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Eular On-line Course on Rheumatic Diseases module n25 Hasan Yazici, Izzet Fresko, Nicole Stbiger

BEHETS DISEASE POLYCHONDRITIS EYE SYMPTOMS IN RHEUMATIC DISEASES


BEHETS DISEASE
HASAN YAZICI MD - IZZET FRESKO MD DIVISION OF RHEUMATOLOGY, DEPARTMENT OF MEDICINE CERRAHPAA MEDICAL FACULTY UNIVERSITY OF ISTANBUL

LEARNING OUTCOMES
Global learning outcome This module will enable the participant to understand, classify and treat patients with Behcets syndrome. Specific learning outcomes To recognize the signs and symptoms of Behets syndrome To describe the distinct geographical distribution of the syndrome related to the ancient Silk Road and its special place among the vasculitides To suggest a differential diagnosis, which is especially important for areas where the syndrome is rare To describe the natural course and the prognostic aspects of the various manifestations To evaluate treatment modalities giving due consideration to evidence stemming from relatively sparse formal studies To plan an individual treatment strategy according to age, gender and to the sites involved

INTRODUCTION
Although there has been a global interest in Behets Syndrome (BS) during the last 2 decades, the condition has been recognized since antiquity. Initial descriptions by Hippocrates have been followed by the seminal paper by Hulusi Behet, a professor of dermatovenereology at the University of Istanbul, in the 1930s (1). He followed three patients for seventeen years and defined the syndrome as the tri-symptom complex of oral aphthae, genital ulcerations and hypopyon uveitis. Later work showed that many other organ systems were also involved. There is a debate whether the entity described by Behet is better designated as a disease or a syndrome. The authors prefer the latter in that we do not know the pathogenesis nor is there a definitive diagnostic test.

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Eular On-line Course on Rheumatic Diseases module n25 Hasan Yazici, Izzet Fresko, Nicole Stbiger

I- EPIDEMIOLOGY
BS has a distinct geographical distribution. Most of the cases are from the countries around the Mediterranean basin and Japan. It is rare in Northern Europe, Northern Asia, most of the continental Africa, Australia and the Americas. Travel along The Silk Route has been implicated as the mechanism through which an etiological agent (eg: genetic or environmental) was spread. Even though it can affect every age group, onset before puberty (2) or after the sixth decade is relatively rare. The usual onset is in the third decade. The condition is frequent in the Middle East (i.e 1/250 of the adult population in Turkey) and the Far East whereas it is rare in Europe and North America. Similarly few cases have been reported from Africa (except along its Mediterranean coast) and Australia. (3,4,5,6). Some of the manifestations of BS also show regional differences. Gastrointestinal findings are common in Japanese patients while they are rather infrequent in Turkey (7) and the Middle East. The same is true for pathergy, the non-specific hypersensitivity of the skin to a needle prick, which is less commonly positive in North European and United States patients (8).

II- CLINICAL FINDINGS


It is usually said that BS is a systemic vasculitis that affects many organs. On the other hand in many instances (i.e parenchymal CNS disease) a true vasculitis cannot be demonstrated (9). Thus a better designation would be to name the condition as a systemic inflammation. Skin and mucosa lesions, uveitis, major vessel disease, musculoskeletal, neurological and gastrointestinal manifestations are observed in varying combinations. The diagnosis is clinical and a course characterized by remissions and exacerbations is typical. The intensity of the attacks decreases with the passage of time. Table 1 shows the frequency of the main clinical manifestations. Table n1 - Frequency of clinical manifestations of BS Frequency Manifestation Oral ulcers 97-99% Genital ulcers ~85% Scar ~50% (likely more prevalent in males) Skin lesions ~85% Papulopustular lesions ~50% Erythema nodosum ~60% (Mediterranean countries and Pathergy reaction Japan) ~50% Uveitis Arthritis 30-50% Subcutaneous 25% thrombophlebitis Deep vein thrombosis ~5% ~4% Arterial occlusion/ aneurysm CNS involvement ~5% Epididymitis ~5% 1-30% (more prevalent in Japan) Gastrointestinal lesions

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III- MUCOCUTANOUS FINDINGS III-1 Oral ulcers


Oral ulcers are seen in 98% of the patients and are frequently the first disease manifestation (Fig. 1). They resemble ordinary canker sores; however they are more frequent and multiple. They frequently appear as erythematous, circular, and slightly raised areas evolving into oval or round ulcers within 48 hours. They have traditionally been defined as minor, major and herpetiform according to their sizes and locations but more than 90% are of the minor type. They are less than 10 mm in diameter and are frequently observed on the mucous membranes of the lips, gingiva, cheeks, and tongue, perhaps more posteriorly (10) than the ordinary canker sores, seen in ~15 % of the normal population. They usually heal in about 15 days without scarring. Tobacco use decreases its prevalence and cessation of smoking seems to exacerbate it (11). Figure 1 - Oral ulcers in Behet's syndrome

III-2 Genital ulcers


Genital ulcers are usually located on the scrotum in males and on the major and minor labiae in females. Less frequent localizations are the shaft and glans penis and the vaginal and cervical areas. The inguinal area, pubis and perineum are occasionally affected in both sexes. They usually begin as papules or pustules that ulcerate in a short time (Fig. 2). Compared to oral ulcers, they are larger, deeper, less recurrent and more resistant to healing. They usually heal in 10-30 days if they are not secondarily infected and leave scars in about 60% of the patients. Scar formation is more frequent if the diameter of the ulcer is more than 1 cm (12). Genital scarring is usually good evidence of BS in a patient suspected of having this syndrome.

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Figure 2 - Genital ulcers in Behet's Syndrome

III-3 Other skin lesions


The other types of skin lesions can be divided into three broad categories: 1) Erythema nodosum like lesions and superficial thrombophlebitis, 2) papulopustular lesions and 3) other lesions such as skin ulcers and Sweets syndrome. Erythema nodosum like lesions are observed in 50 % of the patients and morphologically resemble the idiopathic or secondary variants (Fig. 3). Histopathology shows more evidence vasculitis in lesions associated with BD compared to lesions due to other causes (13). The superficial thrombophlebitis looks like erythema nodosum. It is more common in males and is characterized by a thrombosed vein on biopsy. Ultrasonography may differentiate the two. The papulopustular lesions resemble ordinary acne (Fig. 4). They are seen at the usual acne sites such as the face, upper chest and back and additionally on the legs and arms. They are usually colonized by Staphylococcus aureus and Provotella species and are more common in a subgroup of patient with arthritis (14,15). Skin ulcers and the Sweet syndrome may occasionally be observed.

IV- PATHERGY
The pathergy phenomenon is a non-specific hyperreactivity in response to minor trauma. Although it has a moderate sensitivity (~50%), it is quite specific for BS (~98%) . It is usually used as a diagnostic test and is performed by an inserting a 20 gauge needle into the dermis of the forearm of the patients. The formation of a papule or pustule at 48 hours is considered positive (Fig. 5). The rate of positivity is not related to the severity or the site of involvement (16) although male patients tend to have stronger reactions (17). It also has a limited reproducibility and may vary in intensity in the same patient if performed repeatedly. It is a useful test in the Mediterranean, Near and Far Eastern countries whereas it is not beneficial in Continental Europe or the Americas due to its lower rate of positivity.

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Figure 3 - Erythema nodosum-like lesion in Behet's Syndrome

Figure 4 - Ostiofolliculitis in Behet's Syndrome

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Figure 5 - Positive pathergy reaction

V- EYE INVOLVEMENT
Eye involvement in BS causes serious morbidity and is a common cause of blindness in the Mediterranean basin, Middle East and the Far East. It is observed in 50% of the patients but the frequency reaches 70% in the young male aged less than 25. It is usually observed during the first 2 years of the syndrome and is bilateral in 70-80% of the patients (18,19). The main clinical picture is a pan-uveitis not infrequently accompanied by a retinal vasculitis. Hypopyon formation (Fig. 6), which is a collection of pus in the anterior segment, is seen in about 20% of the patients with eye involvement and is nearly always accompanied by additional posterior inflammation. Isolated anterior involvement is not frequent and findings such as conjunctivitis, corneal ulcerations and scleritis are rare occurrences. Recurrent bouts of inflammation lead to structural damage characterized by posterior synechia, complicated cataracts, optic atrophy and macular degeneration. Total loss of vision is seen in 20% of the cases with uveitis, even after treatment. Ophthalmological consultation with indirect ophthalmoscopic and slit lamp examination is a must for every patient with vision problems since correct diagnosis and the prevention of ocular attacks are the most effective means to prevent blindness.

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Figure 6 - Hypopyon uveitis in a patient with Behet's Syndrome

VI- CENTRAL NERVOUS SYSTEM DISEASE


Neurological involvement is seen in among ~5% of the patients with BS. It is usually observed ~5 years after the onset of the other manifestations and is nearly never the initial finding. There are two main patterns of involvement: 1) Parenchymal (80%) 2) Non-parenchymal (20%). Parenchymal involvement is characterized by non-specific inflammatory lesions and varying degrees of apoptosis on the brain-stem, diencephalon, basal ganglia and less frequently on the spinal cord and the cerebellum. The cerebral cortices seem to be spared. It is usually manifested by bilateral pyramidal signs, unilateral hemiparesis, behavioural changes, sphincter disturbances and headache (20). Brainstem signs and sensory disturbances are less common. Abnormal cerebrospinal fluid (CSF) findings such as pleocytosis and increased cellularity are found in 60% of the patients with parenchymal involvement. MR is more sensitive than CT in imaging and the characteristic lesion is a pathological signal in the brainstem and basal ganglia regions (21) (Fig. 7). Frequent attacks, a progressive course and abnormal CSF findings are signs of bad prognosis. Approximately 25% of the patients in this category will have some sort of disability in 10 years. Patients with non-parenchymal involvement have dural sinus thrombi (Fig. 8), mainly characterized by headache and papilledema. It is usually associated with deep vein thrombi in other areas and has a better prognosis than parenchymal involvement. The presence of headache in a patient should not be ascribed to neurological involvement unless it is associated with neurological symptoms since tension type headaches are common in patients with BS (22).

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Figure 7 - MR of a parenchymal CNS involvement in a patient with Behet's syndrome

Figure 8 - MR of a dural sinus trombosis in a patient with Behet's syndrome

VII- MAJOR VESSEL INVOLVEMENT


BS involves the large vessels of both the arterial and venous sides. The major vascular disease usually starts later than the development of eye disease which has its onset most commonly within a year or two (18), if not at the same time, of diagnosis. It is mainly seen in males and it is observed in 40-50% of the patients. Sixty to 80% of these lesions are venous thromboses of deep veins of the lower extremities. Inferior and superior vena cavae, dural sinuses, axillary, brachial, hepatic and portal veins are affected less frequently (23).
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Chronic recurrent thrombosis of lower extremity leads to erythema, dermatitis, hyperpigmentation and subsequently to crural ulcers (Fig. 9). Chronic obliteration of the caval systems leads to venous collaterals on the thoracic and abdominal walls. Obstruction of superior vena cava may also cause oesophageal varices, chylothorax and chylous pericardial effusions. Budd-Chiari syndrome from hepatic vein occlusion presents with ascites or liver failure. It is a rare complication of BS, but carries a high mortality rate. One should be aware that venous thrombi may impend and precede arterial inflammation in BS. Arterial involvement may be seen in 1.5-7.5 % of the patients (18). They are aneurysmal, or uncommonly, occlusive. The abdominal aorta is the most frequently affected site followed by the iliac, femoral, popliteal, carotid and subclavian vessels. Renal, cerebral or coronary arteritis and abdominal visceral ischemia are uncommon. Peripheral arterial involvement causes reduced or absent pulses with intermittent claudication, cold extremities or even gangrene. Abdominal aortic aneurysms sometimes produce abdominal pain. Bruits can be heard over the affected large arteries and a pulsating mass may be found. Most patients with arterial lesions have constitutional signs and symptoms, such as fever and weight loss. Pulmonary arterial aneurysms are one of the most devastating complications of arterial involvement in BS. They are usually seen in the young male patient who already has thrombosis of the leg veins or the vena cavae and are manifested by recurrent hemoptysis, dyspnea and pleuritic chest pain. The rupture of an aneurysm had a 50% of mortality rate in the 80s that decreased to 20% during the recent years due to earlier recognition and the more rational use of immunosuppressives (24,25). Para or perihilar non-cavitating opacities are found on chest X rays (Fig. 10) and CTs and pulmonary angiograms show a single or multiple aneurysms in the pulmonary arteries. One should be aware that a ventilation-perfusion scan may mimic pulmonary embolism although the ventilation-perfusion defect is due to aneurysms. The thrombi in BS do not embolize presumably due to their sticky nature and their tight adherence to inflamed veins. Figure 9 - Chronic thrombosis and a skin ulcer in a patient with Behet's syndrome with long standing deep vein thrombosis

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Figure 10 - An x-ray of bilateral pulmonary artery aneurysms in a patient with Behet's syndrome

VIII- MUSCULOSKELETAL MANIFESTATIONS


Arthritis or arthralgia is seen in about 50% of the patients along the course of the disease (26). It may precede the other findings by months or years and is usually manifested as an oligoarthritis involving, in decreasing order, the knees, ankles, hands and wrists. It is usually a superficial synovitis that resolves in a couple of days to weeks. Deformities are not usual although they may rarely occur. Synovial fluid examination reveals a mild inflammation dominated by polymorphonuclear leukocytes but the mucin clot is normal. Sacroiliitis is not a prominent part of the clinical picture (27), but the coexistence of acne, arthritis and enthesopathies suggest that at least a subgroup of the patients have reactive arthritis like features (15). Fibromyalgia and local inflammatory myositis confined to the leg are occasionally observed.

