Choroidal nodules and retinal detachments in rheumatoid arthritis

Choroidal Nodules and Retinal Detachments in Rheumatoid Arthritis* improvement Following

with Fall in lmmunoglobulin

Prednisolone

ERtC R. HURD,

B. SNYDER,

MORRIS

ZIFF,

Dallas,

and Cyclophosphamide

Therapy

Bilateral choroidal lesions and secondary retinal detachments developed in a patient with rheumatoid arthritis and a history of vascular abnormalities, iritis and scleromalacia perforans. The changes in the eyes were coincidental with an exacerbation of joint involvement and an extraordinary eruption of rheumatoid subcutaneous nodules. Because of this association, and because the ocular lesions were bilateral, it was concluded that the choroidal lesions were rheumatoid in nature, presumably rheumatoid nodules. Accordingly, the patient was treated with large doses of prednisolone and cyclophosphamide. Improvement in joint symptoms and disap pearance of the subcutaneous nodules occurred simultaneously with the disappearance of the choroidal masses and the return of visual acuity. In addition to clinical improvement, the latex fixation and the sensitized sheep cell agglutination tests became negative, the erythrocyte sedimentation rate decreased to normal and remained in the normal range, and immunoglobulins (IgG and IgM) fell to subnormal levels.

M.D.

WILLIAM

Levels

M.D.

M.D.

Texas

of eye lesions and joint disease is well known [l-4]. Uveal effusions have been observed predominantly in middle-aged men without obvious accompanying systemic disease, but two subjects have been described with associated “rheumatic disease” [l]. Uveitis is frequently associated with rheumatic disease [2,3]; and the presence of rheumatoid nodules in the sclera may result in necrosis with rupture of the globe (scleromalacia perforans) [4-61. Scleritis [4], iritis [5] and keratoconjunctivitis [5] have also been described in patients with rheumatoid arthritis. Exudative detachment of the retina associated with scleritis has been reported [7] but is relatively uncommon. Described herein is a patient with severe rheumatoid arthritis, arteritis and a history of scleromalacia perforans in whom bilateral scleritis and intraocular choroidal- nodules developed in both eyes, in association with uveal effusions and resulting retinal detachments. The development of the choroidal nodules was simultaneous with the appearance of numerous rheumatoid subcutaneous nodules, approximately 1 to 2 cm in diameter, on the occiput and elsewhere on the body. Following treatment with prednisolone and cyclophosphamide there was complete regression of the nodules and reattachment of the retinas. Subsequently, the patient’s eyes and the arthritis became virtually asymptomatic and have remained so over the past two years. In addition, tests for rheumatoid factor have been negative, erythrocyte sedimentation rates normal and immunoglobulin levels (IgM and IgG) reduced to subnormal levels. The association

* From

the

Departments

(Rheumatic The

Diseases

Universitv

School

at

of

D&s,

Dallas, Texas by

U.

S.

75235.

of

an

Center

Grant. to

Dr.

ceived

29,

1969.

Volume

48,

Hines

work

Service

was

from

and

Medical supported

the

for

February 1970

Grants National

Metabolic

Morris

Diseases,

Clinical reprints

Ziff.

CASE

Boulevard,

Research

Foundation

Requests

addressed May

This

Arthritis

Medicine

Ophthalmolonv.

Southwestern

AM-05154,

Arthritis

Internal

and

Harry

Health

and

Institute and

Texas 5323

Public

AM-09989

of Unit)

Study

should

Manuscript

be re-

REPORT

This fifty-two

year old white man (T.M.), a former fire dispatcher, had a twenty year history of recurrent episodes of arthritis involving the knees, ankles, shoulders, wrists and proximal interphalangeal joints of the hands, which confined him to a wheelchair. lritis developed at the age of thirty and was accompanied by erythema, itching and photophobia. This was associated with maxillary sinusitis. At thirty-three years of age, polyarthritis occurred 273

UNUSUAL

1.

