Re: Penicillamine use in scleroderma

[Guest guest]

Hi,

I also was on penicillamine three years ago for scleroderma. I got a

purple colored rash all over my body that itched for 7 weeks. My skin turned

to scales for a time as it was so thick all over my body from the scleroderma

and I had a hard time passing the penicillamine through my body. I also lost

my sense of taste for 7 weeks. Water had a real vulgar taste to it and I

used heavy lemon or lime to tolerate it. It is a very cruel drug and It is

not a proven therapy for scleroderma. I am on the AP for three years now and

I am coming to the end now. I (had) very advanced scleroderma and they did

not know if I would live. They gave me two weeks to live on February 23,

1999. My mouth is finally coming free. The rest of my body is soft now. I

look like me and my life is so different. I thank God for showing me the AP.

Judy/Florida

[Guest guest]

Hi Roni,

Here's an Israeli study for a start. I really feel strongly about

d-penicillamine - my daughter was given this stuff before Ethel told us

about antibiotic therapy. She was so ill already and penicillamine made

her incredibly sicker - her hands swelled up so much she thought they were

going to burst and the itching drove her crazy. The chief rheumatologist

at our biggest hospital prescribed it and then went on holidays for three

months, telling her that 'as she was a laboratory technician, she could do

her own blood tests.' The typically Australian comment that comes to mind

is unprintable in this forum.

I'm looking for the US multi-center trial also.

Chris.

_______________________________________________________________

Rapid Progression of Scleroderma Possibly Associated with Penicillamine

Therapy

Author: Yosef S. Haviv, Rifaat Safadi, Division of Medicine, Hadassah Hebrew

University Medical Center, Jerusalem, Israel

[Clin Drug Invest 15(1):61-63, 1998. © 1998 Adis International Limited]

Systemic sclerosis is a disorder affecting the

skin and internal organs. Its pathogenesis

consists of fibrosis and vasculopathy, secondary

to inflammation and immunological dysregulation.

The latter may involve increased macrophage

synthesis of interleukin (IL)-1, IL-6 and tumour

necrosis factor (TNF), leading to proliferation

of fibroblasts and endothelial cells.

The pathogenesis is probably mainly influenced by

environmental factors rather than genetic

factors.[1] However, chemical-associated systemic

sclerosis has been linked to human leucocyte

antigen (HLA)-type, chromosomal abnormalities,

and enzyme deficiencies.[2] Importantly,

chemical-associated systemic sclerosis cannot be

distinguished pathologically or clinically from

idiopathic systemic sclerosis. Scleroderma-like

skin changes have been associated with several

occupational compounds. Internal organs are

usually not involved in these disorders.

The classic syndrome is the well known toxic oil

syndrome that affected 20 000 people in Spain. In

this epidemic, 10% of affected people developed a

chronic scleroderma-like disorder, with a

positive antinuclear factor. Many of them also

had HLA-DR3 and DR4. Other well characterised

chemicals associated with scleroderma are

solvents such as chlorinated, aliphatic and

aromatic hydrocarbons, silica, plastic materials

such as epoxy resins and vinyl chloride,

detergent, herbicides, silicone prostheses, and

various drugs, among which are bleomycin,

amphetamine, cocaine, amfepramone

(diethylpropion), pentazocine, and

penicillamine.[3]

In this paper, we describe a patient who

presented with scleroderma and while treated with

penicillamine and high-dose corticosteroids,

developed rapidly progressive systemic sclerosis

and normotensive scleroderma renal crisis.

[back] Case Report

A 58-year-old Caucasian male had hypothyroidism

for 20 years, following Hashimoto's thyroiditis.

At the age of 50 years, he presented with weight

loss and lymphadenopathy; Hodgkin's disease,

mixed cellularity type, stage 3B, was diagnosed.

He was treated with chemotherapy [adriamycin,

bleomycin, vinblastine (ABV) and

cyclophosphamide, hydroxydaunorubicin,

vincristine, prednisone (CHOP)] for 6 months, and

complete remission was achieved. Eight years

later the patient presented with malaise,

dysphagia, dyspnoea, night sweats and an 8kg

weight loss within the last 3 months, and

sclerodactyly and Raynaud's phenomenon for the

last 3 weeks.

On physical examination he was anicteric,

afebrile and had a supine blood pressure of

110/80mm Hg. Sclerodactyly and telangiectasis

were the only evidence of skin involvement.

Laboratory data disclosed a Westergren

erythrocyte sedimentation rate of 80 mm/first

hour, and normocytic normochromic anaemia of 10

g/dl. Urinalysis was normal. Serum electrolytes,

renal and liver function tests, including LDH and

bilirubin, were all normal. A serological study

revealed strongly positive antinuclear antibody

(ANA) and antitopoisomerase I antibody (formerly

anti SCL-70 antibody), but normal C3, anti-DNA,

anti-centromere, anti-ribonucleoprotein (RNP),

anti-Ro and anti-La antibodies. No paraprotein

was found in the blood or urine. Chest x-ray and

CT scan showed bilateral basilar interstitial

infiltrates.

