실험적 만성관절염에 미치는 Corticosteroid의 영향

Abstract

[한글]

Effects of Corticosteroid on Experimental Chronic Arthritis in Rats

Ki Hong Choi, M.D.

Department of Pharmacology & Toxicology

Yonsei University College of Medicine, Seoul, Korea

(Directed by Prof. W.C.Lee, M.D. & S.S.Hong. M.D.

Since Hench et al. claimed the beneficial effects of cortisone and ACTH on

rheumatoid arthritis in 1949. the adrenocortical hormones have been widely employed

in the treatment of arthritis. Cortisone is known to effect a marked reduction of

pain and swelling of the arthritic joint with improved range of motion, although

there is less histologic improvement. These changes are thought to be due to the

anti-inflammatory and glucogenic action of cortisone.

In 1951, Hollander et al. first observed that the local administration of

hydrocortisone elicited a better effect in the rheumatoid and degenerative

arthritis than that found following systemic administration. However, some authors

reported the local use of cortisone resulted in a Charcot's change, aseptic

necrosis of bone and occasionally a latent infection in the joint.

In this paper the systemic and local effects of prednisolone acetate on

formaldehyde-induced chronic arthritis will be presented.

Ⅰ. Materials and Methods

One hundred and ten young albino rats, around 90 gm., were used in this study. In

78 rats chronic arthritis had been induced in the right ankle; the rest of the

animals were used as non-arthritic controls.

A. Induction of chronic arthritis

Chronic arthritis was induced by the methods of Selye, injecting formaldehyde

beneath the plantar aponeuroses of the right hind paw: 0.1 cc of 1% solution twice

and 0.1 cc of 2% solution twice at a three days interval. Thereafter the animals

were kept for 32 dyas to allow the chronic arthritic state to develop.

B. Experimental groups

1. Chronic arthritic groups,

68 chronic arthritic rats were grouped and treated as follows;

(a) 14 rats were given normal saline 0.1 cc into the arthritic ankle joint

capsule every three days.

(b) 14 rats were given prednisolone acetate 1.0 mg(0.1cc) in same way as above

group.

(c) 20 rats were given prednisolone acetate 0.33mg, daily, intra-muscularly into

the left gluteal muscle and 10 out of these 20 rats received in addition norsaline

0.1cc into the arthritic joint.

(d) 20 rats were treated as group (c) except daily increasing doses of

prednisolone acetate to 1.5mg.

2. Non-arthritic control groups;

The non-arthritic 32 normal rats were divided and treated the same as group (a)

and (b) in the arthritic groups.

Weights, circumferences of the ankle and limitation of joint motions as well as

systemic changes were cheked every three days for 54 days. The animals were killed

at various time intervals, and histologic examinations were made of the involved

joints.

Ⅱ. Results

A. Induction of chronic arthritis

Marked ankle swelling was produced on every injection of the formaldehyde up to

an average circumference of 27.0mm from the initial average of 18.7mm. The average

joint motion was limited 28 degrees. In 32 days the final circumferential increase

of the ankles averaged 2.3mm in comparison to the uninvolved side, and the average

motion limitation was 11 degrees. The final histologic changes were proliferation

of joint synovium and capsule with abundant capillaries and infiltration of small

round cells which was compatible with a diagnosis of the chronic stage of

rheumatoid arthritis.

B. Body weight and systemic changes

1. Non-arthritic control groups;

Normal saline injections showed no changes in the rats. Their final average

weight gain was 74% of the initial weight. Local injection of prednisolone resulted

in a marked inhibition of weight gain (only 7%) with marked emaciation and skin

erosion of the lips and fore paws.

2. Chronic arthritic groups;

Local injection of normal saline caused results similar to the non-arthritic

control group with an average of 61% final weight gain. Local injection of

prednisolone resulted in an average of 5% weight loss in the first half period of

the experiment but finally there was a 5% gain in 54 days.

Systemic injection of prednisolone caused an average weight loss of 10%

throughout the experiment. Massive doses of prednisolone caused a sudden and marked

loss of weight with severe skin erosion and death in nine to fifteen days.

C. Ankle jiont changes

1. Non-arthritic control groups;

Local injection of normal saline caused no chages in the ankle joint which grew

normally. Local injection of prednisolone over 15 days reduced the circumferences

of the ankle an average of 1.3mm but during the next five weeks the circumference

increase slowly. They became infected.