The

the

right

Fig. In

EYE

COMPLICATIONS

appearance eye,

an

of

OF

the

inferior

RHEUMATOID

fundi

of

retinal

both

ARTHRITIS

eyes

in

detachment

(a)

-

October can

1966. be

seen

and the patient was treated with salicylates and phenylbutazone; a year later he was treated with gold thiomalate and 20 units of ACTH weekly. At the age of thirty-eight synovectomy of the left knee was performed, with a good result, and at forty-seven, synovectomy of the right elbow, also with a good result. In July 1964, at age forty-seven, treatment with prednisolone, 7.5 mg daily, was started. The prednisolone dosage was gradually increased to 20 mg daily. This medication was continued until June 1965 when superficial gangrenous ulcerations of the fingertips and toes developed. This was believed to be due to a peripheral arteritis associated with the rheumatoid arthritis. For this reason the dosage of oral steroids was tapered and the patient was given 10 units of ACTH daily. A right cervical sympathectomy was performed in an attempt to decrease the severity of the gangrene. In February 1965 episcleritis and superficial ulcerations

Fig.

2.

Appearance

eye,

the

retinal

as

274

a

bullous

of

both

detachment weal

effusion

fundi (a) (c)

has with

in

December

extended the

1966. and

underlying

is

In seen mass

the

right

inferiorly (b)

HURD

ET

AL.

overlying normal

a mass at

this

(b)

time.

in the Visual

choroid. acuity

The was

left

fundus

20/80

(OD)

was and

completely

20/50

(OS).

of the inferior aspects of the cornea developed bilaterally and gradually extended to the sclera with superficial vascularization which was most intense on the medial aspect of the left cornea. The scleral lesions took on a bluish ap pearance and in July 1965 a diagnosis of scleromalacia perforans was made. In July 1965, in addition to the progression of cornea1 and scleral involvement described, there was a marked increase in the number and size of the patient’s subcutaneous rheumatoid nodules. New nodules were noted as follows: a 5 by 5 cm nodule along the ulnar aspect of the right elbow, 3 nodules on the occiput measuring 1 by 2 cm and single nodules over the third and fourth metacarpophalangeal joints on t,he right and over the third metacarpophalangeal joint on the left which measured approximately 0.5 by 1 cm. Two nodules measuring 1 by 1 cm overlay the superior aspect of the patella of both the right and left knees. A

present. the

left

A eye.

small Visual

inferior acuity

retinal was

detachment 20/300

COD)

(a) and

is

also

20/40

present

(OS).

still

The

American

Journal

of

Medicine

in

UNUSUAL

Fig.

3.

Appearance

slide latex test cell agglutination gastrointestinal

of

both

fundi

in April

1967.

Clumping

and

dispersion

was 3+ positive and the sensitized sheep titer was 1:224. An x-ray series of the tract disclosed an ulcer on the distal les-

ser curvature of the stomach. This subsequently healed with therapy. The eye lesions diminished following topical steroid therapy. In June 1966 severe gangrenous lesions of the tips of the toes developed, and bilateral lumbar sympathectomies were performed which resulted in some improvement. About this time periorbital edema and chemosis were noted in the right eye with considerable conjunctival injection and pain. In October 1966 the patient noticed vision decreasing in this eye. Visual acuity was 20/80 in the right eye and 20/50 in the left. There was a moderately active episcleritis in the left eye. Both corneas showed a peripheral pannus of keratoconjunctivitis. Ophthalmoscopic examination of the right eye revealed an inferior serous retinal detachment with a moderate amount of subretinal fluid but without retinal breaks. The inferior peripheral choroid contained a flat, slightly elevated mottled mass which transilluminated moderately well (Fig. 1). Although the subretinal fluid imparted some motion to the detached retina with eye movement, the retinal bullae did not shift when the head was in different positions. The retina of the left eye was entirely normal. Initially, a presumptive diagnosis of metastatic carcinoma to the choroid with secondary serous retinal detachment was made. A search for a primary malignancy, including liver function tests, roentgenograms of the gastrointestinal tract, proctoscopy and intravenous pyelogram yielded negative results. Consideration was also given to the presence of a primary tumor for example a fiat melanoma, but the lesion did not have the usual dark appearance. Two months after onset of the lesion in the right eye symptoms developed in the left eye. Ophthalmoscopic examination disclosed a retinal detachment of the inferior periphery without retinal breaks. The choroid behind the detached retina was flat, but it had an abnormal mottled appearance similar to that of the elevated lesion in the right eye. A painful scleritis was present bilaterally and the retinal “mass” in the right eye persisted. The detachment in the right eye involved two thirds of the fundus. The appearance of the fundi at this time is shown in Figure 2. Visual acuity was 20/300 in the right and 20/40 in the left eye. Volume

