Ocular Immunology & Inflammation, Early Online, 1–8, 2014 ! Informa Healthcare USA, Inc. ISSN: 0927-3948 print / 1744-5078 online DOI: 10.3109/09273948.2014.968671
ORIGINAL ARTICLE
The Manchester Uveitis Clinic: The first 3000 patients, 2: Uveitis Manifestations, Complications, Medical and Surgical Management Ocul Immunol Inflamm Downloaded from informahealthcare.com by Yale Dermatologic Surgery on 12/29/14 For personal use only.
N. P. Jones,
FRCOphth,
The Royal Eye Hospital, Manchester, United Kingdom
ABSTRACT Purpose: To demonstrate the manifestations and complications of uveitis, and their medical and surgical management, in a very large group of patients attending the Manchester Uveitis Clinic (MUC), a specialist uveitis clinic in the Northwest of England, UK. Methods: Retrospective retrieval of data on a computerized database incorporating all new referrals to MUC from 1991 to 2013. Results: A total of 3000 new patients with uveitis were seen during a 22-year period, of which 25.2% had a single acute episode, 13.6% had acute recurrent uveitis, 20.2% had chronic fluctuating uveitis, and 41.0% had chronic unremitting uveitis. The commonest complications were cataract (35% of patients), macular edema (20.5%), and glaucoma (19.5%). Oral steroids were required in 36% of patients, oral immunosuppression in 16%, and biologic treatment in 2%. Major intraocular surgery was required in 28%. Conclusions: Oral steroid usage is not an independent risk factor for cataract formation in patients with uveitis. Oral immunosuppression usage has increased 4-fold during this study period. Keywords: Cataract, complications, glaucoma, immunosuppression, macular edema, uveitis
In 1991 the Manchester Uveitis Clinic (MUC) was created at the Manchester Royal Eye Hospital to provide a specialist uveitis service to the population of Greater Manchester and the northwest of England. Immediately a database was created to record prospectively each new patient attending the clinic. Over 3500 patients have now been seen and the collected data provide substantial information on this population. This represents the largest group of patients with uveitis reported in the medical literature. A paper detailing epidemiology and casemix has been published1 and this has recorded modes of referral to the clinic, the geographical distribution of referrals, the age of patient at disease onset and first presentation, a detailed diagnostic index, including SUN categories,
uveitis onset type and behavior, associated systemic symptoms and signs, sex ratio, and racial mix of patients. This paper addresses the manifestations and complications of uveitis and their management.
METHODS The MUC database records 42 information fields on each new patient and, for those continuing to attend, records significant changes in manifestations, diagnosis, and management.1 Data for this study were retrieved entirely from the MUC database. Statistical group comparisons were made using the chi-squared distribution.
Received 13 August 2014; revised 15 September 2014; accepted 18 September 2014; published online 11 November 2014 Correspondence: N. P. Jones, FRCOphth, Consultant Ophthalmic Surgeon, The Royal Eye Hospital, Oxford Road, Manchester M13 9WL, UK. E-mail: [email protected]
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RESULTS Between 1/3/1991 and 6/3/2013 there were 3300 patient entries into the database. Some patients in the database did not have uveitis. They included patients with scleritis but not uveitis (55), patients with juvenile idiopathic arthritis on the uveitis screening program (162), patients with Behc¸et disease who attended for baseline examination (50), patients with HIV retinopathy but no uveitis (3), and sundry others referred from physicians with systemic inflammatory disease, but exhibiting nonuveitic ophthalmic manifestations (30). The remaining 3000 patients had uveitis and all subsequent data relate to this group. The geographical catchment area for the MUC has already been described, as have the age at onset, sex ratio, and diagnostic classification,1 including SUN diagnostic criteria.2 A total of 757 (25.2%) patients had a single acute episode; 407 (13.6%) had acute recurrent uveitis; 607 (20.2%) had chronic fluctuating uveitis; and 1229 (41.0%) had chronic unremitting uveitis.
The most common diagnoses were Fuchs heterochromic uveitis (FHU; 345 patients, 11.5% of total), sarcoidosis-related uveitis (292, 9.7%), idiopathic intermediate uveitis (234, 7.8%), idiopathic acute anterior uveitis (210, 7.0%), and toxoplasmosis (206, 6.9%), these 5 diagnoses together accounting for 43% of all patients. The overall numbers for bilateral or unilateral uveitis have previously been presented.1 The laterality in specific forms of uveitis is shown in Table 1. The most common form of bilateral uveitis was intermediate uveitis (273 patients, 18% of all with bilateral disease), whereas the form of uveitis most likely to be bilateral was Vogt-Koyanagi-Harada disease (VKH, 96%). The most common form of unilateral uveitis was Fuchs heterochromic uveitis (305 patients, 21% of all with unilateral disease), whereas the form of uveitis most likely to be unilateral was herpes simplex virus-associated anterior uveitis (96%). For those with unilateral uveitis, an apparent skew toward either right or left was seen in cytomegalovirus retinitis
TABLE 1. Laterality of uveitis (diagnoses with 420 affected patients). Diagnosis Acute anterior uveitis, unknown etiology APMPPE Behc¸et disease with uveitis Birdshot retinochoroidopathy Chronic anterior uveitis, unknown etiology Chronic panuveitis, unknown etiology Cytomegalovirus retinitis Fuchs heterochromic uveitis Fungal endophthalmitis or retinitis Fungal or bacterial endophthalmitis HSV-associated anterior (kerato)uveitis HLA-B27-related uveitis Inflammatory bowel disease-related: Intermediate uveitis (any cause) Juvenile idiopathic arthritis-related uveitis Masquerade syndromes Multifocal choroiditis, unknown etiology Multiple sclerosis-related uveitis Necrotising viral retinitis (ARN and PORN) Punctate inner choroidopathy Reactive arthropathy-associated uveitis Retinal vasculitis Sarcoidosis-related Tuberculosis-related Primary retinal vasculitis Sarcoidosis-related uveitis Scleritis with uveitis Sympathetic uveitis Syphilis-associated uveitis Toxocariasis Toxoplasmosis Tuberculosis-associated uveitis VZV-associated anterior uveitis Vogt-Koyanagi-Harada disease
Total
Bilateral (%)
210 31 81 36 197 199 23 345 26 34 52 135 32 332 112 22 26 48 36 83 22 136 24 12 63 292 49 33 22 26 206 99 40 23
93 (44) 29 (93) 56 (69) 33 (92) 154 (78) 158 (79) 12 (52) 40 (12) 6 (23) 11 (32) 2 (4) 69 (51) 16 (50) 273 (82) 70 (62) 12 (54) 20 (77) 37 (77) 5 (14) 52 (63) 14 (64) 117 (86) 19 (79) 6 (50) 41 (65) 247 (85) 17 (35) 15 (45)a 10 (45) 1 (4) 7 (3) 79 (80) 0 22 (96)
Side (%)
R9L2 R 13 L 6 R 15 L 7
R 9 L 16 R 122 L 77
APMPPE, acute posterior multifocal placoid pigment epitheliopathy; ARN, acute retinal necrosis; CINCA, chronic infantile neurological, cutaneous & articular; HLA, human leucocyte antigen; HSV, herpes simplex virus; PORN, progressive outer retinal necrosis; VZV, varicella zoster virus. a Unilateral involvement implies the prior removal of the exciting eye. Ocular Immunology & Inflammation
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The Manchester Uveitis Clinic, 2 3 (R9; L2, 2-tailed p = 0.03), fungal endophthalmitis (R13; L6, 2-tailed p = 0.10), and toxocariasis (R9; L16, 2-tailed p = 0.16) but these were not statistically significant; however, for toxoplasmosis (R122; L77, 2-tailed p = 0.001), the difference was highly significant. The complications of uveitis experienced by the MUC patients are listed in Table 2, and the diagnoses most commonly causing these complications are also included. The diagnoses most often causing cataract are shown in Table 3, cystoid macular edema (CMO) in Table 4, and ocular hypertension (OHT) or glaucoma in Table 5. Cataract was the most common complication, affecting 1048 patients (34.9% of total). Of those patients using oral steroid at some stage in their management, 392/1069 (36.7%) developed TABLE 2. Complications of uveitis in patients attending MUC. Complication Cataract Macular edema Ocular hypertension & glaucoma Subretinal fibrosis Retinal detachment Band keratopathy Occlusio pupillae Phthisis Retinal neovascularization Corneal decompensation
No. of patients
% of total
Commonest diagnosis
1048 614 585
34.9 20.5 19.5
FHU INT idio FHU
158 127 78 61 52 50 32
5.3 4.2 2.6 2.0 1.7 1.7 1.1
PIC ARN JIA CAU idio CPU idio PRV FHU
ARN, acute retinal necrosis; CAU idio, idiopathic chronic anterior uveitis; CPU idio, idiopathic chronic panuveitis; INT idio, idiopathic intermediate uveitis; JIA, juvenile idiopathic arthritis; MUC, Manchester Uveitis Clinic; PIC, punctate inner choroidopathy; PRV, primary retinal vasculitis.