IX- GASTROINTESTINAL INVOLVEMENT


This is a frequent finding in the patients in the Far East whereas it usually is not a prominent manifestation in patients from the Middle East. It is characterized by mucosal ulcerations that resemble those found in inflammatory bowel diseases with normal intervening mucosa (7). Threefourths of the ulcerations are found in the terminal ileum and the caecum whereas the remaining are found in the oesophagus, stomach and duodenum. Rectal involvement is rare. The patients complain of vomiting, abdominal pain and diarrhea. A mass is often palpable in the abdomen during exacerbations and ileocecal perforations may occur. It is sometimes difficult to distinguish the findings from Crohns disease but the coexistence of findings of Behets along with milder enteroclysis findings such as the absence of scalloping, ulceronodular pattern, abscess and fistula formation differentiate the two conditions (28).

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X- UROLOGICAL PROBLEMS
The three problems related to the genitourinary system in BS are epididymitis, cystitis and erectile dysfunction. Epididymitis is seen in about 20% of male patients and is manifested as testicular pain (29). A neurogenic bladder can be seen with or without a demonstrable lesion in the spinal cord (30). Erectile dysfunction is seen in 2/3 of the patients with neurological involvement.

XI- OTHER MANIFESTATIONS


The heart is rarely involved during the course of BS. Various conduction abnormalities and valvular problems are occasionally seen. One peculiar manifestation is right sided endomyocardial fibrosis with intracardiac thrombi; a finding observed in males with widespread vascular disease (31). Glomerulonephritis is occasionally observed with underlying lesions ranging from IgA nephropathy to rapidly progressive inflammation (32). Immune complexes are not commonly observed. Secondary amyloidosis of the AA type has been reported in 0.04 to 3% of the patients. It is predominantly seen in males, is closely associated with large vessel disease and arthritis, and has a mortality of over 50% within three and a half years after onset (33).

XII- HISTOPATHOLOGY
BS involves vessels of all sizes, both on the arterial and the venous side (34). In some of these lesions direct injury to the vessel wall can be observed like in oral, genital ulcers, leuokocytoclastic skin lesions (35) erythema nodosum like lesions (13) or in local myositis (36). One also obviously sees the evidence of vascular injury directly in the associated uveitis or histologically in major vascular disease like in arterial aneurysms or major vein occlusions (37). On the other hand there are some lesions that a direct evidence of injury to the vascular wall cannot be shown. Among these are the acne lesions of the skin, where histology is no different than ordinary acne (38) and in brain, where evidence for direct vessel wall injury is difficult to find (39). There is no specific cell type that dominates in vasculitic lesions and immune complex deposition can only be seen in some (40).

XIII- PATHOGENESIS
The pathogenesis of BS remains unclear. Immunological mechanisms and uncontrolled inflammation play a major role. Family studies have provided evidence for a genetic predisposition. The sibling recurrence risk ratio has been estimated to be between 11 and 53 implying a genetic influence on disease expression (41). Although an autosomal recessive inheritance pattern has been suggested among the paediatric patients (42) Mendelian inheritance patterns seem not to be operative. HLA-B51 has been the most consistently reported HLA association. Potential non HLA loci on chromosomes 6p22-23 and 12p12-13 have also been suggested (43). Some have included BS among the autoimmune diseases. The arguments against it are: 1) Clinical and laboratory findings usually found in autoimmune diseases, like Raynauds phenomenon, serosal involvement, sun hypersensitivity, thrombocytopenia, hemolytic anemia, are usually not seen in BS. Most importantly there is no association with Sjgrens syndrome. 2) There is no increased prevalence of autoimmune diseases neither among the patients nor in their families. 3) The HLA association of BS, HLA B51 is not found in autoimmune diseases. On the other hand the usual autoimmune disease associated alleles and haplotypes are not found in BS. 4) Although there is evidence of some polyclonal activation there is no specific association with B cell hyper reactivity (44).
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The absence of the classical features of autoimmunity alongside with the paucity of specific antibodies have led to the suggestion that BS is perhaps an auto inflammatory disorder (45). On the other hand there is no association with the mutations that are usually implicated in the disorders (eg. CARD, MEVF and NOD) that are also classified as auto inflammatory, the syndrome is more frequent than the classical auto inflammatory conditions and the tendency of BS to abate with time does not seem to be present in the nature of these entities (46). A recent review has proposed that both innate and adaptive immune systems are involved in the pathogenesis (47). The mechanisms of responses from innate to adaptive immunity have been summarized as a) a persistent bacterial stimuli activating adaptive immune responses through pattern recognition receptors b) uncontrolled innate-related inflammation c) neutrophil activation with T-cell derived chemokines (CXCL-8) d) defective neutrophil apoptotic clearance and bacterial defence with mannose-binding lectin deficiency e) bacterial gamma delta T cell activation and antigen presentation f) HLA-B51 associated responses such as the presentation of BS related peptide to CD8+ cytotoxic cells, HLAB common peptide activation of CD4+ T cells and Bw4 associated NK receptor activation . There is evidence that the clinical picture is not homogenous and that there are various clusters of disease expression. A factor analyis has shown that acne and arthritis, superficial thrombophlebitis and deep vein thrombosis, oral ulcers along with genital ulcers and erythema nodosum are examples of such clusters (48). This may additionally suggest that different mechanisms are operating in the pathogenesis of the various subgroups. The etiology of the thrombophlebitis has been the subject of controversy since some claim that it is the result of procoagulant factors whether others think that it is caused by endothelial inflammation. Recent work has shown that none of the procoagulant factors are definitely associated with the thrombotic tendency observed in BS (49,50).

XIV- LABORATORY FINDINGS AND DIFFERENTIAL DIAGNOSIS


A mild anemia of chronic disease and neutrophilic leucocytosis are observed in 15% of the patients, but they do not correlate with the clinical activity of the disease. The erythrocyte sedimentation (ESR) rate and the C-reactive protein (CRP) may be moderatly elevated; the latter may correlate with erythema nodosum and acute thrombophlebitis (51). Rheumatoid factors and antinuclear antibodies are absent and tests for anti-neutrophil cytoplasmic antibodies (ANCA) are usually negative. Patients with BS who have gastrointestinal involvement seem to have high levels of Anti-Saccharomyces Cerevisiae Antibodies (ASCA) although larger numbers of patients are needed to confirm this (52). A group of physicians involved in the care of large numbers of patients with BS formed an International Study Group (ISG) and in 1990 published the ISG Criteria of Diagnosis of Behcets Disease (Table 2). After determining the sensitivity and specificity of the various findings, a set of criteria emerged that seemed to perform better than all the previously proposed criteria (53). Oral ulceration was the sine qua non, as its presence was almost universal. However one must be aware of the fact that the utility of the criteria is dependent on the prevalence of the syndrome on the background population. There may be atypical patients who do not fulfil the criteria. Important considerations in the differential diagnosis are summarized in Table 3 (54).

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Table n2 - International Study Group Criteria for diagnosis of Behets disease Definition Manifestation Minor apthous, major aphthous or herpetiform Recurrent oral ulceration ulcers observed by a physician or reported reliably by patient Recurrent at least three times in one 12-month period plus any 2 of the following findings Recurrent genital aphthous ulceration or Recurrent genital ulceration sacrring, observed by a physician or reported reliably by patient Anterior uveitis, posterior uveitis, or cells in Eye lesions vitreous on slit-lamp examination; or retainal vasculitis observed by qualified physician (ophthalmologist) Erythema nodosum-like lesions observed by a Skin lesions physician or reported reliably by patient, pseudofolliculitis or papulopustular lesions; or acneiform nodules observed by a physician in postadolescent patients not receiving corticosteroids Test interpreted as positive by a physician at Positive pathergy test 24-48 hours, performed with oblique insertion of a 20-gauge or smaller needle under sterile conditions

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Table n3 - Highlights of the clinical manifestations of BS and differential diagnosis (44) Clinical features Area affected Mouth ulcers Majority similar to common aphthous ulcers regarding appearance, localisation and discomfort/pain; more frequent and frequently multiple; may scar Genital ulcers Most commonly scrotal or vulval , painful, recurrent and usually with scarring; Urethral discharge and penile lesions very rare Acneiform lesions as common acne in appearance and histology but also at Skin uncommon sites such as the extremities; Erythema nodosum like lesions leaving pigmentation Not Psoriasis Panuveitis and retinal vasculitis, usually bilateral occurring within about two Eyes years of the onset of the disease; Conjunctivitis and sicca syndrome most unusual Monarthritis in 50%, otherwise oligoarticular or polyarticular involving relatively Joints few joints; may be symmetrical; knees most frequently; intermittent resolving in 2-4 weeks or chronic and continuous; not involving sacroiliac joints or spine; deformity and erosions rare, synovial fluid usually inflammatory with good mucin clot. Subclinical peripheral large vein disease uncommon, usually involves large Peripheral arterial and venous disease segments with skip areas without embolisation; arteritis with occlusion and/or pseudo-aneurysms; microaneurysms of the polyarteritic type very uncommon Peripheral neuropathy and isolated cerebellar involvement very unusual, Neurological headaches with dural sinus thrombosis; vascular CNS lesions including involvement transverse myelitis-type manifestation; Multiple sclerosis with aphthous ulcers a problem but no plaques on MRI Haemoptysis associated with pulmonary arterial aneurysm; pulmonary artery Pulmonary occlusion; pleural involvement uncommon; interstitial involvement very rare involvement Severe abdominal pain; ulcerative lesions at any level but mainly in the Gastrointestinal ileocaecal region; mild GI symptoms should not be associated with BS involvement Pericarditis, valve lesions and coronary artery involvement uncommon; rarely Cardiac disease intracardiac thrombi

XV- PROGNOSIS AND MANAGEMENT


The mortality and morbidity of the syndrome is high in young male patients. Females have less severe disease than males. The main reasons of mortality are major vessel disease and especially pulmonary artery aneurysms and neurological involvement. Eye inflammation and its greatest damage occurs during the first two years. The disease abates after 40 years of age but central nervous system involvement and major vessel disease may have a late onset (5 to 10 years after diagnosis). Loss of useful vision ensues in about 20% of the patients despite therapy (18,19). Mortality, quite different from what is observed in SLE and RA, decreases in BS along the disease course (18). This might be related to a. a self-abating disease activity and b. an absence of accelerated atherosclerosis, well known to be associated with the increased late mortality in classical autoimmune diseases. Both seem to be true for BS. Many from an initial cohort of BS patients would not fulfil any of the diagnostic criteria when surveyed 20 years later (18) and preliminary evidence does not indicate accelerated atherosclerosis in BS (55).
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A recent study of pulmonary arterial aneurysms has shown that the mortality has decreased form 50% to around 20% in the last decade due to earlier recognition or more rational use of immunosuppressives (25). Therapeutic options range from simple reassurance to aggressive immunosuppression, depending on the signs and symptoms and the individual needs of the patient. Young male patients have to be managed more aggressively since they have the highest morbidity and mortality. The approach to the management of the systemic manifestations can be summarized as below.