48.

February 1970

EYE

COMPLICATIONS

of subretinal

Since

OF

pigment

(d) are

involvement

appearance ciput and

RHEUMATOID

seen

of

ARTHRITIS

OD

the

and

right

-

HURD

ET

AL

OS

eye

coincided

with

the

of crops of subcutaneous nodules on the ocelbows, and since the ocular involvement was

bilateral, the possibility that the uveal lesions represented rheumatoid lesions of the scleras and that the mass in the right fundus represented a rheumatoid nodule was considered. The maintenance dose of 10 mg of prednisolone per day, which the patient had taken for the previous six months, was continued. Treatment with cyclophosphamide (Cytoxan,@ Mead Johnson) was started on December 20, 1966, 50 mg alternating with 100 mg, daily. Laboratory studies disclosed a white blood cell count of 11,800 per cu mm, an erythrocyte sedimentation (Westergren), hemoglobin 10.9

rate of 69 mm per hour gm per cent, hematocrit

37 per cent. The platelet count was 560,000 per cu mm, the differential count 78 per cent polymorphonuclear leukocytes, 1 band form, 17 per cent lymphocytes, 1 per cent monocytes and 3 per cent eosinophils. At the end of three weeks of cyclophosphamide therapy (average of 75 mg per day for the first two weeks and 100 mg per day the third week), vision was still deteriorating. Therefore prednisolone dosage was increased from 10 to 60 mg per day. Cyclophosphamide therapy was continued at 100 mg daily (1.5 mg per kg per day). At this time, the choroids were mottled and bilateral bullous retinal detachments were present bilaterally. Following one week of combined therapy the patient’s vision began to improve both subjectively and objectively. There was less fluid in the fundi, but bullae were still present. The joint symptoms were much improved. After two weeks of therapy with steroids in large doses, tapering of the dosage was begun. After four weeks, the prednisolone dosage had been decreased to 27.5 mg daily and cyclophosphamide dosage increased to 150 mg daily. Uveal effusions, detachments, mottling of the choroids and the nodule in the right eye persisted but were less marked. Subcutaneous nodules at the right elbow and occiput appeared smaller in size. By this time the patient’s arthritis had subsided dramatically. He was able to leave his wheelchair and walk unassisted for the first time in one and a half years. When he was examined on February 28, 1967, the average daily dose of prednisolone was 27.5 mg and of cyclophosphamide 175 mg. All subretinal fluid had disappeared from both eyes. By March 14 both retinas were reattached and there was no 275

UNUSUAL

TABLE

EYE COMPLICATIONS

I

Correlation

Cytoxan

of Visual

Prednisolone

Dosage

Dosage

Date

(mgldav)

(mglday)

10/66 12166 l/67 2/67 4167

...

b/67 7167 8167 9167 10167 1168 3168 7168 1 l/68 2169 3169 4169

.

$5

100 200 200 200 200 200 250 150 150 100 100 50 50 50

OF RHEUMATOID

10

10 60 4 10 60 Taper Taper Taper 17.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5

Acuity

ARTHRITIS

with

Visual Acuity

-

Serologic

HURD

ET AL.