cataract; of those not using oral steroid, 656/1952 (33.6%) developed cataract. This difference is not significantly different (2-tailed p = 0.22). The most common type of uveitis causing cataract was FHU (243 patients, 70.4% of those with FHU). This was the type of uveitis with the second-highest risk of cataract, the highest being sympathetic uveitis (72.7%). Cystoid macular edema was the next most common complication, affecting 614 patients (20.5% of total). It was diagnosed by clinical observation prior to the introduction of OCT into clinical practice in about 2000, and increasingly using OCT thereafter. The most common type of uveitis causing CMO was intermediate uveitis (128 patients, 38.5% of those with intermediate), whereas the type of uveitis with the highest risk of CMO was acute multifocal placoid pigment epitheliopathy (74.2%), the second being birdshot retinochoroidopathy (69.4%). The third major complication was OHT or glaucoma, affecting 585 patients (19.5% of total). The most common type of uveitis causing OHT or glaucoma was FHU (100 patients, 29.0% of those with FHU), whereas the type of uveitis with the highest risk of OHT or glaucoma was Vogt-Koyanagi-Harada disease (39.1%), the second being herpes simplex virus (HSV)-related anterior uveitis (37.9%). In terms of the medical management of uveitis, a total of 1069 patients (35.6%) were treated with oral steroids. Of these, 667 (62.4%) had bilateral uveitis. The important types of uveitis for which oral steroid was used are shown in Table 6. The diagnosis for which oral steroid was prescribed most often was toxoplasmosis (141 patients), whereas the diagnosis for which oral steroid was most likely to be prescribed was Vogt-Koyanagi-Harada disease (87%).
TABLE 3. Diagnoses leading to cataract formation.
Diagnosis Fuchs heterochromic uveitis Idiopathic chronic panuveitis Idiopathic chronic anterior uveitis Sarcoidosis-related uveitis Idiopathic intermediate uveitis JIA-related uveitis Idiopathic acute anterior uveitis Tuberculosis-related uveitis HLA-B27-related uveitis Sympathetic uveitis Behc¸et disease-related uveitis Toxoplasmosis HSV-related anterior uveitis Primary retinal vasculitis Vogt-Koyanagi-Harada disease Masquerades Other diagnoses
Patients with diagnosis 345 199 197 292 234 112 210 99 135 33 81 206 58 63 23 22 593
Patients with cataract (% of those with diagnosis) 243 106 99 85 35 52 41 39 38 24 23 18 16 14 14 11 161
(70.4) (53.3) (50.2) (29.1) (14.9) (46.4) (19.5) (39.4) (28.1) (72.7) (28.4) (8.7) (27.6) (22.2) (60.8) (50.0) (27.1)
ARN, acute retinal necrosis; HSV, herpes simplex virus; JIA, juvenile idiopathic arthritis. !
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% of patients with cataract 23.2 10.1 9.4 8.1 3.3 5.0 3.9 3.6 3.6 2.3 2.2 1.7 1.5 1.3 1.3 1.0 15.4
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Oral immunosuppression and/or biologic agents were used in a total of 479 patients (15.9%) and the immunosuppressives used are shown in Table 7. The most commonly used immunosuppressive was azathioprine (206 patients) and the disease for which immunosuppression was most often used was Behc¸et disease (68/81 patients, 84%). Immunosuppression was used together with or after oral steroid as secondline therapy in 359 patients (74.9% of those requiring
oral immunosuppression, 33.6% of those using oral steroid); oral immunosuppression (single or combined) was used without oral steroid in a further 120 patients (25% of those using oral immunosuppression). Of the 479 patients requiring immunosuppression, a single drug sufficed for 265 (55%), 214 (44.6%) required combinations of, or sequential immunosuppressives; 132 required two, 51 used 3, and 31 required 4 or more. The order in which oral
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TABLE 4. Diagnoses leading to macular edema.
Diagnosis Intermediate uveitis (any cause) Idiopathic intermediate uveitis Idiopathic chronic panuveitis Sarcoidosis-related uveitis Toxoplasmosis HLA-B27-related uveitis Tuberculosis-related uveitis Idiopathic chronic anterior uveitis Behc¸et disease-related uveitis Birdshot retinochoroidopathy Punctate inner choroidopathy APMPPE Sympathetic uveitis Primary retinal vasculitis JIA-related uveitis Vogt-Koyanagi-Harada disease Fuchs heterochromic uveitis Other diagnoses
Patients with diagnosis
Patients with CMO (% of those with diagnosis)
332 234 199 292 206 135 99 197 81 36 83 31 33 63 112 23 345 831
128 87 78 69 47 31 28 28 27 25 24 23 17 15 15 13 5 82
% of patients with CMO
(38.5) (37.2) (39.2) (23.6) (22.8) (23.0) (28.3) (14.2) (33.3) (69.4) (28.9) (74.2) (51.5) (23.8) (13.4) (56.5) (1.4) (9.9)
20.8 14.2 12.7 11.2 7.6 4.4 4.6 4.6 2.2 4.0 3.9 3.7 2.8 2.4 2.4 2.1 0.8 13.3
ARN, acute retinal necrosis; CMO, cystoid macular edema; HSV, herpes simplex virus; JIA, juvenile idiopathic arthritis.
TABLE 5. Diagnoses leading to ocular hypertension and glaucoma.
Diagnosis Fuchs heterochromic uveitis Idiopathic chronic anterior uveitis Sarcoidosis-related uveitis Idiopathic chronic panuveitis Toxoplasmosis JIA-related uveitis Idiopathic acute anterior uveitis Idiopathic intermediate uveitis HSV-related anterior uveitis HLA-B27-related uveitis VZV-related uveitis Tuberculosis-related uveitis Behc¸et disease Vogt-Koyanagi-Harada disease Sympathetic uveitis Posner-Schlossman syndrome Other diagnoses
Patients with diagnosis 345 197 292 199 206 112 210 234 58 135 70 99 81 23 33 4 702
Patients with OHT& glaucoma (% of those with diagnosis) 100 66 60 46 36 34 32 24 22 20 17 15 11 9 9 4 80
(29.0) (33.5) (20.5) (23.1) (17.5) (30.3) (15.2) (10.2) (37.9) (14.8) (24.3) (15.1) (13.6) (39.1) (27.3) (100.0) (11.4)
% of patients with OHT & glaucoma 17.1 11.3 10.2 7.9 6.1 5.8 5.5 4.1 3.8 3.4 2.9 2.6 1.9 1.5 1.5 0.7 13.7
ARN, acute retinal necrosis; HSV, herpes simplex virus; JIA, juvenile idiopathic arthritis; OHT, ocular hypertension; VZV, varicella zoster virus. Ocular Immunology & Inflammation
The Manchester Uveitis Clinic, 2 5 immunosuppressives were used is shown in Table 8, and the diseases for which immunosuppression was most commonly employed are shown in Table 9. Anti-TNFa monoclonal antibody treatment was used in 63 patients, of whom 34 were children. The most common diagnosis for which treatment was TABLE 6. Main types of uveitis for which oral steroid was used. No. of patients
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Diagnosis Acute anterior uveitis, unknown etiology APMPPE Acute retinal necrosis Birdshot retinochoroidopathy Chronic anterior uveitis, unknown etiology Chronic panuveitis, unknown etiology Intermediate uveitis (all causes) Punctate inner choroidopathy Retinal vasculitis (all causes) Sympathetic uveitis Vogt-Koyanagi-Harada disease HLA-B27-related uveitis Behc¸et disease Juvenile idiopathic arthritis-related Sarcoidosis-related Syphilis Toxoplasmosis Tuberculosis-associated All types
% with diagnosis
41
19
25 26 31 45
65 72 86 23
123
62
126 30 84 27 20 31 66 33 133 14 141 45 1069
38 36 62 82 87 23 81 29 45 64 68 45
There is overlap between some of these groups. APMPPE, acute posterior multifocal placoid pigment epitheliopathy.