XVI- MUCOCUTANEOUS MANIFESTATIONS


Oral and genital ulcers cause pain and interfere with the quality of life. They may lead to difficulty in swallowing and walking. Most of them can be managed by topical glucocorticoids and reassurance but systemic therapy may be required in a substantial number of cases. Colchicine has frequently been used for this problem. However a two year double blind study showed that it was ineffective for oral ulcers. It was equally effective in both sexes for arthritis, but it was beneficial for genital ulcers and erythema nodosum only in the female (56). This was probably due to the more severe course of the disease in males. The usual maximum tolerated dose of colchicine is 1.5 mg/day. A 24 week, double masked, placebo controlled trial compared 100mg/day and 300mg/day of thalidomide with placebo (57). All mucocutaneous symptoms responded to both doses of thalidomide, but the findings recurred after the drug was stopped. There was also a paradoxical increase in the frequency of nodular lesions during the first 8 weeks of the trial. Peripheral neuropathy, the principal toxic effect of the drug, was usually observed in elderly females and was not a major problem. Thalidomide seems to be an effective drug but its use is limited because of its potential teratogenicity. Patients resistant to conventional therapy may be managed by brief courses of prednisolone (20 mg/day) or azathioprine (2.5 mg/kg/day). A recent study evaluated the effect of depot glucocorticoids (40 mg methylprednisolone acetate) every 3 weeks for 27 weeks) on mucocutaneous findings. They were useful only in controlling erythema nodosum lesions especially among the females but were not effective in males (58). Various antibiotics have also been claimed to be effective in suppressing mucocutaneous findings and arthritis with the rationale of eradicating streptococci implicated in the pathogenesis. A prospective study reported favourable results with penicillin (59). The combination of benzathine penicillin with colchicine has been reported to be superior to colchicine alone in managing mucocutaneous and arthritic episodes of BS. Further controlled trials with antibiotics are required before their use can be recommended. TNF- blockers have increasingly been used in the treatment of BS. A controlled, 4 week trial with etanercept among male patients showed that it was effective in controlling most of the mucocutaneous manifestations of BS while it did not suppress the pathergy phenomenon (60).

XVII- JOINT INVOLVEMENT


The arthritis of BS is usually self-limited. Non-steroidal anti-inflammatory drugs and local corticosteroid injections are not very beneficial, but colchicine seems to be helpful in both sexes (56). Brief courses of oral prednisolone (20-30 mg/day) may be tried in patients who have protracted symptoms. Interferon-alpha seems to be effective but the cost of the drug, the absence of a standardized dose and the toxic effects, limit its utilization.

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XVIII- OCULAR INVOLVEMENT


Azathioprine was one of the first drugs that was extensively evaluated for eye disease. It was effective in controlling eye disease at a dose of 2.5 mg/kg/day (61). It was also superior to placebo in preventing progression from unilateral to bilateral eye disease and in decreasing the use of glucocorticoids in patients who had established eye disease. Patients enrolled in the initial study with azathioprine were re-analyzed with the aim of determining the long term effects of the drug. After 8 years, patients who were on azathioprine were still doing better (in terms of emergence of blindness, drop in visual acuity and extraocular complications) than patients who had received placebo (62). The outcome was even better for patients allocated to azathioprine within the first 2 years of eye involvement. This raises the question whether young male patients without eye disease should be treated with this drug without waiting for its emergence. Another immunosuppressive drug that has been consistently utilized since the 1980s is cyclosporin A (CsA). It was found to be superior to monthly pulses of cyclophosphamide in a single blinded study conducted in a limited number of patients (63). It induces a very rapid anti-inflammatory effect in doses of 2-5 mg/kg/day but care is required to monitor its toxic effects such as rises in serum creatinine, hypertension, occasional episodes of neuropathy and hearing loss. Based on evidence from transplantation studies and a retrospective study in BS, its use is not recommended in CNS disease (64). One group regularly combines azathioprine and CsA in cases of severe uveitis with promising results. Alpha interferon has also been used in the uveitis of BD. A retrospective survey of this drug showed that 94% of the patients with uveitis who used the drug exhibited a partial or complete response. The drug was beneficial even in resistant posterior uveitis. Side effects were dose-dependent (65). These results should be interpreted with caution however because the data are mainly uncontrolled and there is no consensus on the dose of interferon. Emerging data suggest that TNF- blockage, either with monoclonal antibodies to TNF- or with soluble TNF- receptors, are effective in BS. The anti-TNF monoclonal antibody infliximab at 5 mg/ kg exerts rapid control of severe and resistant uveitis but relapses necessitate continuous treatment (66,67,68). Many ophthalmologists use glucocorticoids but there are no controlled trials evaluating their efficacy in eye disease. Glucocorticoids should be used as briefly as possible and should be tapered as soon as another immunosuppressive is added to the regimen. Local corticoid eye drops combined with mydriatics are also used during acute attacks with the additional aim of preventing synechiae. Vitrectomy and cataract surgery do not seem to add much to the maintenance of vision in BS. Reports on the beneficial effects of photocoagulation certainly need further evaluation.

XIX- MAJOR VESSEL DISEASE


An important clinical point concerning vascular disease is the relative absence of embolic phenomena in spite of the thrombotic episodes. The role of anticoagulation in deep vein thrombosis has not been evaluated in a controlled study and its use is controversial. Limited experience with fibrinolytic therapy has also been mostly disappointing. Arterial disease in BS causes substantial morbidity and mortality. Aneurysms of the peripheral arteries should be corrected surgically although there is a recurrence rate of about 30% (69). The recommended adjunctive medical treatment consists of monthly pulses of cyclophosphamide combined with 1mg/kg of prednisolone with tapering in the course of a few months to a dose below 30 mg/day.
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The medical management of pulmonary arterial aneurysms should consist of the same regimen. Anticoagulation is contraindicated because of the risk of bleeding and surgical repair should not be performed because of the high risk of mortality. Intra-arterial embolization may be tried in resistant cases although long term complications may occur (70) Endovascular surgery may also be beneficial in major arterial and venous disease.

XX- CENTRAL NERVOUS SYSTEM DISEASE


There are no controlled studies evaluating the management of CNS disease in BS. Thrombosis of the dural sinuses and increased intracranial pressure is empirically and successfully treated with 1g of methylprednisolone administration daily for 3-5 days, followed by oral maintenance. Parenchymal involvement is usually treated with cyclophosphamide or azathioprine combined with glucocorticoids. CyA is usually avoided unless severe eye disease necessitates its use- because of its potential neurotoxicity (64). Chlorambucil, claimed beneficial by some (71) has not found wide use mainly due to its rather pronounced myelotoxicity. An open trial in a small number of patients suggests that low dose oral methotrexate (7.5-12.5 mg/week) stops the progression of chronic neurological involvement (72), but larger studies are needed to confirm this. A few case reports suggest that the TNF- blocker infliximab is beneficial in treating parenchymal neurological disease, refractory to other medications (73).

XXI- GASTROINTESTINAL DISEASE


Sulphasalazine at a dose of 2-4 gr/day has produced no firm evidence of efficacy. Thalidomide seems to be effective in healing the ulcers of certain patients (74). Surgical repair should be instituted in case of resistant ulcerations and perforations. Small case series suggest that the TNF- blocker infliximab is beneficial in treating refractory cases of gastrointestinal involvement of BS (75). In summary, in our day, we are definitely not doing bad in treating the eye disease and the mucocutaneous manifestations of BS. However our management of CNS disease, and the major vascular complications, including the thrombotic events, is still wanting.

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REFERENCES
1. Saylan T (1997). Life story of Dr. Hulusi Behcet. Yonsei Medical Journal 38(6): 327-32. 2. Kone-Paut I, Yurdakul S, Bahabri SA, Shafae N, Ozen S, Ozdogan H, Bernard JL (1998). Clinical features of Behcet's disease in children: an international collaborative study of 86 cases. Journal of Pediatrics 132(4):721-5. 3. Yurdakul S, Gunaydin I, Tuzun Y, Tankurt N, Pazarli H, Ozyazgan Y, Yazici H (1988). The prevalence of Behcet's syndrome in a rural area in northern Turkey. Journal of Rheumatology 15(5):820-2. 4. Azizlerli G, Kose AA, Sarica R, Gul A, Tutkun IT, Kulac M, Tunc R, Urgancioglu M, Disci R (2003). Prevalence of Behcet's disease in Istanbul, Turkey. International Journal of Dermatology 42(10):803-6. 5. Shimizu T, Ehrlich GE, Inaba G, Hayashi K (1979). Behcets disease. Seminars in Arthritis and Rheumatism. 8(4): 223-60. 6. Gonzalez-Gay MA, Garcia-Porrua C, Branas F, Lopez-Lazaro L, Olivieri I (2000). Epidemiologic and clinical aspects of Behcet's disease in a defined area of Northwestern Spain, 1988-1997 Journal of Rheumatology.27(3):703-7. 7. Yurdakul S, Tuzuner N, Yurdakul I, Hamuryudan V, Yazici H (1996). Gastrointestinal involvement in Behcet's syndrome: a controlled study. Annals of the Rheumatic Diseases 55(3):208-10. 8. Yazici H, Chamberlain MA, Tuzun Y, Yurdakul S, Muftuoglu A (1984). A comparative study of the pathergy reaction among Turkish and British patients with Behcet's disease. Annals of the Rheumatic Diseases. 43(1):74-5. 9. Hirohata S, Arai H, Matsumoto T (2003). Immunohistological studies in neuro-Behcet's disease. Advances in Experimental Medicine and Biology.528:385-7. 10. Main DM, Chamberlain MA (1992). Clinical differentiation of oral ulceration in Behcet's disease. British Journal of Rheumatology. 31(11):767-70. 11. Kaklamani VG, Tzonou A, Markomichelakis N, Papazoglou S, Kaklamanis PG (2003). The effect of smoking on the clinical features of Adamantiades-Behcet's disease. Advances in Experimental Medicine and Biology.528:323-7. 12. Mat MC, Goksugur N, Engin B, Yurdakul S, Yazici H (2006). The frequency of scarring after genital ulcers in Behcet's syndrome: a prospective study. International Journal of Dermatology 45(5):554-6. 13. Demirkesen C, Tuzuner N, Mat C, Senocak M, Buyukbabani N, Tuzun Y, Yazici H (2001). Clinicopathologic evaluation of nodular cutaneous lesions of Behcet syndrome. American Journal of Clinical Pathology.116(3):341-6. 14. Hatemi G, Bahar H, Uysal S, Mat C, Gogus F, Masatlioglu S, Altas K, Yazici H (2004). The pustular skin lesions in Behcet's syndrome are not sterile. Annals of the Rheumatic Diseases. 63(11):1450-2. 15. Diri E, Mat C, Hamuryudan V, Yurdakul S, Hizli N, Yazici H (2001). Papulopustular skin lesions are seen more frequently in patients with Behcet's syndrome who have arthritis: a controlled and masked study. Annals of the Rheumatic Diseases. 60(11):1074-6. 16. Krause I, Molad Y, Mitrani M, Weinberger A (2000). Pathergy reaction in Behcet's disease: lack of correlation with mucocutaneous manifestations and systemic disease expression. Clinical and Experimental Rheumatology. 18(1):71-4.