2. Chronic arthritic groups;

Local injection of normal saline into the arthritic ankles reduced the ankle

swelling an average of 1.17mm during the first two weeks, thereafter finally a

fibrous ankylosis occured in the joints. Prednisolone locally reduced the swelling

markedly (2.4mm in average) in 15 days but thereafter the swelling became worse

during the next four weeks. Finally the ankles became infected and there was marked

skin erosion. The joint motion became free in one week.

Systemic injection of prednisolone elicit a very poor effect on the ankle

swelling throughout the experiment and the ankle swelling was reduced less than

0.8mm in average. Limitation of joint motion disappeared within ten days but later

in the experiment there was a tendency for induration around the ankle. Massive

doses of prednisolone systemically markedly reduced swelling until the rats dies in

9 to 15 days.

D. Histological Changes

1. Non-arthritic control groups;

Local injection of normal saline caused no changes but prednisolone locally

resulted in a marked atrophy of the subcutaneous, tendon, ligament and muscle

tissue and small abscess formation during the 54 days study period.

2. Chronic arthritic groups;

Normal saline locally had no effect on the pathologic joint. Finally a fibrous

ankylosis of the ankle joints occured. Prednisolone locally resulted in an almost

complete disappearance of the pathological changes within 18 days, but also there

was a marked atrophy of the normal connective tissue and also abscess formation

noted after 30 days.

Systemic injection of prednisolone were followed by an improvement in the

histological changes which was still incomplete at the last day of the experiment.

Massive doses of prednisolone injection caused a marked atrophy of the connective

tissue with only a little improvement on the arthritic changes until the rats died.

One third showed abscess formation.

1. Formaldehyde-induced chronic arthritis of Selye was reprcduced in close

similarity to the pathological changes in the chronic stage of rheumatoid

arthritis.

2. The administration of prednisolone, either systemic or local, caused marked

inhibition of normal weight gain in young rats, being more pronounced in female.

3. Prolonged or massive administration of prednisolone caused skin erosion and

joint infection. These side effects were more severe after systemic administration

than after local administration.

4. The local administration of prednisolone caused atrophy of the periarticular

connective tissue in intact animals.

5. The administration of prednisolone was followed by a return to the full range

of joint motion in relatively earier stage of treatment in arthritic animals.

6. Almost complete recovery of the pathological changes of experimental chronic

arthritis were obtained in prolonged local injections of prednisolone. However, a

prolonged administration was accompanied by atrophy of intact connective tissue and

increased chance to infection.

7. The greatest therapeutic effects of involved arthritic tissue were obtained in

first eight days by local injection of prednisolone in minimum involvement of

intact tissue.

From the data obtained, it is concluded that the greatest effect of

corticosteroid in chronic arthritis is secured by a local and short term

administration of the drug.

[영문]

Since Hench et al. claimed the beneficial effects of cortisone and ACTH on rheumatoid arthritis in 1949. the adrenocortical hormones have been widely employed in the treatment of arthritis. Cortisone is known to effect a marked reduction of pain and swelling of the arthritic joint with improved range of motion, although there is less histologic improvement. These changes are thought to be due to the anti-inflammatory and glucogenic action of cortisone.

In 1951, Hollander et al. first observed that the local administration of hydrocortisone elicited a better effect in the rheumatoid and degenerative arthritis than that found following systemic administration. However, some authors reported the local use of cortisone resulted in a Charcot's change, aseptic necrosis of bone and occasionally a latent infection in the joint.

In this paper the systemic and local effects of prednisolone acetate on formaldehyde-induced chronic arthritis will be presented.

Ⅰ. Materials and Methods

One hundred and ten young albino rats, around 90 gm., were used in this study. In 78 rats chronic arthritis had been induced in the right ankle; the rest of the animals were used as non-arthritic controls.

A. Induction of chronic arthritis

Chronic arthritis was induced by the methods of Selye, injecting formaldehyde beneath the plantar aponeuroses of the right hind paw: 0.1 cc of 1% solution twice and 0.1 cc of 2% solution twice at a three days interval. Thereafter the animals

were kept for 32 dyas to allow the chronic arthritic state to develop.

B. Experimental groups

1. Chronic arthritic groups,

68 chronic arthritic rats were grouped and treated as follows;

(a) 14 rats were given normal saline 0.1 cc into the arthritic ankle joint capsule every three days.

(b) 14 rats were given prednisolone acetate 1.0 mg(0.1cc) in same way as above group.

(c) 20 rats were given prednisolone acetate 0.33mg, daily, intra-muscularly into the left gluteal muscle and 10 out of these 20 rats received in addition norsaline 0.1cc into the arthritic joint.

(d) 20 rats were treated as group (c) except daily increasing doses of prednisolone acetate to 1.5mg.