Determinations

and Drug

Dosages Reci-

Erythrocyte Sedimentation

Latex Fixation

procal SSCA+ Titer

I,G

Right

Left

Rate*

White Blood Cell Count

Eye

Eve

(mm/hr)

(per cu mm)

Test

20180 20/300

20150 20/40

‘ii

3+

28

1,630

50

206

1 l-,&o

...

... ...

2&o

2bj300

... ...

... ...

‘G

1:.

... ... ...

... ... ...

... ... ...

261-50

2bj60 20150 20150 20150 20140 20130 20130 20130 20130 20130 20130 20130

2+

7

...

...

...

ii 20140 20150 20140 20130 20130 20150 20140 20130 20150 20150 20150

2

1 l&O

8 16

6,900 6,300 4,800 8,800 3,650 4,850 7,500 5,100 5,900 7,400 4,800

... ...

36 9 10 6 6 7

lmmunoglobulins

(m9 %)

I,M

......

I,A

...

‘1;

. ‘;

‘Go

50

;bs

...

...

...

...

...

.0 . .

. .0 .

‘ii0

‘18

;;4

18

133

11 19 17 17

120 150 175 175

0

0

0

0

570 440

0 0 0

0 0 0

560 480 480

*Westergren method tsensitized sheep cell agglutination.

evidence of uveal effusion. However, visual acuity was still impaired, with 20/60 vision in the right eye and 20/300 in the left eye. With reattachment of the right macula there was marked improvement of vision in this eye. There was also gradual improvement of vision in the left eye. A remarkable amount of clumping and dispersion of subretinal pigment had developed in both eyes (Fig. 3). The sclera of the right eye at this time again began to show evidence of scleromalacia perforans with several round bluish areas appearing on the inferior sclera. These were asymptomatic, and only an occasional aqueous cell with a trace of flare was seen. In April 1967 while taking 200 mg of cyclophosphamide and 15 mg of prednisolone daily, cellulitis of the left ankle developed. This promptly subsided following treatment with penicillin. During this episode cyclophosphamide therapy was discontinued for a two week period, then reinstituted. Subsequently the patient did well until May 1967 when, while on a daily regimen of 10 mg of prednisolone and 200 mg of cyclophosphamide, a choroidal nodule appeared in the left eye with secondary retinal detachment. Prednisolone dosage was again increased to 60 mg per day and cyclophosphamide continued at 200 mg per day. In one month there was complete resolution of the lesion in the left eye. Again the dosage of steroids was slowly reduced to 10 mg per day and, in October 1967, in order to guard against an exacerbation as noted five months previously at this dosage level, the cyclophosphamide dosage was increased to 250 mg per day. The patient continued to ambulate, and vision continued to improve. Ophthalmologic examination showed an absence of choroidal nodules, reattachment of the retinas and disappearance of the uveal effusions with objective evidence of increased visual acuity. Visual acuity was now 20/50 in the right eye and 20/60 in the left. A moderate degree of scleritis, which caused intermittent pain and decreased vision, continued. There was no further gangrene in the fingers following initiation of the prednisolone-cyclophosphamide regimen. The subcutaneous nodules had completely disappeared. Whereas the erythrocyte sedimentation rate was elevated prior to the start of therapy with cyclophosphamide and large doses of prednisolone, the values since June 1967 276