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17. Yazici H, Tuzun Y, Tanman AB, Yurdakul S, Serdaroglu S, Pazarli H, Muftuoglu A (1985). Male patients with Behcet's syndrome have stronger pathergy reactions. Clinical and Experimental Rheumatology. 3(2):137-41. 18. Kural-Seyahi E, Fresko I, Seyahi N, Ozyazgan Y, Mat C, Hamuryudan V, Yurdakul S, Yazici H (2003). The long-term mortality and morbidity of Behcet syndrome: a 2-decade outcome survey of 387 patients followed at a dedicated center. Medicine (Baltimore) 82(1):60-76. 19. Tugal-Tutkun I, Onal S, Altan-Yaycioglu R, Huseyin Altunbas H, Urgancioglu M (2004). Uveitis in Behcet disease: an analysis of 880 patients. American Journal of Ophthalmology.138(3):373-80. 20. Akman-Demir G, Serdaroglu P, Tasci B (1999). Clinical patterns of neurological involvement in Behcet's disease: evaluation of 200 patients. The Neuro-Behcet Study Group. Brain.122(Pt11):2171-82. 21. Akman-Demir G, Bahar S, Coban O, Tasci B, Serdaroglu P (2003). Cranial MRI in Behcet's disease: 134 examinations of 98 patients. Neuroradiology. 45(12):851-9. 22. Saip S, Siva A, Altintas A, Kiyat A, Seyahi E, Hamuryudan V, Yazici H. Headache in Behcet's syndrome (2005). Headache.45(7):911-9. 23. Koc Y, Gullu I, Akpek G, Akpolat T, Kansu E, Kiraz S, Batman F, Kansu T, Balkanci F, Akkaya S, et al (1992). Vascular involvement in Behcet's disease Journal of Rheumatology 19(3):40210. 24. Hamuryudan V, Yurdakul S, Moral F, Numan F, Tuzun H, Tuzuner N, Mat C, Tuzun Y, Ozyazgan Y, Yazici H (1994). Pulmonary arterial aneurysms in Behcet's syndrome: a report of 24 cases. British Journal of Rheumatology. 33(1):48-51. 25. Hamuryudan V, Er T, Seyahi E, Akman C, Tuzun H, Fresko I, Yurdakul S, Numan F, Yazici H (2004). Pulmonary artery aneurysms in Behcet syndrome. American Journal of Medicine 117(11):867-70. 26. Yurdakul S, Yazici H, Tuzun Y, Pazarli H, Yalcin B, Altac M, Ozyazgan Y, Tuzuner N, Muftuoglu A (1983). The arthritis of Behcet's disease: a prospective study. Annals of the Rheumatic Diseases. 42(5):505-15. 27. Olivieri I, Salvarani C, Cantini F (1997). Is Behcet's disease part of the spondyloarthritis complex? Journal of Rheumatology. 24(10):1870-2. 28. Korman U, Cantasdemir M, Kurugoglu S, Mihmanli I, Soylu N, Hamuryudan V, Yazici H (2003). Enteroclysis findings of intestinal Behcet disease: a comparative study with Crohn disease. Abdominal Imaging. 28(3):308-12. 29. Cetinel B, Obek C, Solok V, Yaycioglu O, Yazici H (1998). Urologic screening for men with Behcet's syndrome. Urology.52(5):863-5. 30. Cetinel B, Akpinar H, Tufek I, Uygun N, Solok V, Yazici H (1999). Bladder involvement in Behcet's syndrome. Journal of Urology. 161(1):52-6. 31. Huong DL, Wechsler B, Papo T, de Zuttere D, Bletry O, Hernigou A, Delcourt A, Godeau P, Piette JC(1997). Endomyocardial fibrosis in Behcet's disease. Annals of the rheumatic Diseases 56(3):205-8. 32. Altiparmak MR, Tanverdi M, Pamuk ON, Tunc R, Hamuryudan V (2002). Glomerulonephritis in Behcet's disease: report of seven cases and review of the literature. Clinical Rheumatology. 21(1):14-8. 33. Melikoglu M, Altiparmak MR, Fresko I, Tunc R, Yurdakul S, Hamuryudan V, Yazici H (2001). A reappraisal of amyloidosis in Behcet's syndrome. Rheumatology (Oxford). 40(2):212-5. 34. Lie JT (1992). Vascular involvement in Behcet's disease: arterial and venous and vessels of all sizes. Journal of Rheumatology. 19(3):341-3.
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35. Chun SI, Su WP, Lee S (1990). Histopathologic study of cutaneous lesions in Behcet's syndrome. Journal of Dermatology. 17(6):333-41. 36. Yazici H, Tuzuner N, Tuzun Y, Yurdakul S (1981). Localized myositis in Behcet's disease. Arthritis and Rheumatism. 24(4):636. 37. Matsumoto T, Uekusa T, Fukuda Y (1991). Vasculo-Behcet's disease: a pathologic study of eight cases. Human Pathology. 22(1):45-51. 38. Ergun T, Gurbuz O, Dogusoy G, Mat C, Yazici H (1998). Histopathologic features of the spontaneous pustular lesions of Behcet's syndrome. International Journal of Dermatology. 37(3):194-6. 39. Hadfield MG, Aydin F, Lippman HR, Sanders KM (1997). Neuro-Behcet's disease. Clinical Neuropathology. 16(2):55-60 40. Ehrlich GE (1997). Vasculitis in Behcet's disease. International Review of Immunology. 14(1):81-8. 41. Gul A, Inanc M, Ocal L, Aral O, Konice M (2000). Familial aggregation of Behcet's disease in Turkey. Annals of The Rheumatic Diseases 59(8):622-5. 42. Molinari N, Kone Paut I, Manna R, Demaille J, Daures JP, Touitou I (2003). Identification of an autosomal recessive mode of inheritance in paediatric Behcet's families by segregation analysis. American Journal of Medical Genetics 122(2):115-8. 43. Karasneh J, Gul A, Ollier WE, Silman AJ, Worthington J (2005). Whole-genome screening for susceptibility genes in multicase families with Behcet's disease. Arthritis and Rheumatism. 52(6):1836-42. 44. Yazici H (1997). The place of Behcet's syndrome among the autoimmune diseases. International Review of Immunology. 14(1):1-10. 45. Gul A (2005). Behcet's disease as an autoinflammatory disorder. Current Drug Targets Inflammation and Allergy 4(1):81-3. 46. Yazici H, Fresko I (2005). Behcet's disease and other autoinflammatory conditions: what's in a name? Clinical and Experimental Rheumatology. 23(4 Suppl38):S1-2. 47. Direskeneli H (2006). Autoimmunity vs autoinflammation in Behcet's disease: do we oversimplify a complex disorder? Rheumatology (Oxford). (in print) 48. Tunc R, Keyman E, Melikoglu M, Fresko I, Yazici H (2002). Target organ associations in Turkish patients with Behcet's disease: a cross sectional study by exploratory factor analysis. Journal of Rheumatology. 29(11):2393-6. 49. Espinosa G, Font J, Tassies D, Vidaller A, Deulofeu R, Lopez-Soto A, Cervera R, Ordinas A, Ingelmo M, Reverter JC (2002). Vascular involvement in Behcet's disease: relation with thrombophilic factors, coagulation activation, and thrombomodulin. American Journal of Medicine. 112(1):37-43. 50. Leiba M, Seligsohn U, Sidi Y, Harats D, Sela BA, Griffin JH, Livneh A, Rosenberg N, Gelernter I, Gur H, Ehrenfeld M (2004). Thrombophilic factors are not the leading cause of thrombosis in Behcet's disease. Annals of The Rheumatic Diseases. 63(11):1445-9. 51. Muftuoglu AU, Yazici H, Yurdakul S, Tuzun Y, Pazarli H, Gungen G, Deniz S (1986). Behcet's disease. Relation of serum C-reactive protein and erythrocyte sedimentation rates to disease activity. International Journal of Dermatology. 25(4):235-9. 52. Fresko I, Ugurlu S, Ozbakir F, Celik A, Yurdakul S, Hamuryudan V, Yazici H. AntiSaccharomyces cerevisiae antibodies (ASCA) in Behcet's syndrome (2005). Clinical and Experimental Rheumatology. 23(4 Suppl 38):S67-70.

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53. International Study Group for Behets Disease (1992). Evaluation of diagnostic (classification) criteria in Behets disease-towards internationally agreed criteria. British Journal of Rheumtology 31: 299-308. 54. Barnes CG, Yazici H (1999). Behcet's syndrome. Rheumatology (Oxford). 38(12):1171-4. 55. Seyahi E, Memisoglu E, Hamuryudan V, Tepe S, Aker UT, Balci H, Ongen Z, Yurdakul S, Yazici H (2004). Coronary atherosclerosis in Behcet's syndrome: a pilot study using electronbeam computed tomography. Rheumatology (Oxford). 43(11):1448-50. 56. Yurdakul S, Mat C, Tuzun Y, Ozyazgan Y, Hamuryudan V, Uysal O, Senocak M, Yazici H (2001). A double-blind trial of colchicine in Behcet's syndrome. Arthritis and Rheumatism. 44(11):2686-92. 57. Hamuryudan V, Mat C, Saip S, Ozyazgan Y, Siva A, Yurdakul S, Zwingenberger K, Yazici H (1998). Thalidomide in the treatment of the mucocutaneous lesions of the Behcet syndrome. A randomized, double-blind, placebo-controlled trial. Annals of Internal Medicine 15;128(6):44350. 58. Mat C, Yurdakul S, Uysal S, Gogus F, Ozyazgan Y, Uysal O, Fresko I, Yazici H (2006). A double-blind trial of depot corticosteroids in Behcet's syndrome. Rheumatology (Oxford). 45(3):348-52. 59. Calguneri M, Kiraz S, Ertenli I, Benekli M, Karaarslan Y, Celik I (1996). The effect of prophylactic penicillin treatment on the course of arthritis episodes in patients with Behcet's disease. A randomized clinical trial. Arthritis and Rheumatism. 39(12):2062-5. 60. Melikoglu M, Fresko I, Mat C, Ozyazgan Y, Gogus F, Yurdakul S, Hamuryudan V, Yazici H (2005). Short-term trial of etanercept in Behcet's disease: a double blind, placebo controlled study.Journal of Rheumatology. 32(1):98-105. 61. Yazici H, Pazarli H, Barnes CG, Tuzun Y, Ozyazgan Y, Silman A, Serdaroglu S, Oguz V, Yurdakul S, Lovatt GE, et al (1990). A controlled trial of azathioprine in Behcet's syndrome. New England Journal of Medicine. 322(5):281-5. 62. Hamuryudan V, Ozyazgan Y, Hizli N, Mat C, Yurdakul S, Tuzun Y, Senocak M, Yazici H (1997). Azathioprine in Behcet's syndrome: effects on long-term prognosis. Arthritis and Rheumatism. 40(4):769-74. 63. Ozyazgan Y, Yurdakul S, Yazici H, Tuzun B, Iscimen A, Tuzun Y, Aktunc T, Pazarli H, Hamuryudan V, Muftuoglu A (1992). Low dose cyclosporin A versus pulsed cyclophosphamide in Behcet's syndrome: a single masked trial. British Journal of Ophthalmology 76(4):241-3. 64. Kotter I, Gunaydin I, Batra M, Vonthein R, Stubiger N, Fierlbeck G, Melms A (2006). CNS involvement occurs more frequently in patients with Behcet's disease under cyclosporin A (CSA) than under other medications--results of a retrospective analysis of 117 cases. Clinical Rheumatology 25(4):482-6. 65. Kotter I, Gunaydin I, Zierhut M, Stubiger N (2004). The use of interferon alpha in Behcet disease: review of the literature. Seminars in Arthritis and Rheumatism. 33(5):320-35. 66. Ohno S, Nakamura S, Hori S, Shimakawa M, Kawashima H, Mochizuki M, Sugita S, Ueno S, Yoshizaki K, Inaba G (2004). Efficacy, safety, and pharmacokinetics of multiple administration of infliximab in Behcet's disease with refractory uveoretinitis. Journal of Rheumatology. 31(7):1362-8. 67. Tugal-Tutkun I, Mudun A, Urgancioglu M, Kamali S, Kasapoglu E, Inanc M, Gul A (2005). Efficacy of infliximab in the treatment of uveitis that is resistant to treatment with the combination of azathioprine, cyclosporine, and corticosteroids in Behcet's disease: an openlabel trial. Arthritis and Rheumatism. 52(8):2478-84.

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68. Sfikakis PP, Kaklamanis PH, Elezoglou A, Katsilambros N, Theodossiadis PG, Papaefthimiou S, Markomichelakis N (2004). Infliximab for recurrent, sight-threatening ocular inflammation in Adamantiades-Behcet disease. Annals of Internal Medicine 140(5):404-6. 69. Tuzun H, Besirli K, Sayin A, Vural FS, Hamuryudan V, Hizli N, Yurdakul S, Yazici H (1997). Management of aneurysms in Behcet's syndrome: an analysis of 24 patients. Surgery. 121(2):150-6. 70. Cil BE, Turkbey B, Canyigit M, Kumbasar OO, Celik G, Demirkazik FB (2006). Transformation of a ruptured giant pulmonary artery aneurysm into an air cavity after transcatheter embolization in a Behcet's patient. Cardiovascular Interventional Radiology 29(1):151-4. 71. O'Duffy JD, Robertson DM, Goldstein NP (1984). Chlorambucil in the treatment of uveitis and meningoencephalitis of Behcet's disease. American Journal of Medicine. 76(1):75-84. 72. Hirohata S, Suda H, Hashimoto T (1998). Low-dose weekly methotrexate for progressive neuropsychiatric manifestations in Behcet's disease. Journal of neurological Sciences. 159(2):181-5. 73. Licata G, Pinto A, Tuttolomondo A, Banco A, Ciccia F, Ferrante A, Triolo G (2003). Antitumour necrosis factor alpha monoclonal antibody therapy for recalcitrant cerebral vasculitis in a patient with Behcet's syndrome. Annals of The Rheumatic Diseases 62(3):280-1. 74. Postema PT, den Haan P, van Hagen PM, van Blankenstein M (1996). Treatment of colitis in Behcet's disease with thalidomide. European Journal of Gastroenterology and Hepatology. 8(9):929-31. 75. Travis SP, Czajkowski M, McGovern DP, Watson RG, Bell AL (2001). Treatment of intestinal Behcet's syndrome with chimeric tumour necrosis factor alpha antibody. Gut 49(5):725-8.