2. Non-arthritic control groups;

The non-arthritic 32 normal rats were divided and treated the same as group (a) and (b) in the arthritic groups.

Weights, circumferences of the ankle and limitation of joint motions as well as systemic changes were cheked every three days for 54 days. The animals were killed at various time intervals, and histologic examinations were made of the involved

joints.

Ⅱ. Results

A. Induction of chronic arthritis

Marked ankle swelling was produced on every injection of the formaldehyde up to an average circumference of 27.0mm from the initial average of 18.7mm. The average joint motion was limited 28 degrees. In 32 days the final circumferential increase

of the ankles averaged 2.3mm in comparison to the uninvolved side, and the average motion limitation was 11 degrees. The final histologic changes were proliferation of joint synovium and capsule with abundant capillaries and infiltration of small

round cells which was compatible with a diagnosis of the chronic stage of rheumatoid arthritis.

B. Body weight and systemic changes

1. Non-arthritic control groups;

Normal saline injections showed no changes in the rats. Their final average weight gain was 74% of the initial weight. Local injection of prednisolone resulted in a marked inhibition of weight gain (only 7%) with marked emaciation and skin

erosion of the lips and fore paws.

2. Chronic arthritic groups;

Local injection of normal saline caused results similar to the non-arthritic control group with an average of 61% final weight gain. Local injection of prednisolone resulted in an average of 5% weight loss in the first half period of the experiment but finally there was a 5% gain in 54 days.

Systemic injection of prednisolone caused an average weight loss of 10% throughout the experiment. Massive doses of prednisolone caused a sudden and marked loss of weight with severe skin erosion and death in nine to fifteen days.

C. Ankle jiont changes

1. Non-arthritic control groups;

Local injection of normal saline caused no chages in the ankle joint which grew normally. Local injection of prednisolone over 15 days reduced the circumferences of the ankle an average of 1.3mm but during the next five weeks the circumference increase slowly. They became infected.

2. Chronic arthritic groups;

Local injection of normal saline into the arthritic ankles reduced the ankle swelling an average of 1.17mm during the first two weeks, thereafter finally a fibrous ankylosis occured in the joints. Prednisolone locally reduced the swelling

markedly (2.4mm in average) in 15 days but thereafter the swelling became worse during the next four weeks. Finally the ankles became infected and there was marked skin erosion. The joint motion became free in one week.

Systemic injection of prednisolone elicit a very poor effect on the ankle swelling throughout the experiment and the ankle swelling was reduced less than 0.8mm in average. Limitation of joint motion disappeared within ten days but later in the experiment there was a tendency for induration around the ankle. Massive doses of prednisolone systemically markedly reduced swelling until the rats dies in 9 to 15 days.

D. Histological Changes

1. Non-arthritic control groups;

Local injection of normal saline caused no changes but prednisolone locally resulted in a marked atrophy of the subcutaneous, tendon, ligament and muscle tissue and small abscess formation during the 54 days study period.

2. Chronic arthritic groups;

Normal saline locally had no effect on the pathologic joint. Finally a fibrous ankylosis of the ankle joints occured. Prednisolone locally resulted in an almost complete disappearance of the pathological changes within 18 days, but also there

was a marked atrophy of the normal connective tissue and also abscess formation noted after 30 days.

Systemic injection of prednisolone were followed by an improvement in the histological changes which was still incomplete at the last day of the experiment.

Massive doses of prednisolone injection caused a marked atrophy of the connective tissue with only a little improvement on the arthritic changes until the rats died.

One third showed abscess formation.

1. Formaldehyde-induced chronic arthritis of Selye was reprcduced in close similarity to the pathological changes in the chronic stage of rheumatoid arthritis.

2. The administration of prednisolone, either systemic or local, caused marked inhibition of normal weight gain in young rats, being more pronounced in female.

3. Prolonged or massive administration of prednisolone caused skin erosion and joint infection. These side effects were more severe after systemic administration than after local administration.

4. The local administration of prednisolone caused atrophy of the periarticular connective tissue in intact animals.

5. The administration of prednisolone was followed by a return to the full range of joint motion in relatively earier stage of treatment in arthritic animals.

6. Almost complete recovery of the pathological changes of experimental chronic arthritis were obtained in prolonged local injections of prednisolone. However, a prolonged administration was accompanied by atrophy of intact connective tissue and

increased chance to infection.

7. The greatest therapeutic effects of involved arthritic tissue were obtained in first eight days by local injection of prednisolone in minimum involvement of intact tissue.

From the data obtained, it is concluded that the greatest effect of corticosteroid in chronic arthritis is secured by a local and short term administration of the drug.