have been within the normal range. The sensitized sheep cell agglutination titer fell from 1:28 to 0 between November 1966 and June 1967. Throughout the treatment period the white blood celt count never dropped below 3,500 per cu mm. Since June 1967 the patient’s condition has improved markedly. Cyclophosphamide dosage has been maintained between 50 and 200 mg daily. Prednisorone dosage was tapered from 60 to 7.5 mg per day between June 1967 and January 1968 and has been maintained at 7.5 mg per day since then. The eyes are completely asymptomatic. Visual acuity has improved markedly: October 1967, 20/30 in the right eye, 20140 in the left; January 1968, 20/30 in both eyes; March 1968, 20/50 in the right eye, 20/30 in the left; November 1968, 20/30 in both eyes; and currently, 2OJ50 in the right eye and 20/30 in the left eye. Between September 1968 and April 1969, platelet counts fell to the range of 60,000 to 80,000 per cu mm leading to reduction of cyclophosphamide dosage to 50 mg daily in February 1969. In April the platelet count was 125,000 per cu mm. The arthritis is essentially in remission except for occasional joint pain which occurs after prolonged activity. The patient is now able to work. Serologic Determinations. Tests for rheumatoid factor were performed on the serum by the latex slide (RA-Hyland) test and by the sensitized sheep cell agglutination test, sensitizing with one-fourth the basic agglutinating titer of amboceptor. lmmunodiffusion plates (Immune-Plate,@ Hyland) were used for the determination of IgG, IgM and IgA in the serum. It is apparent from Table I and Figure 4 that, concomitantly with the clinical improvement, there was also considerable improvement in the laboratory findings. These changes included (1) a decrease in the erythrocyte sedimentation rate to normal; (2) conversion of latex fixation and sensitized sheep ceil agglutination tests to negative; and (3) decrease of serum IgG and IgM to subnormal levels. The decrease in gamma globulin was also evident by serum protein electrophoresis (Fig. 5).

COMMENTS This

patient

unusual

demonstrates

systemic

many

manifestations

of the

usual

of rheumatoid

The American

and

some

arthritis.

Journal of Medlcina

UNUSUAL

EYE

COMPLICATIONS

OF

RHEUMATOID

ARTHRITIS

-

In addition to severe seropositive rheumatoid arthritis, he has had recurring symptoms of vasculitis in the form of intermittent gangrenous changes of the tips of the fingers and toes. He has also had numerous subcutaneous nodules on the olecranon processes, over finger joints and on the occiput. Areas of scleromalacia indicative of previous rheumatoid involvement appeared, and he has shown a number of other ocular manifestations of rheumatoid arthritis. Secondary retinal detachments due to uveal rheumatoid mass lesions such as rheumatoid nodules have been seen infrequently. Sears [7] reported two cases and reviewed the literature. In his patients a diffuse brawny scleritis, similar to that observed in our patient, was observed. In the cases cited by Sears the intraocular lesion was also diagnosed initially as a tumor until, as in the present instance, involvement of the opposite eye led to a change in the diagnosis. In another report [l] two of

75

I

50

200

HURD

ET

al

alb.

Ul

alb.

AL.

IMMUNOGLOBULINS (mg %I

I2

100

W

W .-.

4G

- 1400

300

- 1000 25

600

100

100

mm./hr. ESR 60

3+ - sz& - I.112 LATEX 2+ ; TEST I+ -

Latex

Fixation

-

1:7

Fig.

5.

Serum

and

(b)

February

globulin %6

‘167

I

‘;o” 60

(MG./DAY)

PREDNISOIBNE

40 20 0

Fig.

4.

lmmunoglobulin

sensitized

sheep

measured

over

prednisolone to

negative

and were

January,

Volume

the

erythrocyte

agglutination

two

year

period.

erythrocyte

1968.

48, February

1970

On

latex

combined

rheumatoid

sedimentation when

and

prednisolone

G

factor

rate

fell

dosage

rate,

fixation

tests

therapy

immunoglobulins

levels;

maintained

sedimentation

titers

cyclophosphamide,

hypogammaglobulinemic

changes in

and

levels,

cell

level

protein with

1969.

electrophoretic There

treatment

is and

a

pattern marked

subsidence

(a)

decrease of

November in

the

1966 gamma

symptoms.