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RELAPSING POLYCHONDRITIS
HASAN YAZICI MD DIVISION OF RHEUMATOLOGY, DEPARTMENT OF MEDICINE CERRAHPAA MEDICAL FACULTY UNIVERSITY OF ISTANBUL

LEARNING OUTCOMES
Global learning outcome This module will enable the participant to diagnose and treat patients with relapsing polychondritis (RP) Specific learning outcomes To recognize RP To list and describe the disease associations of RP, especially with Behets syndrome To evaluate whether RP is a disease or a syndrome To state that RP may be a benign or a very severe disease To manage different disease presentations

INTRODUCTION AND DEFINITION


Relapsing Polychondritis (RP) is rare condition, autoimmune or autoinflammatory in origin, characterized by recurrent episodes of inflammation of cartilage, especially of the ears, nose and the tracheobronchial tree. A variety of other organ systems can be involved including joints, heart and the kidney. It may occur alone (primary) or can be associated with a long list of conditions (secondary) (Table 1). It has also been proposed that it .is not a primary disease, but a syndrome associated with multiple precipitating factors that appears in a genetically susceptible subject. (1). RP may run a rather benign or alternatively, a very severe course ending in death.

I- EPIDEMIOLOGY AND GENETICS


RP is distinctly rare. Males and females are equally affected. The peak incidence is in the 5th decade but older adults and children can also be afflicted. No familial clustering has been noted. On the other hand there is an increased frequency of HLA DR4 among the patients (2).

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Systemic Vasculitides Behets syndrome Wegeners granulomatosis Polyarteritis nodosa Takayasus arteritis Leukocytoclastic vasculitis Cogans syndrome HenochSchonlein purpura Thromboangiitis obliterans

Table n1 - Systemic diseases associated with RP Connective Blood Autoimmune and other Tissue Dyscrasias Conditions Diseases Rheumatoid Myelodysplastic Vitiligo arthritis syndrome SLE Hematological malignancies Autoimmune thyroid disease

Sjgrens syndrome Juvenile chronic arthritis

Cryoglobulinemia Myasthenia gravis Pernicious anemia Thymoma Primary biliary cirrhosis

Dermatitis herpatiformis Atopic dermatitis

Primary biliary cirrhosis Lichen Planus Psoriasis Glomerulonephritis Inflammatory bowel disease Diabetes mellitus FMF Panniculitis Retroperitoneal fibrosis Spondarthritides Sweets syndrome

II- CLINICAL FINDINGS


The usual onset is usually abrupt and episodic. In secondary forms the associated condition has usually been present for some time before the RP sets in. Table 2 summarizes the various clinical findings, with their approximate frequency of involvement at presentation or during the disease course (3). It is to be noted that if one takes the primary and secondary forms there is practically not a single organ system that is spared. The commonest form of onset (~ 50%) is inflammation of the external ear which can be on one side or bilateral. In a patient with inflammation in a single ear this is usually not attributed to a systemic disease especially in the primary form where there is no associated disease to alert the patient or the physician. All too often it is ascribed to infection and antibiotics are prescribed. On the other hand one should also search for such a recent local infection if the involvement is unilateral.

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It should not also be forgotten that frost bite or burns including ultraviolet can cause such inflammation in the external ear, even after weeks after the original trauma (1). Table n2 - Clinical findings (~ %)* Feature Auricular Auricular Chondritis Arthritis Nasal Chondritis Ocular disease Laryngotracheal involvement Reduced hearing and/or vestibular dysfunction Skin - mucosa Kidney disease Heart disease Vasculitis Ref 3 (modified) Frequency At presentation During course 45 90 30 70 20 60 20 60 20 55 5 40 5 30 5 25 0 10 2 15

It is the auricular portion of the external ear that is inflamed in RP. The earlobes, since they do not have cartilage are spared. With ongoing inflammation the auricular portions of the external ear become flabby (Fig. 11) since the cartilage matrix has been destroyed. Figure 11 - Earlobe destruction in relapsing polychondritis (Courtesy of Pr. Ina Kotter - Tubingen Germany)

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There might be disease in the ear and related structures as well. The Eustachian tubes may be closed leading to hearing loss and otitis. Not infrequently there is also the associated arteritis of the internal auditory artery causing tinnitus and vertigo through due to impaired cochleal blood supply. The presence of additional sites of inflammation eases the diagnosis. Nasal cartilage is the most frequent second site. There is pain, local tenderness and, if it progresses, a saddle nose deformity may ensue. The nose feels stuffy and the patient may complain of frequent nose-bleeds. Laryngotracheal involvement can be life threatening. The initial symptoms are hoarseness, cough, stridor along with tenderness over the larynx and trachea. Upper airway obstruction necessitates emergency tracheostomy. The disease of the cartilaginous structures of the lower airways can cause repeated bouts of pneumonia by interfering with normal drainage in the lungs. RP does not usually involve the articular cartilage (see pathogenesis) apart from the fibrocartilaganoues costochondral joints, mimicking the so-called Tietze syndrome, a common and benign condition, causing local sternal pain. In rare instances the sternal disease might be more severe with involvement of the sternomanubrial and sternoclavicular joints with structural changes leading to pes excavatum. Even though the articular cartilage is spared arthritis is common in RP and it is not unusual to precede its onset by weeks or months. It is non-deforming, episodic oligo-arthritis involving both the large and small peripheral joints. While the involved joints are warm and swollen the synovial fluid is noninflammatory (1). The eye disease in RP can take many forms and affects more than half of the patients during the entire course (4). The most common lesions are episcleritis, scleritis and conjunctivitis. However keratitis, corneal melt, uveitis, retinal vasculitis even periadnexal disease leading to proptosis can be seen. MALT (mucosa associated lymphoid tissue) lymphomas around the eye have also been described (5). Retinal disease can lead to visual loss. Heart involvement is an integral part of the clinical picture in RP. It is seen in around 10% of the patients with RP and its insidious and potentially sinister course necessitates due attention. The cardiac involvement in RP (6,7,8) can be due to valvular disease, notably aortic with associated aortitis , coronary vasculitis sometimes leading to myocardial infarction, problems with the conduction system and myocarditis or pericarditis (rare). It is to be noted that especially aortic root involvement may develop years after the inital diagnosis and can progress despite immunosuppressive treatment utilized for disease involvement in other sites. Thus it is important that patients with RP be followed for developing murmurs especially in the setting of congestive hear failure. Also a chest radiograph, an EKG and an echocardiogram should be part of the initial evaluation of a patient with RP even if he/she does not have any cardiovascular symptoms. Both arteries and veins of all sizes can also be diseased. The aortic and the abdominal aorta can be diseased with a clinical picture similar to Takayasus arteritis (9) and like in many other disease associations of RP it can be a matter of unfruitful debate whether the cartilage inflammation in such a patient is due to a primary Takayasus arteritis with secondary cartilage involvement or vice versa. The thrombosis of the large and small veins this time just like in Behcets syndrome- can be also be observed.

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The neurological involvement can be seen both in the central nervous system and in the peripheral nerves (10,11). When in the CNS cranial nerves are most commonly involved. Optic atrophy leading to visual loss and abducens paralysis leading to loss of lateral gaze are the most frequent followed by lesions in the 7th and 8th nerves. Cortical lesions with pyramidal lesions, loss of cognitive function and seizures have also been described. The CNS and peripheral neuropathy in RP has been ascribed to the generalized vasculitis seen in it primary or secondary forms. On the other hand hard proof for this is seldom found. The skin-mucosa involvement in RP can present in many forms (12). The most common lesion is recurrent oral ulceration while the most frequent histology is a leukocytoclastic vasculitis. There is a subgroup of RP patients in whom skin involvement is seen with an increased frequency. The patients with RP and myelodysplastic syndrome are in the average a decade or two older than other RP patients and 90% have skin disease. As just mentioned in the context of dermal involvement patients with RP and the myelodysplastic syndrome have been reported (13) and some of these patients can present as fever of unknown origin. About 20% of patients with RP have renal problems (14). This can range from mesangial disease and IgA nephropathy to crescentic glomerulonephritis. The patients with renal disease have a more guarded prognosis. The so called MAGIC (Mouth and Genital Ulcers with Inflamed Cartilage) (15) is probably nothing different from Behets syndrome with secondary RP (16).

III- LABORATORY FINDINGS


There are no laboratory findings specific for RP and patients with secondary forms can demonstrate the more specific findings, if any, of the associated diseases. An augmented acute phase response is seen in the majority of the patients. Antibodies to native collagen- II, present in about 50% of the patients is still a research tool and not specific enough to be diagnostically useful (17).

IV- DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS


Over the years several sets of criteria have been proposed for diagnosis (18,19) all based on combinations of the spread of involvement cartilaginous sites and the common clinical findings of the associated diseases. As is true for all rare diseases, formulating diagnostic criteria useful in an individual patient is probably unrealistic in RP, as well. The very low pre-test probability makes the likelihood of false positives unacceptably high even with criteria of sensitivity and sensitivities even near unity (20). In the clinical setting symmetrical cartilage involvement in the ears with an additional site of cartilage disease is usually adequate for diagnosis. Only in doubtful cases one resorts to histological diagnosis.

IV-1 Ear problems


The foremost consideration is bacterial or fungal infection especially when the involvement is unilateral. The sparing of the ear lobes in RP and the presence of lymph nodes in infection are helpful.

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Chemical and physical trauma like frostbite and sunburn are other considerations and it should be born in mind that it might sometimes take weeks after the initial trauma before the ear inflammation begins. (1)

IV-2 Nasal findings


Especially indolent infections with mycobacteria (both tuberculosis and leprosy) and fungi can cause damage in the nasal cartilage. Wegeners granulomatosis and the lymphamatous involvement in midline granuloma are other considerations. The sparing of the mucosa and the relative paucity of surrounding inflammation in RP might be helpful in diagnosis.

IV-3 Eye involvement


Episcleritis, scleritis, keratitis and uveitis can be seen both in primary RP and as part of the clinical spectrum of the long list of associated conditions. Important points to consider here are a. Scleritis and keratitis are not usual in BS while episcleritis can be seen; b. Uveitis is not part of RA; Wegeners granulomatosis can cause all the eye findings of RP and in addition proptosis, which can also be seen in the latter disease. Interstitial keratitis is an integral part of Cogans syndrome which, with its vestibular neuritis, can be difficult to tell from RP.

IV-4 Laryngotracheal involvement


Tracheal involvement is a very useful finding in differential diagnosis because, apart from direct trauma such as can be seen as a complication of intubation, there are no other diseases that can cause a similar problem.

IV-5 Aortic involvement


The enlargement of the aortic root can also be seen in ankylosing spondylitis, Marfans or Ehlers Danlos syndrome.

V- PATHOLOGY (1)
The early and active lesions in the cartilage show an infiltration with lymphocytes (mainly CD4+) and along with C3 and immunoglobulin deposition. This is followed in time by more immunoglobulin and complement deposition with increasing amounts of cartilage destruction. The chondrocytes initially phagocytose the degraded material and later they themselves degenerate. The final stages show fibrosis with focal areas of calcification, gelatinous cysts and new bone formation. A similar histology is seen at other cartilaginous sites. At the diarthrodial joints, on the hand, there is chronic synovitis, only. Aortitis is characterized by a mononuclear cell infiltration with destruction of the collagen and elastic fibers. The inflammation can involve the whole arterial wall and lead to aneurysm formation. The kidney involvement can range from mild mesangial disease to IgA nephropathy or segmental crescentic glomerulonephritis, mostly representing the pathological landmarks of the associated diseases.