given was uveitis related to juvenile idiopathic arthritis (25 patients). The most commonly prescribed biologic was adalimumab (46 patients). The drugs prescribed and the order in which they were used are shown in Tables 7 and 8. Etanercept was also prescribed by pediatric rheumatologists to 16 children with juvenile idiopathic arthritis and uveitis, but this drug (a TNFa receptor fusion protein) is not therapeutic for uveitis and is not included in the tables. Rescue therapy for very severe and/or immunosuppression-unresponsive uveitis led to either cyclophosphamide treatment (13 patients) or rituximab treatment (anti-B lymphocyte monoclonal antibody, 1 patient). The pattern of immunosuppressive usage changed with time. During the first quarter of the study period (March 1991–September 1996) 37 out of 610 (6.0%) new patients were commenced on immunosuppression. During the final quarter (October 2007–March 2013) that number was 213/887 (24.0%). The choice of first immunosuppressive used during each of the 4 time periods is shown in Figure 1. A total of 841 patients (28% of total, 80% of those with cataract) underwent cataract surgery. The most common underlying diagnosis was Fuchs heterochromic uveitis (199 patients, 24% of those undergoing cataract surgery). Between January 2001 and March 2013, 491 cataract procedures have been performed in adults with uveitis. Of these, 483 have been cornealapproach phacoemulsification with foldable acrylic intraocular lens (IOL) implantation. Of the remaining 8, 7 underwent planned phacoemulsification without IOL implantation (all with substantial AC
TABLE 7. Oral immunosuppressive and biologic agents used in patients attending MUC. Agent Any immunosuppression With oral steroid Without oral steroid Single immunosuppressive 2 or more immunosuppressives 2 or more (with oral steroid) Adalimumab Anakinra Azathioprine Cyclosporine Golimumab Cyclophosphamide Infliximab Methotrexate Uveitis onset 516 yrs Mycophenolate mofetil Rituximab Tacrolimus
No. of patients (%)
% of total
% of immunosuppressed
479 359 120 265 214 177 46 1 208 154 1 13 26 173 115 149 1 11
15.9 75 25 55 45a 37a 1.5
9.7
6.9 5.1
43.9 32.5
0.4 0.9 5.8
2.7 5.5 36.5
4.9
31.4
0.4
2.3
Sixteen children were using etanercept to control juvenile idiopathic arthritis, but this drug is not used for the management of uveitis and is not included above a Either sequential or simultaneous. !
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flare following previously severe uveitis, 3 with JIAassociated uveitis, 5 with HLA-B27-associated uveitis), and in 1 case, planned implantation proved undesirable owing to intraoperative total crystalline lens dislocation. Since the creation of MUC in 1991, no IOL implanted here has required explantation. For those 585 patients with OHT or glaucoma, 178 (30%) underwent glaucoma surgery once or more (enhanced trabeculectomy using 90Sr or 5-fluorouracil,3 glaucoma drainage tube or cyclodiode laser). The most common underlying diagnosis was chronic anterior uveitis (57 patients, 32% of those undergoing surgery; 164 (5%) underwent vitreoretinal surgery); and 129 (4%) underwent other surgery, including band keratopathy removal, corneal transplantation, aqueous or vitreous tap. Overall, 845 patients (28%) required major intraocular surgery of some form in the management of their uveitis. In addition, intravitreal injection of triamcinolone for CMO secondary to uveitis commenced in 2002, and since then 245 procedures have been undertaken up to March 2013. Intravitreal bevacizumab injection for uveitisassociated CMO in patients with glaucoma, or for choroidal neovascular membrane, commenced in 2008 TABLE 8. Order of immunosuppressive or biologic used. Agent Adalimumab Anakinra Azathioprine Cyclosporine Cyclophosphamide Golimumab Infliximab Methotrexate Mycophenolate mofetil Rituximab Tacrolimus
Total
1st line
2nd
3rd
4th/+
46 1 208 154 13 1 26 173 149 1 11
3 0 148 108 6 0 2 154 51 0 6
26 1 56 36 1 1 11 8 61 0 3
13 0 4 9 2 0 9 6 29 0 1
4 0 0 1 4 0 4 5 8 1 1
For the purposes of this table, the usage of etanercept in 16 children with juvenile idiopathic arthritis was ignored.
and 35 procedures have been undertaken up to March 2013.
DISCUSSION The data presented here represent a cross-section of nontrivial uveitis seen within a specialist clinic serving a catchment population of approximately 4 M.1 The MUC is located in a large university hospital in a western city at 53 North latitude within a temperate large island. This geographical location and population have implications for disease mix, for access to care, and for provision of management. The population is mostly indigenous white Caucasian derived from Anglo-Saxon or Celtic genetics but there is a significant and increasing minority of those particularly from the Indian subcontinent but also from within the European Union, Eastern Europe, and Africa. This has implications for the import of infectious diseases, but the UK climate does not (yet) permit the proliferation of arthropod-borne viral or rickettsial diseases. No access to medical or surgical treatment was prevented for financial reasons during the period under study. The laterality of uveitis was studied. For anterior uveitis, bilateral inflammation in this series was more common than characteristically reported for population-based studies,4 but this undoubtedly reflects selection bias in referrals to a specialist uveitis service. Fuchs heterochromic uveitis is characteristically a unilateral inflammation, but in this large series as many as 12% had bilateral disease; bilateral involvement is more difficult to diagnose5 (especially in those with heavily pigmented irides) and is underdiagnosed. For patients with unilateral uveitis, a comparison was made between the involvement of right and left eyes and those with unexpected results are shown in Table 1. The discrepancy between right and left eye involvement was highly significant for toxoplasmosis
TABLE 9. Most used first-line immunosuppression for important diagnoses. Diagnosis (No. immunosuppressed) Birdshot retinochoroidopathy (20) Chronic anterior uveitis, unknown etiology (22) Chronic panuveitis, unknown etiology (45) Intermediate uveitis (all causes) (47) Primary retinal vasculitis (22) Sympathetic uveitis (12) HLA-B27-related uveitis (26) Behc¸et disease (68) Juvenile idiopathic arthritis-related (66) Sarcoidosis-related (59)
Most common (No.)
2nd (No.)
3rd (No.)
