlying conjunctiva from calcific plaque formation and scleral necrosis.
5 Bilateral scleritis is more often seen in patients with rheumatic disease.
6 Two or more surgical procedures may be associated with the onset of surgically induced scleritis.
Pathophysiology
1 As there are different forms of scleritis, the pathophysiology is also varied.
2 Scleritis associated with autoimmune disease is characterized by zonal necrosis of the sclera surrounded by granulomatous inflammation and vasculitis.
3 Eosinophilic fibrinoid material may be found at the center of the granuloma.
4 These eyes may exhibit vasculitis with fibrinoid necrosis and neutrophil invasion of the vessel wall.
5 There is an increase in inflammatory cells including T-cells of all types and macrophages.
6 T-cells and macrophages tend to infiltrate the deep episcleral tissue with clusters of B-cells in perivascular areas.
7 There may be cell-mediated immune response as there is increased HLA-DR expression as well as increased IL-2 receptor expression on the T-cells.
8 Plasma cells may be involved in the production of matrix metalloproteinases and TNF-alpha.
9 In idiopathic necrotizing scleritis, there may be small foci of scleral necrosis and mainly nongranulomatous inflammation with mainly mononuclear cells (lymphocytes, plasma cells and macrophages).
10 Microabscesses may be found in addition to necrotizing inflammation in infectious scleritis.
11 Vasculitis is not prominent in non-necrotizing scleritis.
CLASSIFICATION
1 is proposed by Watson and Hayreh and is widely accepted
2 broadly divided Into 2
1 EPISCLERITIS - NODULAR OR DIFFUSE
2 SCLERITIS - ANTERIOR AND POSTERIOR
ANTERIOR DIVIDED INTO NECROTIZING AND NON NECROTIZING
NECROTIZING INTO WITH INFLAMMATION AND WITHOUT INFLAMMATION
NON NECROTIZING INTO DIFFUSE AND NODULAR
3 since sclera is mainly dependent on episclera providing a response to an inflammatory stimuli , scleritis is always accompanied with episcleritis however episcleritis is not always accompanied with scleritis
CAUSES
1 INFECTIOUS - A ) most commonly caused by pseudomonas aeruginosa
B ) endogenous spread of bacteria , fungi ( aspergillus ) , viruses ( herpes simplex , herpes zoster ) or parasites ( toxocara , toxoplasmosis , onchocerciasis )
C ) occurs most commonly in association with injury or surgical trauma
D ) also associated with excision of pterygium
E ) adjuvant therapies like mitomycin C or beta irradiation is associated with increased risk of infection
2 SYSTEMIC
A ) RHEUMATOID ARTHRITIS - woman are affected 3 times more than man mostly aged 40 to 60 yrs of age
Episcleritis is associated in 5 % of cases
Is the most common systemic association
17 to 30 % of all patients with scleritis is associated with it whereas 0.2 to 6.3 % of RA is associated with scleritis
B ) WEGNER GRANULOMATOSIS - anybody at any age is affected
15 % of population is affected
The orbit is specifically affected with proptosis - only systemic inflammatory disease associated with proptosis
Is associated with compressive optic neuropathy
is also associated with cellulitis secondary to excessive sinus involvement
C ) RELAPSING PERICHONDRITIS
D ) SYSTEMIC LUPUS ERYTHEMATOSUS - scleritis is associated with 5 % of cases
E ) POLYARTERITIS NODOSA - similar to SLE
F ) PRIMARY SJOGREN SYNDROME
G ) SCLERODERMA
H ) SYSTEMIC VASCULITIS - POLYARTERITIS NODOSA , CHURG STRAUSS SYNDROME , TAKAYASU ARTERITIS , GIANT CELL ARTERITIS , COGAN SYNDROME
I ) REACTIVE ARTHRITIS - conjunctivitis
J ) PSORIATIC ARTHRITIS - conjunctivitis
3 MALIGNANCIES
1 ) ocular adnexal lymphoproliferative lesions
2 ) intraocular tumors