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VI- PATHOGENESIS
The exact pathogenesis is not known but an autoimmune mechanism is strongly implicated The evidence for this is several fold: 1. The histology of the involved tissue as discussed above. 2. Matrilin 1 is a cartilage matrix protein and is found in the cartilaginous structures other than that of the diarthrodial cartilage. Injection of this protein into mice causes a clinical picture quite similar to RP (21) and antibodies to the same has been described human disease (22). 3. About half of the patients with RP develop antibodies to native collagen type-II, found in abundance in cartilage. Furthermore immunizing DQ8 and HLA DQ6 double transgenic mice with of collagen type II can induce chondritis in these animals (23). 4. The frequency HLA DR4 - an allele associated with several autoimmune diseases, starting with rheumatoid arthritis is increased among patients with RP (16). 5. Finally cartilage is considered to be an immunologically privileged site like the eye, meaning that immunological tolerance is not present to its structural proteins in the healthy organism. This, in turn, makes the cartilage prone to an autoimmune insult. Thus it can be said that the cartilage damage seen in RP associated with many autoimmune/autoinflammatory diseases can be likened to the uveal disease seen in some of these conditions as well.

VII- PROGNOSIS AND MANAGEMENT


It used to be thought RP had a poor prognosis in the majority of patients. We now know this probably is not the case. Two decades ago the reported 10 year survival was 55% in a case series (24) while a more recent figure puts this close to 95 %. (25). Increased general awareness with recognition of milder cases probably also plays an important role in this improved survival. Due to the rarity of the condition and perhaps to the association with many other diseases we do not have any evidence based treatment options for managing RP at hand. What follows then is mainly based published expert opinion which, in turn, based on uncontrolled observations.

As expected management is tailored to diseases extent and severity (3). If involvement is limited to the external ear and the cartilage of the nose with no apparent destructive changes or arthritis is a problem, NSAIDs could be all that is required. A second choice would be Dapsone (50-200Mg/day). Still others prefer small dose steroids (10-20 mg prednisone/day) in this setting. More destructive changes in the cartilage or tracheolaryngeal, vestibuloneural, lung, eye, heart, kidney involvement or systemic vasculitis requires higher dose steroids (prednisone at 60mg/day). To this cyclophosphamide at 1-2 mg/kg/day is usually added in more severe, life threatening lung, heart or kidney disease. Azathioprine, methotrexate or cyclosporine A (with due attention to kidney function) can also be used either as remission inducing or steroid sparing additional therapy. There have also been case reports of successful use of TNF alpha antagonists in RP; especially with infliximab (26, 27). Involvement of the cartilaginous structures of the airways may require physical measures which include continuous positive airway pressure especially at night-, tracheostomy or stents.

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As discussed, the cardiac valvular involvement may be insidious and resistant to medical therapy. It turns out that in patients undergoing aortic valve replacement it is a good idea also to put a synthetic graft to the ascending aorta to minimize the post op aneurysm formation and valvular leaks (28).

REFERENCES
1. Herman JH (2206). Relapsing Polychondritis.in UpToDate Rheumatology . www.uptodate.com 2. Zeuner M, Straub RH, Rauh G, Albert ED, Scholmerich J, Lang B (1997). Relapsing polychondritis: Clinical and immunogenetic analysis of 62 patients. Journal of Rheumatology 24(1):96-101. 3. Kent PD, Michet CJ Jr, Luthra HS (2004). Relapsing polychondritis. Current Opinion in Rheumatology.16(1):56-61. 4. Isaak, BL, Liesegang, TJ, Michet, CJ Jr (1986). Ocular and systemic findings in relapsing polychondritis. Ophthalmology 93(5):681-689. 5. Lichauco JJ, Lauer S, Shigemitsu HH, Bello JA, Bhattacharyya PK, Barland P, Putterman C (2001). Orbital mucosa-associated lymphoid tissue (MALT)-type lymphoma in a patient with relapsing polychondritis. Arthritis and Rheumatism 44(7):1713-5. 6. Marshall DA, Jackson R, Rae AP, Capell HA (1992). Early aortic cusp rupture in relapsing polychondritis. Annals of the Rheumatic Diseases 51(3):413-5. 7. Buckley LM, Ades PA (1992). Progressive aortic valve inflammation occurring despite apparent remission of relapsing polychondritis. Arthritis and Rheumatism 35(7):812-14. 8. Selim AG, Fulford LG, Hohiaddin RH, Sheppard MN (2001). Active aortitis in relapsing polychondritis. Journal of Clinical Pathology 54(11):890-92. 9. Giordano M, Valentini G, Sodano A (1984). Relapsing polychondritis with aortic arch aneurysm and aortic arch syndrome. Rheumatology International 4(4):191-3. 10. Sundaram MBM, Rajput AH (1983). Nervous system complications of relapsing polychondritis. Neurology 33(4):513-15. 11. Hanslik T, Wechsler B, Piette J-C, Vidailhat M, Robin PM, Godeau P (1994). Central nervous system involvement in relapsing polychondritis. Clinical and Experimental Rheumatology 12(5):539 41. 12. Frances C, el Rassi R, Laporte JL, Rybojad M, Papo T, Piette JC (2001). Dermatologic manifestations of relapsing polychondritis. A study of 200 cases at a single center. Medicine (Baltimore) 80(3):173-9. 13. Hebbar M, Brouillard M, Wattel E, Decoulx M, Hatron PY, Devulder B, Fenaux P (1995). Association of myelodysplastic syndrome with relapsing polychondritis: Further evidence. Leukemia 9(4):731-3.

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14. Chang-Miller A, Okamura M, Torres VE, Michet CJ, Wagoner RD, Donadio JV Jr, Offord KP, Holley KE (1987). Renal involvement in relapsing polychondritis. Medicine 66(3):202 17. 15. Orme RL, Nordlund JJ, Barich L, Brown T (1990). The MAGIC syndrome (mouth and genital ulcers with inflamed cartilage). Archives of Dermatology 126(7):940-44. 16. Ktter, I. The Magic of syndromes. Clinical and Experimental Rheumatology, in print. 17. Foidart JM, Abe S, Martin GR, Zizic TM, Barnett EV, Lawley TJ, Katz SI (1978). Antibodies to type II collagen in relapsing polychondritis. New England Journal of Medicine ; 299(22):1203-7. 18. McAdam LP, O'Hanlan MA, Bluestone R, Pearson CM (1976). Relapsing polychondritis: Prospective study of 23 patients and a review of the literature. Medicine 55(3):193-215. 19. Damiani JM, Levine HL (1979). Relapsing polychondritis report of ten cases. Laryngoscope 89(6Pt1): 929-46. 20. Mark DB (2005). Decision-making in clinical medicine. in Harrisons Principles of Internal Medicine pp. 6-13. 1th edition. McGraW Hill.Eds. Kapser DL, Braunwald G; Fauici AS, Huaser SL, Longo DL, Jameson JL New York. 21. Hansson AS, Heinegard D, Holmdahl R (1999). A new animal model for relapsing polychondritis, induced by cartilage matrix protein (matrilin-1). Journal of Clinical Investigation 104(5):589-98. 22. Hansson AS, Heinegard D, Piette JC, Burkhardt H, Holmdhal R (2001). The occurrence of autoantibodies to matrilin 1 reflects a tissue-specific response to cartilage of the respiratory tract in patients with relapsing polychondritis. Arthritis and Rheumatism 44(10):2402-12. 23. Bradley DS, Das P, Griffiths MM, Luthra HS, David CS (1998).HLA-DQ6/8 double transgenic mice develop articular chondritis following type II collagen immunization: a model for human relapsing polychondritis. Journal of Immunology 161(9):5046-53. 24. Michet CJ, McKenna CH, Luthra HS, OFallon WM (1986). Relapsing polychondritis. Survival and predictive role of early disease manifestations. Annals of Internal Medicine 104(1):74-8. 25. Trentham DE, Le CH (1998). Relapsing polychondritis. Annals of Internal Medicine 129(2):114-22. 26. Saadoun D, Deslandre CJ, Allanore Y, Paham XV, Kahan A (2003). Sustained response to infliximab in 2 patients with refractory relapsing polychondritis. Journal of Rheumatology 30(6):13945. 27. Mpofu S, Estrach C, Curtis J, Moots RJ (2003). Treatment of respiratory complications in recalcitrant relapsing polychondritis with infliximab. Rheumatology (Oxford) 42(9):1117-8. 28. Lang-Lazdunski L, Hvass U, Paillole C, Pansard Y, Langlois Jl (1995). Cardiac valve replacement in relapsing polychondritis. A review. The Journal of Heart Valve Disease 4(3):227-35.

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EYE INVOLVEMENT IN RHEUMATIC DISEASE


NICOLE STUBIGER MD

LEARNING OUTCOMES
At the end of this section participants will be able to: Describe, explain and investigate the various eye manifestations observed during the course of the rheumatic diseases Differentiate the prognoses of the different eye manifestations Identify conditions where an ophthalmological consultation is appropriate

Autoimmune disorders can have fatal systemic and ocular effects, so an early diagnosis is the key to successful treatment and better prognosis. Ocular symptoms may include dry or red eyes, pruritus, photophobia, pain, foreign-body sensation, visual changes and even complete loss of vision. Because a number of these diseases may initially present with non-specific ocular manifestations physicians should keep in mind that they might be the presenting symptom of active, potentially lethal systemic disease, despite their vague character. A thorough ophthalmic examination, including ocular motility, pupillary reaction, visual acuity, visual field testing, external inspection with the slit lamp, corneal staining with fluorescein and direct or indirect ophthalmoscopy should be completed. In dry eye syndrome simple tools such as the Schirmers test or the break up time of the tear film can be useful in diagnosis (1, 2).

I- OPHTHALMOLOGICAL MANIFESTATIONS I-1 Keratoconjunctivitis Sicca (KCS)


Patients with primary or secondary Sjgrens syndrome, which is caused by an inflammatory lymphocytic infiltration of the tear gland, suffer from KCS due to reduction of tear film secretion. Patients with the dry eye syndrome mostly complain about dryness, foreign body sensation, burning, grittiness, blurred vision, and blepharospasm. The symptoms are more prominent in the morning, due to incomplete lid closure during the night and during the latter part of the day because of the evaporation of the tear film (1-3). Simple tests for diagnosis of KCS are the Schirmer test without local anaesthesia (Schirmer I - for measuring the basal secretion rate of the lachrymal gland) (Fig. 12), tear break-up time (BUT), and slit lamp examination after fluorescein and /or rose Bengal staining (Fig. 13) (1, 4, 5). In addition, the corneal examination with the slit lamp could reveal punctate keratopathy (Fig. 13) or even filaments (5). The treatment of dry eye symptom consists of topical lubricant therapy and immunomodulating agents, such as cyclosporine A (CSA) eye drops. Due to the fact that preservatives in eye drops can be toxic to the cornea, the artificial tear substitutes should be free of preservatives. Another treatment option is the use of permanent lachrymal plugs (Fig. 14). These plugs should be inserted intracanalicularly with the aim of stopping tear fluid drainage (6). Patients should be educated in addition about simple therapeutical features, such as using sunglasses and room humidifiers, and to avoid dry environments (1).
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It is known that lachrymal gland functions return to normal in patients with secondary Sjgrens syndrome when the disease remits so it is necessary to consider systemic application of immunosuppressive substances (7). Figure 12 - Schirmer test

Figure 13 - Punctate erosive kerotopathy (yellow colored spots stained with fluorescein)

Figure 14 - Intracanalicular implant with a lacrimal plug

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I-2 Keratopathy
Corneal disease can be an isolated complication, but it is most commonly associated with keratoconjunctivitis sicca (chapter I-1) or scleritis (chapter I-3) and may include keratitis, sclerosing keratitis, and paracentral or peripheral ulcerative keratitis (Fig 15). The origin of this sterile keratitis is an immune complex mediated vasculitis of the limbal area and it is marked by an inflammatory corneal cell infiltrate that may result in corneal scarring, ulceration, or melting (1-3,8,9). The patients with keratitis mostly complain of red eye, pain, tearing, and blurred vision. The diagnosis is made by slit lamp examination; in patients with acute keratitis or sclerosing keratitis the inflamed areas are mostly opacified and this may be more evident by fluorescein staining (1,8,9). Especially in patients with sclerosing keratitis, which is a chronic process, the slit lamp examination discloses an area of opacification and vascularisation that progresses towards the optic axis (1). Peripheral ulcerative keratitis is often described with emphasis on rheumatic keratomalacia. This particular disorder, whether affecting the central and paracentral or the peripheral parts of the cornea, is characterized by thinning of the corneal stroma, loss of epithelium, ulceration, and eventually by corneal perforation (1,8,9). Without treatment, the incidence of visual loss is very high. Treatment options consist of local therapies, esp. topical lubricant therapy and CSA eye drops (10). Because of their antiproliferative character, care must be taken when steroids are used locally. Due to the fact that ulcerative keratitis is a sign for active systemic vasculitis and a higher mortality, immunosuppressive therapy will be required to preserve life and vision. Despite the above mentioned aggressive medical treatment, surgical intervention will be often required. Surgical options mostly include penetrating keratoplasty or the application of tissue adhesives (1,8-11). Figure 15 - Peripheral corneal ulceration in RA