CyA (9) MTX (14) AZA (16) AZA (19) AZA (13) AZA (6) MTX (15) CyA (30) MTX (62) AZA (27)
AZA (6) AZA (4) MYC (11) CyA (12) CyA (4) CyA (5) AZA (4) AZA (23) CyA (3) MTX (16)
MYC (3) MYC (3) MTX (9) MTX (9) MYC (3) MYC (1) CyA (3) MTX (6) AZA (1) CyA (10)
There is overlap between some of these groups. AZA, azathioprine; CyA, ciclosporin; MTX, methotrexate; MYC, mycophenolate. Ocular Immunology & Inflammation
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The Manchester Uveitis Clinic, 2 7 but for no other disease; the cause is unknown and no previous reports of the same phenomenon could be located. Cataract was the most common complication of uveitis in this study, affecting over one-third of patients. More patients using oral steroid developed cataract, compared to those who did not use steroids. However, this difference was not significantly significant. This is somewhat surprising: firstly, those using oral steroid should by definition be in a group with greater uveitis severity; secondly, chronic oral steroid usage is potentially cataractogenic. These results therefore reassure that oral steroid usage is not a significant additional risk factor for cataract in those patients with underlying uveitis. Almost all patients undergoing cataract surgery during the existence of MUC had an IOL implanted; this reflects modern close control of uveitis perioperatively according to a strict MUC protocol,6 and the efficacy and safety of this approach, both in terms of results obtained (and in the fact that no IOL has required removal) has been proven.6,7 For those very few patients in whom a decision was made not to implant an IOL (because of high perceived risk), no patient has subsequently undergone secondary IOL implantation. However, secondary implantation has been performed successfully in a total of 9 patients referred following cataract surgery elsewhere (6 with FHU8). Glaucoma is a substantial cause of permanent visual loss in patients with uveitis. Risk factors include specific diseases (in this clinic, particularly VKH disease and HSV-related and JIA-related uveitis), and chronic disease9,10 as opposed to acute uveitis, and this difference becomes greater with time.8 The prevalence of OHT or glaucoma in patients with uveitis in tertiary referral centers has varied from 8.8%11 to 41.8%,9 and this clinic, at 19.5% is well
FIGURE 1. First-choice immunosuppressives or biologics used for patients registered during the existence of the Manchester Uveitis Clinic, divided into 4 equal time quarters. !
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within that expected range. The causes of OHT and glaucoma in patients with uveitis are multifactorial and relate to casemix, timeliness of first treatment for uveitis, aggressiveness of uveitis control, use of strong topical steroid (especially prednisolone acetate), and the use of intravitreal steroid injection. Since all these parameters will vary between specialist clinics in ways that are difficult to quantify, attempts directly to compare between studies should always be made with caution. Nevertheless, secondary glaucoma or steroid-induced OHT/glaucoma is recognized as a common and important complication in patients with uveitis. There were clear trends over time in the use of oral immunosuppression. A comparison of the proportion of patients treated during the first and last quarters of this study makes clear a very large change in treatment patterns, with the use of oral immunosuppression being quadrupled over the study period. An undefined proportion of this change reflects the progressively increasing throughput of MUC, but the majority cause is undoubtedly an increasing willingness to introduce oral immunosuppression coupled with the clinic’s experience of steroidinduced side effects.12 The individual immunosuppressives used reflect changing prescription choice and the emergence of better or better-tolerated drugs: azathioprine has remained an effective and economical stalwart, and has for the last 17 years been the most commonly used immunosuppressive. The use of cyclosporine has decreased over the last decade, firstly because of problematic side effects,13 secondly, after reports of cyclosporine-associated neurological involvement in patients with Behc¸et disease,14 and, thirdly, because of the emergence of mycophenolate as a better-tolerated drug.15 These changes have occurred notwithstanding substantial reductions in the cost of cyclosporine from an average (300 mg/day) of £3000 per annum in 1991 to £1300pa now. Mycophenolate mofetil, initially (2 g/day) £3500pa is also now considerably less expensive at 5£500pa and its use has substantially increased during the last quarter of this study period, reflecting reasonable tolerability and expense. Low-dose methotrexate utilization has also progressively increased over 20 years, predominantly in children with juvenile idiopathic arthritis-related uveitis as evidence of efficacy gradually appeared.16 Recent estimates of topical steroidinduced cataract in children with uveitis17 have led to a change in management in MUC to introduce oral methotrexate for children requiring more than three times daily topical steroid to control anterior uveitis. The introduction of effective monoclonal antibody treatment for uveitis has also changed management, especially during the previous 8 years. There is increasing evidence of efficacy as rescue treatment for immunosuppression-resistant uveitis18 and as primary or secondary therapy in Behc¸et disease.19
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REFERENCES In children with JIA-related uveitis, MUC management has progressively changed in the last 5–8 years so that for those with methotrexate-resistant disease, adalimumab has now almost replaced cyclosporine or mycophenolate as second-line treatment. Biologic treatment is expensive, with direct and indirect costs per patient from £9000–£12,000 pa. However, the introduction of a direct UK national funding process for Behc¸et disease in 2012 has facilitated their usage for this group of patients. As monoclonal antibody treatment is not yet approved for adult or childhood uveitis by the UK National Institute for Clinical Excellence, other treatments have been preceded by direct individual funding application; this system is in the process of change as NHS England restructures commissioning of specialist services, with the concern that funding for biologic treatment for uveitis may be withdrawn despite increasing evidence of efficacy. In summary, this paper has examined the largest group of patients attending a specialist uveitis service thus far published. The Manchester Uveitis Clinic, during the 22 years of this study period, has witnessed three major changes: Firstly, subspecialization in ophthalmology progressively increases in the United Kingdom, in parallel with a challenging medicolegal environment; referrals therefore progressively increase in number, especially where surgery or immunosuppression is anticipated. As uveitis is a group of predominantly chronic diseases in predominantly young people, uveitis services have an inexorable tendency to expand with time, and currently MUC deals with about 150 patient episodes weekly. The future may require the provision of an allencompassing uveitis service (rather than the current system of selective referral of more severe cases), and staffing may have to change to reflect that. Secondly, a recent 22-year period in any field of medicine reflects enormous changes in medical technology and expertise so that outcomes in uveitis continue to improve. Thirdly, all such developments come at a financial cost, and even fiscally well-endowed countries such as the United Kingdom are seeking to curtail increasing public expenditure; in future the ability to provide optimal care for patients with severe uveitis may be limited.
DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
1. Jones N. The Manchester Uveitis Clinic. The first 3000 patients: epidemiology and casemix. J Ocul Immunol Inflamm. 2013. Epub ahead of print. 2. Jabs DA, Nussenblatt RB, Rosenbaum JT. Standardisation of Uveitis Nomenclature (SUN) working group. Am J Ophthalmol. 2005;140:509–516. 3. Chawla A, Mercieca C, Fenerty CH, Jones NP. Outcomes and complications of trabeculectomy enhanced with 5-fluorouracil in adults with glaucoma secondary to uveitis. J Glaucoma. 2013;22:663–666. 4. Hwang DK, Chou YJ, Pu CY, Chou P. Epidemiology of uveitis among the Chinese population in Taiwan: a population-based study. Ophthalmology. 2012;119: 2371–2376. 5. Jones NP. Fuchs’ heterochromic uveitis: a reappraisal of the clinical spectrum. Eye. 1991;5:649–661. 6. Rahman I, Jones NP. Long-term follow-up of cataract extraction with intraocular lens implantation in patients with uveitis. Eye. 2005;19:191–197. 7. Suresh P, Jones NP. Phakoemulsification with intraocular lens implantation in patients with uveitis. Eye. 2001;15: 621–628. 8. Jones NP. Secondary intraocular lens implantation in Fuchs’ heterochromic uveitis. Eye. 2002;16:494–496. 9. Neri P, Azuara-Blanco A, Forrester JV. Incidence of glaucoma in patients with uveitis. J Glaucoma. 2004;13:461–465. 10. Herbert HM, Viswanathan A, Jackson H, Lightman SL. Risk factors for elevated intraocular pressure in uveitis. J Glaucoma. 2004;13:96–99. 11. Heinz C, Koch JM, Zurek-Imhoff B, Heiligenhaus A. Prevalence of uveitic secondary glaucoma and success of nonsurgical treatment in adults and children in a tertiary referral center. Ocul Immunol Inflamm. 2009;17:243–248. 12. Jones NP, Anderton LC, Cheong FM, et al. Corticosteroidinduced osteoporosis in patients with uveitis. Eye. 2002;16: 587–593. 13. Matthews J, Matthews D, Jones NP. Long-term ciclosporin for sight-threatening uveitis: efficacy and tolerability. Indian J Ophthalmol. 2010;58:55–58. 14. Akman-Demir G, Ayranci O, Kurtuncu M, et al. Cyclosporine for Behc¸et’s disease: is it associated with an increased risk of neurological involvement? Clin Exp Rheumatol. 2008;26:S84–S89. 15. Larkin G, Lightman S. Mycophenolate mofetil: a useful immunosuppressive in inflammatory eye disease. Ophthalmology. 1999;106:370–374. 16. Foeldvari I, Wierk A. Methotrexate is an effective treatment for chronic uveitis associated with juvenile idiopathic arthritis. J Rheumatol. 2005;32:362–365. 17. Thorne JE, Woreta FA, Dunn JP, Jabs DA. Risk of cataract development among children with juvenile idiopathic arthritis-related uveitis treated with topical corticosteroids. Ophthalmology. 2010;117:1436–1441. 18. Diaz-Llopis M, Salom D, Garcia-de-Vicuna C, et al. Treatment of refractory uveitis with adalimumab: a prospective multicenter study of 131 patients. Ophthalmology. 2012;119:1575–1581. 19. Okada AA, Goto H, Ohno S, Mochizuki M. Multicenter study of infliximab for refractory uveoretinitis in Behc¸et disease. Arch Ophthalmol. 2012;130:592–598.
Ocular Immunology & Inflammation
ORIGINAL ARTICLE
The Manchester Uveitis Clinic: The first 3000 patients, 2: Uveitis Manifestations, Complications, Medical and Surgical Management Ocul Immunol Inflamm Downloaded from informahealthcare.com by Yale Dermatologic Surgery on 12/29/14 For personal use only.
N. P. Jones,
FRCOphth,
The Royal Eye Hospital, Manchester, United Kingdom
ABSTRACT Purpose: To demonstrate the manifestations and complications of uveitis, and their medical and surgical management, in a very large group of patients attending the Manchester Uveitis Clinic (MUC), a specialist uveitis clinic in the Northwest of England, UK. Methods: Retrospective retrieval of data on a computerized database incorporating all new referrals to MUC from 1991 to 2013. Results: A total of 3000 new patients with uveitis were seen during a 22-year period, of which 25.2% had a single acute episode, 13.6% had acute recurrent uveitis, 20.2% had chronic fluctuating uveitis, and 41.0% had chronic unremitting uveitis. The commonest complications were cataract (35% of patients), macular edema (20.5%), and glaucoma (19.5%). Oral steroids were required in 36% of patients, oral immunosuppression in 16%, and biologic treatment in 2%. Major intraocular surgery was required in 28%. Conclusions: Oral steroid usage is not an independent risk factor for cataract formation in patients with uveitis. Oral immunosuppression usage has increased 4-fold during this study period. Keywords: Cataract, complications, glaucoma, immunosuppression, macular edema, uveitis
In 1991 the Manchester Uveitis Clinic (MUC) was created at the Manchester Royal Eye Hospital to provide a specialist uveitis service to the population of Greater Manchester and the northwest of England. Immediately a database was created to record prospectively each new patient attending the clinic. Over 3500 patients have now been seen and the collected data provide substantial information on this population. This represents the largest group of patients with uveitis reported in the medical literature. A paper detailing epidemiology and casemix has been published1 and this has recorded modes of referral to the clinic, the geographical distribution of referrals, the age of patient at disease onset and first presentation, a detailed diagnostic index, including SUN categories,
uveitis onset type and behavior, associated systemic symptoms and signs, sex ratio, and racial mix of patients. This paper addresses the manifestations and complications of uveitis and their management.
METHODS The MUC database records 42 information fields on each new patient and, for those continuing to attend, records significant changes in manifestations, diagnosis, and management.1 Data for this study were retrieved entirely from the MUC database. Statistical group comparisons were made using the chi-squared distribution.
Received 13 August 2014; revised 15 September 2014; accepted 18 September 2014; published online 11 November 2014 Correspondence: N. P. Jones, FRCOphth, Consultant Ophthalmic Surgeon, The Royal Eye Hospital, Oxford Road, Manchester M13 9WL, UK. E-mail: [email protected]
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RESULTS Between 1/3/1991 and 6/3/2013 there were 3300 patient entries into the database. Some patients in the database did not have uveitis. They included patients with scleritis but not uveitis (55), patients with juvenile idiopathic arthritis on the uveitis screening program (162), patients with Behc¸et disease who attended for baseline examination (50), patients with HIV retinopathy but no uveitis (3), and sundry others referred from physicians with systemic inflammatory disease, but exhibiting nonuveitic ophthalmic manifestations (30). The remaining 3000 patients had uveitis and all subsequent data relate to this group. The geographical catchment area for the MUC has already been described, as have the age at onset, sex ratio, and diagnostic classification,1 including SUN diagnostic criteria.2 A total of 757 (25.2%) patients had a single acute episode; 407 (13.6%) had acute recurrent uveitis; 607 (20.2%) had chronic fluctuating uveitis; and 1229 (41.0%) had chronic unremitting uveitis.