2’69

3/60

250 (MGJDAY)

a2

B

l:28

to

and

tests

fell

became

normal. was

with M

These

decreased

seventeen patients with retinal detachment due to uveal effusion had associated “rheumatic disorders”. The retinal detachments without retinal breaks in these two patients, the presence of choroidal masses and the tendency in these patients for the uveal effusions to be bilateral were similar to the changes observed in our patient. The clinical and ophthalmologic findings in our case, when compared with previous experience, favor the con. elusion that the bilateral lesions which produced the choroidal masses and effusive (secondary) retinal detachments were of rheumatoid origin. This conclusion is based on (1) the presence of active rheumatoid arthritis associated with marked systemic involvement including vasculitis; (2) the appearance of the eye lesions simul277

UNUSUAL

EYE

COMPLICATIONS

OF

RHEUMATOID

ARTHRITIS

-

HURD

taneously with an extraordinary eruption of subcutaneous rheumatoid nodules on the elbows, metacarpophalangeal joints and occiput; (3) the presence of masses in the choroid; (4) the bilateral nature of the ocular involvement; and (5) the simultaneous disappearance of both the masses in the eye and the subcutaneous nodules following therapy with large doses of prednisolone and cyclophosphamide. Although histologic proof that the choroidal lesions were of rheumatoid origin is not available, we believe that other etiologies can be excluded. For example, the more important differential diagnoses for secondary retinal detachment due to a solid uveal lesion would include malignant melanoma, metastatic carcinoma and hemangioma. It is unlikely that these lesions would occur bilaterally and that they would have disappeared rapidly with therapy. A granulomatous process would be unlikely since there was no evidence of inflammation. Although sarcoidosis could produce a lesion that might respond similarly to this treatment, the chest roentgenogram was within normal limits, and there were no other findings suggestive of this diagnosis. Considering the possibility that the masses seen represented choroidal detachments, it is true that the resulting collections of fluid in the subchoroidal space could simulate solid lesions. However, transillumination is usually unimpaired in this condition, and the distribution of the fluid tends to be circumferential. Typical choroidal detachment would also not produce the diffuse subretinal pigmentary disturbance which this patient exhibited following the remission of the detachment. Thus we believe that the most likely basis for the changes observed is a nodular scleritis secondary to the rheumatoid process. In patients with rheumatoid arthritis who have early ocular lesions, e.g., nongranulomatous iritis, keratoconjunctivitis or episcleritis, the administration of steroids has usually produced marked improvement [4]. Steroids, given in large doses, have frequently been shown to cause disappearance of rheumatoid nodules although

ET

AL.

older and larger nodules have been unaffected [8]. Cyclophosphamide therapy has been reported to produce clinical improvement in 75 per cent of cases of rheumatoid arthritis [9], presumably by virtue of its properties as a potent, immunosuppressive drug [lo-121. It is of interest that in our case the erythrocyte sedimentation rate was normal and the rheumatoid factor titer negative during the prolonged period of quiescence of the eye lesions and subcutaneous nodules. Both of these indices were elevated during the months the patient was receiving steroids alone. The levels of IgG, IgM and IgA, although normal at the onset of therapy, decreased subsequently and IgG and IgM levels are presently in the subnormal range. The diminution of eye lesions and associated improvement in vision were clearly related to prednisolone therapy and it is probable that the disappearance of the subcutaneous nodules was also due to the steroid treatment. What role cyclophosphamide therapy played, if any, in control of the eye lesions is not certain. Nevertheless, it is noteworthy that complete remission of eye symptoms, subcutaneous nodules and joint activity was not obtained until the cyclophosphamide dosage was increased to 250 mg daily and that only at this dosage level was it possible to decrease the prednisolone dosage without an exacerbation in eye lesions. Furthermore, the virtual absence of joint symptoms, eye lesions and subcutaneous nodules, the normal erythrocyte sedimentation rates, negative rheumatoid factor tests and subnormal immunoglobulin levels over the past twenty-four months would appear to be related to the cyclophosphamide therapy. During this period the prednisolone dosage has been maintained at 7.5 mg daily. At this steroid dosage level, prior to the institution of cyclophosphamide therapy, the patient had demonstrated persistent and severely active rheumatoid arthritis for many years.

ACKNOWLEDGMENT We gratefully acknowledge the technical Estelle Lotief and Miss Carole Smith.

assistance of Miss

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