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I-3 Episcleritis / Scleritis


Inflammation of the sclera is a common eye manifestation among the several rheumatic disorders and includes a spectrum that ranges from harmless simple episcleritis to painful, sight threatening, destructive necrotizing scleritis (12). The inflammatory process can be confused with severe conjunctivitis because of the bright-red appearance of the eye (in episcleritis due to engorged episcleral and in scleritis due to engorged scleral vessels) (Fig. 16 a,b) and may extend to the adjacent tissues causing ocular complications such as uveitis, keratitis, glaucoma, cataract, optic neuritis, macular edema, serous retinal detachment, or perforation of the globe (12-16). Figure 16a - Episcleritis with engorged episcleral vessels in SLE

Figure 16b - Scleritis in a patient with RA, the inflamed vessels give the eye a bright red appearance

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The importance of correctly diagnosing and distinguishing between scleritis and episcleritis is based on the potential ocular and systemic complications associated with scleritis. Particularly important is the recognition of necrotizing scleritis, since it is frequently associated with ocular complications and a bad prognosis. In patients who suffer from associated vasculitic systemic disease, the appearance of scleritis indicates a generalization of the vasculitis, which can result in potentially lethal systemic complications (16). Only the early diagnosis and an adequate aggressive therapy can preserve ocular functions and the patients life. Scleritis and episcleritis are distinguished on the basis of anatomy and appearance (table 1) (1,1216). Scleritis usually presents gradually with deep and boring pain, which may radiate into cheek, eyebrows, and temples and causes blurred vision and photophobia in the affected eyes. Patients with episcleritis have more often a sudden onset with a mild ache which may radiate to the cheek, eyebrows, and temples but they do not complain of blurred vision and photophobia. In conclusion, symptoms may be similar, but the pain in scleritis is more evident and severe. For distinguishing dilated vessels caused by scleritis from those caused by episcleritis topical applied phenylephrine 2.5% can help: while in episcleritis blanching of the vessels occurs after installation of phenylephrine eye drops, in scleritis the engorged vessels remain dilated (1, 12-16), because phenylephrine reaches only the episcleral vessels which are located near the conjunctiva. Other typical ocular manifestations, which slit lamp examination could reveal, are subconjunctival nodules, and especially in scleritis, scleral edema and avascular areas (1,12-17). Table n1 - In 1976 Watson and Hayreh (15) classified several forms of episcleritis and scleritis based upon the anatomic location of the inflammation and the observed alterations in the associated vascular structures. Prevalence (%) Episcleritis: 80 Simple episcleritis 20 Nodular episcleritis Scleritis Anterior scleritis a) Diffuse scleritis 45 b) Nodular scleritis 23 c) Necrotizing scleritis 1. with inflammation 23 2. without inflammation 3,5 (scleromalacia perforans) Posterior scleritis 6,5 These types of scleritis (table 1) differ in degree of severity: diffuse anterior scleritis is more benign than nodular anterior scleritis, which in turn is less severe than necrotizing anterior scleritis (17). Among the two variations of necrotizing scleritis, the one with inflammation is the most destructive. Complications due to necrotizing scleritis include scleral thinning, uveal prolapse, or even perforation (1,12,14,15,17). Posterior scleritis, based upon the posterior location of inflammation, relative to the equator of the globe, can lead to rapid and permanent visual loss but is often a diagnostic challenge due to the fact, that about 40% of patients have no anterior scleral inflammation. Therefore diagnosis is mostly based on ultrasound examination. The classic sign of posterior scleritis is the T-sign on B-scan, due to accumulation of fluid in the posterior episcleral space and around the optic nerve. Scleral thickening seen on CT or MRI can additionally confirm posterior scleritis (18,19).
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The initial treatment of episcleritis should be focused on administering nonsteroidal anti-inflammatory drugs (NSAIDs), at first topically and, second line, systemically. In patients who do not respond to these medications corticosteroids or even immunosuppressants should be given (1,14-16). Therapy alone with topical non-steroidal or steroidal anti-inflammatory drugs is routinely insufficient for scleritis, and subconjunctival steroid injections are not only ineffective but are contraindicated because of their enhancement of the risk of scleral perforation (17). In many cases of diffuse and nodular scleritis systemic NSAIDs are efficacious; if not, short term therapy with systemic corticosteroids is recommended. In case of therapeutic failure or if only high-dose systemic steroidal anti-inflammatory drugs are efficacious in controlling the scleral disease, immunosuppressive drugs should be added or substituted. In patients with posterior scleritis or necrotizing scleritis, immunosuppressants should be the initial treatment (15-17) and, if surgical management is required in necrotizing scleritis (in 5-10% of cases), immunosuppressive therapy needs to be implemented prior to or concomitantly with grafting (scleral patch grafting) in order to improve the prognosis of the graft (16,19).

I-4 Uveitis
Uveitis, an intraocular inflammation, is defined as anterior or intermediate or posterior, based upon the location of inflammation, relative to the equator of the eye. Two types of uveitis are commonly found in rheumatic disorders: uveitis anterior and uveitis posterior. The course of inflammation is mostly a chronic relapsing one with an acute onset.
I-4-1 Anterior segment changes

Anterior uveitis is an inflammation, which is limited to the iris and the vitreous. The synonym of anterior uveitis is iritis or iridocyclitis. The patients often complain of redness, periorbital pain, photophobia, and blurred vision. Slit lamp examination reveals conjunctival injection, ciliary flash in the perilimbal area, cells and flare in the anterior chamber, and fine keratic precipitates (Fig. 17), which confirm the diagnosis. This anterior segment inflammation may not be accompanied by posterior segment involvement. Common complications due to intraocular inflammation include posterior synechiae (adhesions between iris and lens), secondary glaucoma, secondary cataract formation and development of macular edema (Fig. 18). During an acute inflammatory attack local treatment should consist of eye drops or ointments containing corticosteroids. Application frequency depends on the severity of the inflammation. In case of severe anterior uveitis, e.g. if a fibrinous reaction is present, subconjunctival steroid injections may be helpful. In contrast topical steroids are not effective in case of macular edema. For this condition steroids and acetazolamide administered systemically are useful. In addition it is necessary to apply sympathomimetics or parasympatholytics locally both to prevent posterior synechiae (Fig. 19) and to relieve ocular pain. If local treatment is insufficient, systemic treatment with, first line, corticosteroids and, second line, immunosuppressants should be discussed (20-22).

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Figure 17 - Acute anterior uveitis, note the keratic precipitates

Figure 18 - Cystoid macular edema in fluorescein angiography

Figure 19 - Posterior synechia

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I-4-2 Posterior segment changes

Involvement of the posterior part of the eye, so called posterior uveitis, includes the vitreous, the retina and the choroid. If the inflammation starts at the choroid and then involves the retina, it is named chorioretinitis. If the inflammation begins in the retina and secondarily affects secondary the choroid, it is called retinochoroiditis. These manifestations both lead to retinal, optic nerve, and macular edema. Inflammatory signs in the vitreous body could range from a moderate number of cells to a dense plasmoid reaction, but an isolated vitreous inflammation is not characteristic of rheumatic disease (21). Another severe inflammatory involvement of the posterior segment is retinal vasculitis. Typical for this condition are dilatation and engorgement of retinal vessels, cotton-wool spots (ischemic infarcts of the retinal ganglion cell layer), (Fig. 20), perivascular sheathing with inflammatory whitish yellow exudates and retinal hemorrhages (Fig. 21, 22, 23). Especially in the beginning these condition appears in the ophthalmoscopy like an early hypertensive retinopathy. In case of occlusive retinal vasculitis the fundoscopy could reveal occluded, so called silver wired (Fig. 24), chorioretinal scars, alterations of retinal pigment epithelium, and retinal and also optic nerve atrophy. In addition occlusive retinal vasculitis causes tissue hypoxia, which stimulates the growth of new vessels at the optic disc or elsewhere at the retinal layer. These neovascularisations (Fig. 25) can rupture and bleed, leading to organization with membrane formation, causing retinal holes with subsequent retinal detachment. In the beginning of posterior segment inflammation or if the involvement is located in the peripheral retinal areas, the patients usually do not complain. Later on they could suffer from seeing floaters due to vitreous involvement and, esp. when the inflammation is located on the posterior pole, from blurring vision up to severe visual loss. Diagnosis is based on slit lamp examination, ophthalmoscopy and on performing fluorescein angiography. Complications could be secondary cataract formation, secondary glaucoma, and, as mentioned above, retinal detachment, phytisis of the eye, optic disc atrophy, and visual loss that may lead to blindness. As far as retinal vasculitis indicates systemic activity of the underlying disease and as a consequence of bad prognosis, initiation of therapy is urgent. Due to the fact, that local treatment is ineffective in case of retinal involvement, systemic application of corticosteroids or immunosuppressants are required. Additional therapy for macular edema is already described in chapter I-4-1. It is necessary to keep in mind that ocular surgery, e.g. laser coagulation, vitrectomy, cataractextraction, should be done only if anti-inflammatory therapy is already substituted because of the otherwise high risk of relapse. In case of retinal hypoperfusion and secondary neovascularisations laser coagulation is often recommended. Laser coagulation with interferon-alpha combined with corticosteroids are also very helpful (24).

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Figure 20 - Multiple cotton wool spots in SLE retinopathy

Figure 21 - Retinal vasculitis with inflammatory whitish-yellow exudates and retinal hemorrhage

Figure 22 - Perivascular sheathing

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Figure 23 - Retinal vasculitis in fluorescein angiography in Behet's

Figure 24 - Silver wired (=already occluded) vessels in a patient with Behets Disease

Figure 25 - Optic disk neovascularization in a patient with Behet's disease

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I-5 Side Effects of Drugs used to treat Rheumatic Diseases


The most significant side effects of the drugs used to treat rheumatic diseases are the maculopathy associated with anti-malarial agents and cataracts and glaucoma associated with corticosteroid use (25).
I-5-1 Antimalarial drugs

The incidence of hydroxychloroquine retinopathy is low. A review of more than 1200 hydroxychloroquine prescriptions filled in a Kaiser Permanente Medical Care Program found only one case of definitive retinopathy (0.08%) and a few cases of indeterminate but probable toxicity (0.4%) (26). The condition is closely related to the daily dose of medication and duration of treatment. Risk factors for developing retinopathy include doses of chloroquine higher than 3mg/kg daily and doses of hydroxychloroquine higher than 6.5mg/kg daily, doses of hydroxychloroquine higher than 400mg/d, and cumulative doses higher than 500g (26,27). The American Academy of Ophthalmology issued in 2000 recommendations on screening for chloroquine and hydroxychloroquine toxicity. They suggested that all patients beginning either chloroquine or hydroxychloroquine therapy should have a full dilated-eye baseline examination within the first year and should then receive an annual follow up, especially in high risk patients (27).
I-5-2 TNF alpha antagonists

Treatment with TNF alpha blockers will often be initiated in inflammatory diseases resistant to conventional immunosuppressives - However, paradoxically ocular inflammation is a reported adverse event following the use of etanercept. Up to now review of the literature reveals eighteen cases of inflammatory eye disease (uveitis, scleritis, orbital myositis) believed to be associated with etanercept (28).

II- AUTOIMMUNE DISEASES II-1 Athritides


II-1-1 Rheumatoid Arthritis (RA)

Ocular involvement in RA is common, approximately 25-30 % of patients suffering from ocular pathologies. Keratoconjunctivitis sicca (KCS) can be detected in 15-25% of the RA patients, which means, that it is the most frequent manifestation in this disease. Interestingly, the severity of dry eye is independent of RA activity (1,3,13,25). Scleritis or episcleritis occur with a frequency of 4% to 10% and in scleritis RA is the most common cause of this manifestation, accounting for approximately 18%-33% of cases (1,3,13,25). Corneal disease in patients with RA can be an isolated complication, but it is most commonly associated with KCS or a form of anterior scleritis (1). Other rare manifestations are choroiditis, retinal vasculitis, idiopathic retinal hemorrhage, retinal detachment, and macular edema (1,3,13,25).