The most common diagnoses were Fuchs heterochromic uveitis (FHU; 345 patients, 11.5% of total), sarcoidosis-related uveitis (292, 9.7%), idiopathic intermediate uveitis (234, 7.8%), idiopathic acute anterior uveitis (210, 7.0%), and toxoplasmosis (206, 6.9%), these 5 diagnoses together accounting for 43% of all patients. The overall numbers for bilateral or unilateral uveitis have previously been presented.1 The laterality in specific forms of uveitis is shown in Table 1. The most common form of bilateral uveitis was intermediate uveitis (273 patients, 18% of all with bilateral disease), whereas the form of uveitis most likely to be bilateral was Vogt-Koyanagi-Harada disease (VKH, 96%). The most common form of unilateral uveitis was Fuchs heterochromic uveitis (305 patients, 21% of all with unilateral disease), whereas the form of uveitis most likely to be unilateral was herpes simplex virus-associated anterior uveitis (96%). For those with unilateral uveitis, an apparent skew toward either right or left was seen in cytomegalovirus retinitis
TABLE 1. Laterality of uveitis (diagnoses with 420 affected patients). Diagnosis Acute anterior uveitis, unknown etiology APMPPE Behc¸et disease with uveitis Birdshot retinochoroidopathy Chronic anterior uveitis, unknown etiology Chronic panuveitis, unknown etiology Cytomegalovirus retinitis Fuchs heterochromic uveitis Fungal endophthalmitis or retinitis Fungal or bacterial endophthalmitis HSV-associated anterior (kerato)uveitis HLA-B27-related uveitis Inflammatory bowel disease-related: Intermediate uveitis (any cause) Juvenile idiopathic arthritis-related uveitis Masquerade syndromes Multifocal choroiditis, unknown etiology Multiple sclerosis-related uveitis Necrotising viral retinitis (ARN and PORN) Punctate inner choroidopathy Reactive arthropathy-associated uveitis Retinal vasculitis Sarcoidosis-related Tuberculosis-related Primary retinal vasculitis Sarcoidosis-related uveitis Scleritis with uveitis Sympathetic uveitis Syphilis-associated uveitis Toxocariasis Toxoplasmosis Tuberculosis-associated uveitis VZV-associated anterior uveitis Vogt-Koyanagi-Harada disease
Total
Bilateral (%)
210 31 81 36 197 199 23 345 26 34 52 135 32 332 112 22 26 48 36 83 22 136 24 12 63 292 49 33 22 26 206 99 40 23
93 (44) 29 (93) 56 (69) 33 (92) 154 (78) 158 (79) 12 (52) 40 (12) 6 (23) 11 (32) 2 (4) 69 (51) 16 (50) 273 (82) 70 (62) 12 (54) 20 (77) 37 (77) 5 (14) 52 (63) 14 (64) 117 (86) 19 (79) 6 (50) 41 (65) 247 (85) 17 (35) 15 (45)a 10 (45) 1 (4) 7 (3) 79 (80) 0 22 (96)
Side (%)
R9L2 R 13 L 6 R 15 L 7
R 9 L 16 R 122 L 77
APMPPE, acute posterior multifocal placoid pigment epitheliopathy; ARN, acute retinal necrosis; CINCA, chronic infantile neurological, cutaneous & articular; HLA, human leucocyte antigen; HSV, herpes simplex virus; PORN, progressive outer retinal necrosis; VZV, varicella zoster virus. a Unilateral involvement implies the prior removal of the exciting eye. Ocular Immunology & Inflammation
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The Manchester Uveitis Clinic, 2 3 (R9; L2, 2-tailed p = 0.03), fungal endophthalmitis (R13; L6, 2-tailed p = 0.10), and toxocariasis (R9; L16, 2-tailed p = 0.16) but these were not statistically significant; however, for toxoplasmosis (R122; L77, 2-tailed p = 0.001), the difference was highly significant. The complications of uveitis experienced by the MUC patients are listed in Table 2, and the diagnoses most commonly causing these complications are also included. The diagnoses most often causing cataract are shown in Table 3, cystoid macular edema (CMO) in Table 4, and ocular hypertension (OHT) or glaucoma in Table 5. Cataract was the most common complication, affecting 1048 patients (34.9% of total). Of those patients using oral steroid at some stage in their management, 392/1069 (36.7%) developed TABLE 2. Complications of uveitis in patients attending MUC. Complication Cataract Macular edema Ocular hypertension & glaucoma Subretinal fibrosis Retinal detachment Band keratopathy Occlusio pupillae Phthisis Retinal neovascularization Corneal decompensation
No. of patients
% of total
Commonest diagnosis
1048 614 585
34.9 20.5 19.5
FHU INT idio FHU
158 127 78 61 52 50 32
5.3 4.2 2.6 2.0 1.7 1.7 1.1
PIC ARN JIA CAU idio CPU idio PRV FHU
ARN, acute retinal necrosis; CAU idio, idiopathic chronic anterior uveitis; CPU idio, idiopathic chronic panuveitis; INT idio, idiopathic intermediate uveitis; JIA, juvenile idiopathic arthritis; MUC, Manchester Uveitis Clinic; PIC, punctate inner choroidopathy; PRV, primary retinal vasculitis.
cataract; of those not using oral steroid, 656/1952 (33.6%) developed cataract. This difference is not significantly different (2-tailed p = 0.22). The most common type of uveitis causing cataract was FHU (243 patients, 70.4% of those with FHU). This was the type of uveitis with the second-highest risk of cataract, the highest being sympathetic uveitis (72.7%). Cystoid macular edema was the next most common complication, affecting 614 patients (20.5% of total). It was diagnosed by clinical observation prior to the introduction of OCT into clinical practice in about 2000, and increasingly using OCT thereafter. The most common type of uveitis causing CMO was intermediate uveitis (128 patients, 38.5% of those with intermediate), whereas the type of uveitis with the highest risk of CMO was acute multifocal placoid pigment epitheliopathy (74.2%), the second being birdshot retinochoroidopathy (69.4%). The third major complication was OHT or glaucoma, affecting 585 patients (19.5% of total). The most common type of uveitis causing OHT or glaucoma was FHU (100 patients, 29.0% of those with FHU), whereas the type of uveitis with the highest risk of OHT or glaucoma was Vogt-Koyanagi-Harada disease (39.1%), the second being herpes simplex virus (HSV)-related anterior uveitis (37.9%). In terms of the medical management of uveitis, a total of 1069 patients (35.6%) were treated with oral steroids. Of these, 667 (62.4%) had bilateral uveitis. The important types of uveitis for which oral steroid was used are shown in Table 6. The diagnosis for which oral steroid was prescribed most often was toxoplasmosis (141 patients), whereas the diagnosis for which oral steroid was most likely to be prescribed was Vogt-Koyanagi-Harada disease (87%).
TABLE 3. Diagnoses leading to cataract formation.
Diagnosis Fuchs heterochromic uveitis Idiopathic chronic panuveitis Idiopathic chronic anterior uveitis Sarcoidosis-related uveitis Idiopathic intermediate uveitis JIA-related uveitis Idiopathic acute anterior uveitis Tuberculosis-related uveitis HLA-B27-related uveitis Sympathetic uveitis Behc¸et disease-related uveitis Toxoplasmosis HSV-related anterior uveitis Primary retinal vasculitis Vogt-Koyanagi-Harada disease Masquerades Other diagnoses
Patients with diagnosis 345 199 197 292 234 112 210 99 135 33 81 206 58 63 23 22 593
Patients with cataract (% of those with diagnosis) 243 106 99 85 35 52 41 39 38 24 23 18 16 14 14 11 161
(70.4) (53.3) (50.2) (29.1) (14.9) (46.4) (19.5) (39.4) (28.1) (72.7) (28.4) (8.7) (27.6) (22.2) (60.8) (50.0) (27.1)
ARN, acute retinal necrosis; HSV, herpes simplex virus; JIA, juvenile idiopathic arthritis. !
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% of patients with cataract 23.2 10.1 9.4 8.1 3.3 5.0 3.9 3.6 3.6 2.3 2.2 1.7 1.5 1.3 1.3 1.0 15.4
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Oral immunosuppression and/or biologic agents were used in a total of 479 patients (15.9%) and the immunosuppressives used are shown in Table 7. The most commonly used immunosuppressive was azathioprine (206 patients) and the disease for which immunosuppression was most often used was Behc¸et disease (68/81 patients, 84%). Immunosuppression was used together with or after oral steroid as secondline therapy in 359 patients (74.9% of those requiring
oral immunosuppression, 33.6% of those using oral steroid); oral immunosuppression (single or combined) was used without oral steroid in a further 120 patients (25% of those using oral immunosuppression). Of the 479 patients requiring immunosuppression, a single drug sufficed for 265 (55%), 214 (44.6%) required combinations of, or sequential immunosuppressives; 132 required two, 51 used 3, and 31 required 4 or more. The order in which oral
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TABLE 4. Diagnoses leading to macular edema.
Diagnosis Intermediate uveitis (any cause) Idiopathic intermediate uveitis Idiopathic chronic panuveitis Sarcoidosis-related uveitis Toxoplasmosis HLA-B27-related uveitis Tuberculosis-related uveitis Idiopathic chronic anterior uveitis Behc¸et disease-related uveitis Birdshot retinochoroidopathy Punctate inner choroidopathy APMPPE Sympathetic uveitis Primary retinal vasculitis JIA-related uveitis Vogt-Koyanagi-Harada disease Fuchs heterochromic uveitis Other diagnoses
Patients with diagnosis
Patients with CMO (% of those with diagnosis)
332 234 199 292 206 135 99 197 81 36 83 31 33 63 112 23 345 831
128 87 78 69 47 31 28 28 27 25 24 23 17 15 15 13 5 82
% of patients with CMO
(38.5) (37.2) (39.2) (23.6) (22.8) (23.0) (28.3) (14.2) (33.3) (69.4) (28.9) (74.2) (51.5) (23.8) (13.4) (56.5) (1.4) (9.9)
20.8 14.2 12.7 11.2 7.6 4.4 4.6 4.6 2.2 4.0 3.9 3.7 2.8 2.4 2.4 2.1 0.8 13.3
ARN, acute retinal necrosis; CMO, cystoid macular edema; HSV, herpes simplex virus; JIA, juvenile idiopathic arthritis.
TABLE 5. Diagnoses leading to ocular hypertension and glaucoma.
Diagnosis Fuchs heterochromic uveitis Idiopathic chronic anterior uveitis Sarcoidosis-related uveitis Idiopathic chronic panuveitis Toxoplasmosis JIA-related uveitis Idiopathic acute anterior uveitis Idiopathic intermediate uveitis HSV-related anterior uveitis HLA-B27-related uveitis VZV-related uveitis Tuberculosis-related uveitis Behc¸et disease Vogt-Koyanagi-Harada disease Sympathetic uveitis Posner-Schlossman syndrome Other diagnoses
Patients with diagnosis 345 197 292 199 206 112 210 234 58 135 70 99 81 23 33 4 702
Patients with OHT& glaucoma (% of those with diagnosis) 100 66 60 46 36 34 32 24 22 20 17 15 11 9 9 4 80
(29.0) (33.5) (20.5) (23.1) (17.5) (30.3) (15.2) (10.2) (37.9) (14.8) (24.3) (15.1) (13.6) (39.1) (27.3) (100.0) (11.4)
% of patients with OHT & glaucoma 17.1 11.3 10.2 7.9 6.1 5.8 5.5 4.1 3.8 3.4 2.9 2.6 1.9 1.5 1.5 0.7 13.7
ARN, acute retinal necrosis; HSV, herpes simplex virus; JIA, juvenile idiopathic arthritis; OHT, ocular hypertension; VZV, varicella zoster virus. Ocular Immunology & Inflammation
The Manchester Uveitis Clinic, 2 5 immunosuppressives were used is shown in Table 8, and the diseases for which immunosuppression was most commonly employed are shown in Table 9. Anti-TNFa monoclonal antibody treatment was used in 63 patients, of whom 34 were children. The most common diagnosis for which treatment was TABLE 6. Main types of uveitis for which oral steroid was used. No. of patients
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Diagnosis Acute anterior uveitis, unknown etiology APMPPE Acute retinal necrosis Birdshot retinochoroidopathy Chronic anterior uveitis, unknown etiology Chronic panuveitis, unknown etiology Intermediate uveitis (all causes) Punctate inner choroidopathy Retinal vasculitis (all causes) Sympathetic uveitis Vogt-Koyanagi-Harada disease HLA-B27-related uveitis Behc¸et disease Juvenile idiopathic arthritis-related Sarcoidosis-related Syphilis Toxoplasmosis Tuberculosis-associated All types
% with diagnosis
41
19
25 26 31 45
65 72 86 23
123
62
126 30 84 27 20 31 66 33 133 14 141 45 1069
38 36 62 82 87 23 81 29 45 64 68 45
There is overlap between some of these groups. APMPPE, acute posterior multifocal placoid pigment epitheliopathy.
given was uveitis related to juvenile idiopathic arthritis (25 patients). The most commonly prescribed biologic was adalimumab (46 patients). The drugs prescribed and the order in which they were used are shown in Tables 7 and 8. Etanercept was also prescribed by pediatric rheumatologists to 16 children with juvenile idiopathic arthritis and uveitis, but this drug (a TNFa receptor fusion protein) is not therapeutic for uveitis and is not included in the tables. Rescue therapy for very severe and/or immunosuppression-unresponsive uveitis led to either cyclophosphamide treatment (13 patients) or rituximab treatment (anti-B lymphocyte monoclonal antibody, 1 patient). The pattern of immunosuppressive usage changed with time. During the first quarter of the study period (March 1991–September 1996) 37 out of 610 (6.0%) new patients were commenced on immunosuppression. During the final quarter (October 2007–March 2013) that number was 213/887 (24.0%). The choice of first immunosuppressive used during each of the 4 time periods is shown in Figure 1. A total of 841 patients (28% of total, 80% of those with cataract) underwent cataract surgery. The most common underlying diagnosis was Fuchs heterochromic uveitis (199 patients, 24% of those undergoing cataract surgery). Between January 2001 and March 2013, 491 cataract procedures have been performed in adults with uveitis. Of these, 483 have been cornealapproach phacoemulsification with foldable acrylic intraocular lens (IOL) implantation. Of the remaining 8, 7 underwent planned phacoemulsification without IOL implantation (all with substantial AC
TABLE 7. Oral immunosuppressive and biologic agents used in patients attending MUC. Agent Any immunosuppression With oral steroid Without oral steroid Single immunosuppressive 2 or more immunosuppressives 2 or more (with oral steroid) Adalimumab Anakinra Azathioprine Cyclosporine Golimumab Cyclophosphamide Infliximab Methotrexate Uveitis onset 516 yrs Mycophenolate mofetil Rituximab Tacrolimus
No. of patients (%)
% of total
% of immunosuppressed
479 359 120 265 214 177 46 1 208 154 1 13 26 173 115 149 1 11
15.9 75 25 55 45a 37a 1.5
9.7
6.9 5.1
43.9 32.5
0.4 0.9 5.8
2.7 5.5 36.5
4.9
31.4
0.4
2.3
Sixteen children were using etanercept to control juvenile idiopathic arthritis, but this drug is not used for the management of uveitis and is not included above a Either sequential or simultaneous. !
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flare following previously severe uveitis, 3 with JIAassociated uveitis, 5 with HLA-B27-associated uveitis), and in 1 case, planned implantation proved undesirable owing to intraoperative total crystalline lens dislocation. Since the creation of MUC in 1991, no IOL implanted here has required explantation. For those 585 patients with OHT or glaucoma, 178 (30%) underwent glaucoma surgery once or more (enhanced trabeculectomy using 90Sr or 5-fluorouracil,3 glaucoma drainage tube or cyclodiode laser). The most common underlying diagnosis was chronic anterior uveitis (57 patients, 32% of those undergoing surgery; 164 (5%) underwent vitreoretinal surgery); and 129 (4%) underwent other surgery, including band keratopathy removal, corneal transplantation, aqueous or vitreous tap. Overall, 845 patients (28%) required major intraocular surgery of some form in the management of their uveitis. In addition, intravitreal injection of triamcinolone for CMO secondary to uveitis commenced in 2002, and since then 245 procedures have been undertaken up to March 2013. Intravitreal bevacizumab injection for uveitisassociated CMO in patients with glaucoma, or for choroidal neovascular membrane, commenced in 2008 TABLE 8. Order of immunosuppressive or biologic used. Agent Adalimumab Anakinra Azathioprine Cyclosporine Cyclophosphamide Golimumab Infliximab Methotrexate Mycophenolate mofetil Rituximab Tacrolimus
Total
1st line
2nd
3rd
4th/+
46 1 208 154 13 1 26 173 149 1 11
3 0 148 108 6 0 2 154 51 0 6
26 1 56 36 1 1 11 8 61 0 3
13 0 4 9 2 0 9 6 29 0 1
4 0 0 1 4 0 4 5 8 1 1
For the purposes of this table, the usage of etanercept in 16 children with juvenile idiopathic arthritis was ignored.
and 35 procedures have been undertaken up to March 2013.