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II-1-2 Spondylarthropathies

Among the seronegative spondylarthropathies, the most frequent ocular manifestation is an acute anterior, unilateral, relapsing, uveitis. It may occasionally be bilateral. Often the anterior uveitis is the first symptom of a previous undiagnosed HLA-B27-associated disease, especially among the females. The prognosis of uveitis usually is excellent with topical treatment, and only those with posterior pole involvement with a tendency to chronicity might benefit from systemic anti-inflammatory treatment (30). Other rare ocular involvement includes KCS, keratitis, scleritis, and posterior uveitis (30,31).

II-1-2-1 Ankylosing spondylitis (AS). Approximately 25% to 40% of patients with AS develop during their course of disease anterior uveitis which occurs relatively more often in HLA-B27-positive than in HLA-B27-negative patients (1,29-31). There is a minor correlation between the activity of AS and the development of anterior uveitis. Especially in AS, but also in other HLA-B27 associated inflammatory disease, sulphasalazine may be a treatment option in preventing recurrences and reducing the severity of anterior uveitis (32). II-1-2-2 Reactive arthritis. Conjunctivitis is the most common ocular symptom and usually appears within a few weeks of the onset of arthritis or urethritis in about 58 % of patients. The second most common ocular symptom is anterior uveitis, occurring in up to 12% of patients. In individuals who are HLA-B27 positive and in those patients who have sacroiliitis, anterior uveitis is more frequent. In addition, episcleritis, scleritis, keratitis, retinal edema, and retinal vasculitis have all been reported (30,31,33). II-1-2-3 Psoriatic arthritis (PA). Eye involvement in patients with PA occurs in up to 10% and is described mainly in patients with associated arthritis. In the literature scaling of the eyelids, conjunctivitis, dry eye syndrome and anterior uveitis have been noted, interestingly twice as frequently in men as in women (29-31,34). II-1-2-4 Enteropathic arthritis. The eye is involved in 4% to 10% of patients. Acute anterior uveitis but also episcleritis and marginal keratitis have been most frequently reported (29-31,35). Salmon and coworkers described in 1991, that patients with additional arthritis or arthralgia had a higher incidence of ocular inflammation than patients without joint involvement (35).

II-2 Connective Tissue Disease


II-2-1 Systemic lupus erythematosus

Ocular manifestations of lupus are most often the reflection of systemic disease and occur in 20% of patients (1,23,36,37), but independent studies also reveal the possibility of ocular inflammatory problems preceding diagnosable SLE by five or more years (29). KCS is the most common and is present in 10% to 25% of cases. Episcleritis and scleritis can be found in approximately 10% of patients and in 23% of the inflamed eyes necrotizing scleritis occurs. Other ocular changes of the anterior eye segment include uveitis, interstitial keratitis and a discoid lupus rash over the eyelids which is often confused with blepharitis (1,23,29,36,37). In the posterior eye segment the retina and the choroid are frequently involved, second only to KCS, and in 88% of these affected patients active SLE is present (29). Cotton-wool spots (Fig. 10) and hemorrhages are the most commonly reported retinal findings, but retinal and macular edema, microaneurysms, and occlusive retinal vasculitis have also been noted (1,23,36).

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Several reports indicate a role of antiphospholipid antibodies in the retinal and choroidal vasculopathy, although their precise role in this process is uncertain (29,36). In addition neuroophthalmologic manifestations like optic neuritis, ischemic optic neuropathy, and chiasmal and retrochiasmal problems such as internuclear ophthalmoplegia (INO), have been seen. The possibility of a false diagnosis of multiple sclerosis due to the presence of INO and optic neuritis should be kept in mind (29). If retinal involvement is present aggressive therapy is required due to high morbidity (1,23,29,36,37).
II-2-2 Systemic sclerosis

The main ocular feature in this disease entity is KCS and is seen in about 40-70% of patients. In addition to the inflammatory changes of the lachrymal gland, patients will have fibrotic changes of the eyelids, the conjunctiva and the lachrymal ducts. In 5 % of patients episcleritis is present. Even retinal involvement occurs in about 50% and it is manifested most often by a mild retinopathy with cottonwool spots and intraretinal hemorrhages (29,38).
II-2-3 Primary Sjgrens syndrome (PSS)

PSS is characterised by an active inflammatory stage followed by a chronic stage. The KCS is probably due to residual lachrymal gland damage from the initial active process. Corneal ulceration and perforation due to KCS is described in patients with Sjgrens syndrome (7-9). In addition to the treatment noted above, oral pilocarpine (Salagen) may improve the symptoms of dry eyes and dry mouth (39).
II-2-4 Dermatomyositis

The hallmark of ocular involvement is the heliotrope rash affecting the eyelids. In addition episcleritis, scleritis, keratitis, anterior uveitis and retinal vasculitis rarely occur (29,40).

II-3 Vasculitides
II-3-1 Large Vessel Vasculitis II-3-1-1 Giant cell (temporal) arteritis (GCA). It is important to note that ocular involvement is not uncommon in the absence of systemic signs and symptoms. Hayreh and co-workers reported that about 50% of their patients had both ocular and extraocular symptoms, whereas 21.2% presented with ocular involvement only (41). Patients may complain of pain, visual loss, diplopia, and amaurosis fugax. The most severe ocular involvement of GCA is sudden loss of vision from ischemic optic neuropathy (in 81-94% of GCA patients) or central retinal artery occlusion. Both manifestations may be irreversible and bilateral. The reported prevalence of vision loss ranges from 15-50% (41,42). Diagnosis is confirmed with biopsy of the temporal artery and elevated titres of ESR and C-reactive protein. Biopsy will remain positive for up to two weeks after initiation of corticosteroid treatment. Immediate therapy with intravenous corticosteroids has a very fast effect and prevents permanent visual loss (1,41,42). II-3-1-2 Takayasu Arteritis. Up to 40% of patients with TA disclose microaneurysms and arteriovenous anastomoses due to underlying retinal vasculitis in fluorescein angiography.

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Neovascularisations and consequent vitreous hemorrhage could occur secondary to retinal ischemia (29,42,43).
II-3-2 Medium sized vessel vasculitis II-3-2-1 Polyarteritis nodosa (PAN). An ocular manifestation is present in 10-20% of patients and includes episcleritis, scleritis (diffuse, nodular or necrotizing), peripheral ulcerative keratitis (which could be the initial presenting symptom), and inflammation of the orbital vessels. The last may lead to bilateral orbital pseudotumor resulting in exophthalmus. Manifestation of the posterior eye segment is common in PAN and choroidal involvement is the most common. Also direct involvement of the retinal vasculature (arteries) can cause occlusive retinal vasculitis, cotton-wool spots, and central retinal artery occlusion, whereas vasculitis of the optic nerve vasculature could lead to papilledema, papillitis, and optic nerve atrophy. The described retinal findings may also occur secondary to systemic hypertension or renal disease. In addition neuroophthalmologic manifestations could occur and include extraocular muscle palsies, amaurosis fugax, homonymous hemianopia, and nystagmus (29,42,44). In case of eye involvement immediate therapy with systemic corticosteroids and/or immunosuppressants is required. II-3-2-2 Kawasaki disease. Anterior uveitis occurs in up to 66% of patients, mostly in between the first week of disease manifestation. Other ocular involvement includes conjunctival hyperemia, keratitis, papilledema, and rarely retinal vasculitis (29,42,45). II-3-3 Small-Vessel Vasculitis II-3-3-1 Churg-Strauss syndrome. Involvement of the anterior eye segment may present as granulomatous nodules of the conjunctiva and the eyelids, episcleritis, and marginal ulcerative corneal ulcer. Panuveitis, retinal vasculitis with branch retinal artery occlusion and optic disc vasculitis have been described as manifestations of the posterior eye segment. Neuro-ophthalmologic involvement might be present as ischemic optic neuropathy, amaurosis fugax, and cranial nerve palsies. In most of the cases the intraocular inflammation resolves after systemic corticosteroid therapy (42,46,47). II-3-3-2 Cutaneous leukocytoclastic vasculitis. Ocular involvement is rare. In the literature only few cases with anterior uveitis, panuveitis, multifocal chorioretinitis and vasculitis have been reported. Treatment with systemic corticosteroids was sufficient to control the ocular disease in most cases (42,48). II-3-3-3 Essential cryoglobulinemic vasculitis. The slit lamp examination may reveal corneal deposits of cryoglobulin. Therapeutic options could be superficial keratectomy or excimer laser phototherapeutic keratectomy. In addition a purtscher-like retinopathy (retinopathy of the central retina after thoracal trauma with cotton wool spots, exudates, hemorrhages, and engorgement of retinal veins), retinal vasculitis, and serous retinal detachment have been reported (42,49). II-3-3-4 Henoch-Schnlein purpura (HSP). Manifestations in the eye are rare in HSP. Only few cases have been reported in the literature, and they include episcleritis, keratitis and anterior uveitis (42,50). II-3-3-5 Microscopic polyangiitis (MPA). Ocular involvement is rare but in patients with MPA the eye inflammation may be the first presenting symptom and prompts the patient to look for an appointment by the ophthalmologist. Most often these presenting symptoms are nodules of the eyelids and of the conjunctiva with central ulceration or peripheral ulcerative keratitis (42,51).

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II-3-3-6 Wegeners granulomatosis (WG). In Wegeners granulomatosis ocular manifestation is seen in 29-52% of patients, 15% of these present already with ocular disease. In principle WG can affect any ocular or periocular structure, but the most common is orbital involvement (50%). As a consequence of this, secondary changes like compressive optic neuropathy, exophthalmus, and exposure keratopathy could be seen. Another complication, which occurs in about 25% of the patients are dacryoadenitis, -zystitis and occlusion of the naso-lachrymal duct. Due to inflammation of the lachrymal gland dry eye syndrome is present in about 50% of patients and episcleritis, scleritis and marginal corneal ulceration may be present in an additional 25%. Especially patients with scleritis demonstrate the necrotizing or the posterior type, which both has a bad prognosis and require immunosuppressive therapy. Occlusive retinal vasculitis, retinitis, choroiditis, and ischemic optic neuritis have also been described. Neuro-ophthalmologic involvement may result in Horners syndrome, cranial nerve palsy and cavernous sinus thrombosis (42,52,53).

III- AUTOIMMUNE DISEASES WITH SECONDARY VASCULITIS III-1 Relapsing Polychondritis (RP)
In up to 59% of patients with RP, ocular manifestations occur and the most common is scleral involvement with a frequency of 41%. In these patients all types of scleral inflammation (recurrent episcleritis, necrotizing and posterior scleritis) could be seen, anterior diffuse scleritis have most frequently been reported. Other eye manifestations include anterior uveitis (25%), keratitis (10%-15%) and ischemic fundus changes, like cotton wool spots, intraretinal hemorrhages, branch or central retinal vein occlusions, and ischemic optic neuropathy (29,54).

III-2 Cogans Syndrome


The typical ocular manifestation consists of bilateral nonsyphilitic interstitial keratitis with patchy vascularisation of the middle and deep corneal stroma. Other reported manifestations are eyelid edema, conjunctival injection, scleritis and mild iritis (29,55,56).

III-3 Sarcoidosis
Eye involvement occurs in 25%-30% of patients with sarcoidosis. In 50% of these patients inflammatory changes of the lachrymal glands are present. Anterior uveitis could be seen in 20% up to 70 % of patients with a possible occurrence of iris granulomas. Changes of the posterior eye segment (14-43%) include retinal vasculitis with a typical candle wax phenomena of the retinal vessels and often a multifocal choroiditis (white (inflammatory) spots on the retina) will occur. In about 10%-17% of the sarcoidosis patients an intermediate uveitis has been reported in combination with a retinal periphlebitis (esp. venous sheathing) (57).

IV- PSEUDOVASCULITIDES IV-1 Angoid streaks


Angoid streaks are seen in Pseudoxanthma elasticum, to Pagets disease, and to the Ehlers-Danlos syndrome. However in 50% of these patients no systemic disease will be diagnosed. The underlying pathological course are ruptures in the Bruchs membrane and the phenotype of these angoid streaks is like the appearance of the choriocapillaries. Development of subretinal membranes, with a marked impairment of visual function, are possible when the defects reach the macular region. Therapy with photocoagulation is in the most cases unsatisfactory (58).

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