DISCUSSION The data presented here represent a cross-section of nontrivial uveitis seen within a specialist clinic serving a catchment population of approximately 4 M.1 The MUC is located in a large university hospital in a western city at 53 North latitude within a temperate large island. This geographical location and population have implications for disease mix, for access to care, and for provision of management. The population is mostly indigenous white Caucasian derived from Anglo-Saxon or Celtic genetics but there is a significant and increasing minority of those particularly from the Indian subcontinent but also from within the European Union, Eastern Europe, and Africa. This has implications for the import of infectious diseases, but the UK climate does not (yet) permit the proliferation of arthropod-borne viral or rickettsial diseases. No access to medical or surgical treatment was prevented for financial reasons during the period under study. The laterality of uveitis was studied. For anterior uveitis, bilateral inflammation in this series was more common than characteristically reported for population-based studies,4 but this undoubtedly reflects selection bias in referrals to a specialist uveitis service. Fuchs heterochromic uveitis is characteristically a unilateral inflammation, but in this large series as many as 12% had bilateral disease; bilateral involvement is more difficult to diagnose5 (especially in those with heavily pigmented irides) and is underdiagnosed. For patients with unilateral uveitis, a comparison was made between the involvement of right and left eyes and those with unexpected results are shown in Table 1. The discrepancy between right and left eye involvement was highly significant for toxoplasmosis
TABLE 9. Most used first-line immunosuppression for important diagnoses. Diagnosis (No. immunosuppressed) Birdshot retinochoroidopathy (20) Chronic anterior uveitis, unknown etiology (22) Chronic panuveitis, unknown etiology (45) Intermediate uveitis (all causes) (47) Primary retinal vasculitis (22) Sympathetic uveitis (12) HLA-B27-related uveitis (26) Behc¸et disease (68) Juvenile idiopathic arthritis-related (66) Sarcoidosis-related (59)
Most common (No.)
2nd (No.)
3rd (No.)
CyA (9) MTX (14) AZA (16) AZA (19) AZA (13) AZA (6) MTX (15) CyA (30) MTX (62) AZA (27)
AZA (6) AZA (4) MYC (11) CyA (12) CyA (4) CyA (5) AZA (4) AZA (23) CyA (3) MTX (16)
MYC (3) MYC (3) MTX (9) MTX (9) MYC (3) MYC (1) CyA (3) MTX (6) AZA (1) CyA (10)
There is overlap between some of these groups. AZA, azathioprine; CyA, ciclosporin; MTX, methotrexate; MYC, mycophenolate. Ocular Immunology & Inflammation
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The Manchester Uveitis Clinic, 2 7 but for no other disease; the cause is unknown and no previous reports of the same phenomenon could be located. Cataract was the most common complication of uveitis in this study, affecting over one-third of patients. More patients using oral steroid developed cataract, compared to those who did not use steroids. However, this difference was not significantly significant. This is somewhat surprising: firstly, those using oral steroid should by definition be in a group with greater uveitis severity; secondly, chronic oral steroid usage is potentially cataractogenic. These results therefore reassure that oral steroid usage is not a significant additional risk factor for cataract in those patients with underlying uveitis. Almost all patients undergoing cataract surgery during the existence of MUC had an IOL implanted; this reflects modern close control of uveitis perioperatively according to a strict MUC protocol,6 and the efficacy and safety of this approach, both in terms of results obtained (and in the fact that no IOL has required removal) has been proven.6,7 For those very few patients in whom a decision was made not to implant an IOL (because of high perceived risk), no patient has subsequently undergone secondary IOL implantation. However, secondary implantation has been performed successfully in a total of 9 patients referred following cataract surgery elsewhere (6 with FHU8). Glaucoma is a substantial cause of permanent visual loss in patients with uveitis. Risk factors include specific diseases (in this clinic, particularly VKH disease and HSV-related and JIA-related uveitis), and chronic disease9,10 as opposed to acute uveitis, and this difference becomes greater with time.8 The prevalence of OHT or glaucoma in patients with uveitis in tertiary referral centers has varied from 8.8%11 to 41.8%,9 and this clinic, at 19.5% is well
FIGURE 1. First-choice immunosuppressives or biologics used for patients registered during the existence of the Manchester Uveitis Clinic, divided into 4 equal time quarters. !
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within that expected range. The causes of OHT and glaucoma in patients with uveitis are multifactorial and relate to casemix, timeliness of first treatment for uveitis, aggressiveness of uveitis control, use of strong topical steroid (especially prednisolone acetate), and the use of intravitreal steroid injection. Since all these parameters will vary between specialist clinics in ways that are difficult to quantify, attempts directly to compare between studies should always be made with caution. Nevertheless, secondary glaucoma or steroid-induced OHT/glaucoma is recognized as a common and important complication in patients with uveitis. There were clear trends over time in the use of oral immunosuppression. A comparison of the proportion of patients treated during the first and last quarters of this study makes clear a very large change in treatment patterns, with the use of oral immunosuppression being quadrupled over the study period. An undefined proportion of this change reflects the progressively increasing throughput of MUC, but the majority cause is undoubtedly an increasing willingness to introduce oral immunosuppression coupled with the clinic’s experience of steroidinduced side effects.12 The individual immunosuppressives used reflect changing prescription choice and the emergence of better or better-tolerated drugs: azathioprine has remained an effective and economical stalwart, and has for the last 17 years been the most commonly used immunosuppressive. The use of cyclosporine has decreased over the last decade, firstly because of problematic side effects,13 secondly, after reports of cyclosporine-associated neurological involvement in patients with Behc¸et disease,14 and, thirdly, because of the emergence of mycophenolate as a better-tolerated drug.15 These changes have occurred notwithstanding substantial reductions in the cost of cyclosporine from an average (300 mg/day) of £3000 per annum in 1991 to £1300pa now. Mycophenolate mofetil, initially (2 g/day) £3500pa is also now considerably less expensive at 5£500pa and its use has substantially increased during the last quarter of this study period, reflecting reasonable tolerability and expense. Low-dose methotrexate utilization has also progressively increased over 20 years, predominantly in children with juvenile idiopathic arthritis-related uveitis as evidence of efficacy gradually appeared.16 Recent estimates of topical steroidinduced cataract in children with uveitis17 have led to a change in management in MUC to introduce oral methotrexate for children requiring more than three times daily topical steroid to control anterior uveitis. The introduction of effective monoclonal antibody treatment for uveitis has also changed management, especially during the previous 8 years. There is increasing evidence of efficacy as rescue treatment for immunosuppression-resistant uveitis18 and as primary or secondary therapy in Behc¸et disease.19
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N. P. Jones
Ocul Immunol Inflamm Downloaded from informahealthcare.com by Yale Dermatologic Surgery on 12/29/14 For personal use only.
REFERENCES In children with JIA-related uveitis, MUC management has progressively changed in the last 5–8 years so that for those with methotrexate-resistant disease, adalimumab has now almost replaced cyclosporine or mycophenolate as second-line treatment. Biologic treatment is expensive, with direct and indirect costs per patient from £9000–£12,000 pa. However, the introduction of a direct UK national funding process for Behc¸et disease in 2012 has facilitated their usage for this group of patients. As monoclonal antibody treatment is not yet approved for adult or childhood uveitis by the UK National Institute for Clinical Excellence, other treatments have been preceded by direct individual funding application; this system is in the process of change as NHS England restructures commissioning of specialist services, with the concern that funding for biologic treatment for uveitis may be withdrawn despite increasing evidence of efficacy. In summary, this paper has examined the largest group of patients attending a specialist uveitis service thus far published. The Manchester Uveitis Clinic, during the 22 years of this study period, has witnessed three major changes: Firstly, subspecialization in ophthalmology progressively increases in the United Kingdom, in parallel with a challenging medicolegal environment; referrals therefore progressively increase in number, especially where surgery or immunosuppression is anticipated. As uveitis is a group of predominantly chronic diseases in predominantly young people, uveitis services have an inexorable tendency to expand with time, and currently MUC deals with about 150 patient episodes weekly. The future may require the provision of an allencompassing uveitis service (rather than the current system of selective referral of more severe cases), and staffing may have to change to reflect that. Secondly, a recent 22-year period in any field of medicine reflects enormous changes in medical technology and expertise so that outcomes in uveitis continue to improve. Thirdly, all such developments come at a financial cost, and even fiscally well-endowed countries such as the United Kingdom are seeking to curtail increasing public expenditure; in future the ability to provide optimal care for patients with severe uveitis may be limited.
DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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