Trans-bronchial biopsy showed interstitial

fibrosis (fig. 1) compatible with systemic

sclerosis, without evidence of malignancy or

infection.

[Click to zoom] Figure 1. (click image to zoom)

Trans-bronchial biopsy showing

interstitial fibrosis

compatible with systemic

sclerosis, without evidence of

malignancy or infection.

Bone marrow aspiration and biopsy were normal,

except for erythroid hyperplasia. The patient was

diagnosed clinically as having systemic

sclerosis, involving the lung but without renal

vascular disease. There was no evidence of

relapse of the Hodgkin's disease.

The patient was treated with penicillamine 250

mg/day and prednisone 60 mg/day. However, he

displayed rapidly progressive skin thickening,

spreading from the hands centripetally to the

trunk in a few weeks. Therapy was not altered

during that period and the blood pressure

remained normal. Urine was not tested during this

period.

Four months later the patient presented with

acute renal failure and anaemia of 5 g/dl. Mental

status and temperature were normal, and the blood

pressure was 108/72mm Hg. A blood smear disclosed

schistocytes, reticulocytes and thrombocytopenia

of 65 000/µl. The total bilirubin was 34 µmol/L

with undetectable direct bilirubin,LDH 850 IU/L,

blood urea 22 mmol/L, and blood creatinine 212

µmol/L. Proteinuria, haematuria and granular

casts were found on urinalysis. Activated partial

thromboplastin time, prothrombin time, fibrinogen

and liver enzymes were normal.

The clinical picture was compatible with

haemolytic uraemic syndrome, secondary to

systemic sclerosis, and necessitated acute

peritoneal dialysis and plasmapheresis.

Microangiopathic haemoytic changes resolved

within a month, but the severe renal failure

persisted. Unfortunately, the patient eventually

succumbed to fulminant sepsis, 6 months after the

initial cutaneous manifestations.

[back] Discussion

Penicillamine is a heavy metal chelator used for

the treatment of 's disease, rheumatoid

arthritis, primary biliary cirrhosis, heavy metal

poisoning and cystinuria. It is used occasionally

for scleroderma, but its efficiency is

controversial.[4,5] Penicillamine may induce

several autoimmune disorders, such as systemic

lupus erythematosus, membranous nephropathy,

polymyositis, myasthenia gravis and pemphigus.

In these diseases, abnormal immunoregulation is

probably the main pathophysiology, perhaps

involving dysregulation of T-lymphocytes and

deposition of immune-complexes at the

dermal-epidermal junction.[6,7] However,

pemphigus is not the only adverse dermatological

effect of penicillamine, as lichen planus,[8]

elastosis perforans serpinginosa,[9] cutis laxa

and pseudoxanthoma elasticum,[10] have also been

associated with prolonged high-dose

administration of penicillamine.

In the latter cases, histology usually reveals

irregular thickening of the elastic fibres of the

dermis, with bleb-like protrusions perpendicular

to their long axes. Similar changes associated

with penicillamine have also been described in

other tissues, such as the upper respiratory

tract,[11] lungs,[12] joints[13] and aorta.[10]

The mechanism is postulated to be maturation

arrest and destabilisation of collagen and

elastin, by interference with their

cross-linking.[11] These histological findings

are not usually found in scleroderma,[6] but

penicillamine may induce various related

connective tissue disorders, such as morphea,[14]

systemic sclerosis,[6] vasculitis in rheumatoid

arthritis,[15] and dermatomyositis and

polymyositis, often associated with antinuclear

antibodies and B8, DR-3 HLA-B8, DR3,[16,17] and

transiently positive anti Jo-1 antibodies.[18]

Penicillamine is probably not significantly

effective in systemic sclerosis, except for mild

lung function improvement.[4] This case raises

the possibility that penicillamine may even be

harmful in certain patients, and may perhaps be

associated with acceleration of the decline in

the course of the disease. The mechanism may

involve either immune dysregulation or the

generation of free radicals, directly toxic to

the endothelium and leading to fibrotic tissue

repair and intimal thickening.[3]

Correspondence and reprints: Dr Yosef S. Haviv,

Division of Medicine, Hadassah Hebrew University

Medical Center, Jerusalem, P.O.B 12000, Israel.

E-mail: havivyo@...

References for:

[back] Rapid Progression of Scleroderma Possibly Associated with

Penicillamine Therapy

[Clin Drug Invest 15(1):61-63, 1998. © 1998 Adis International Limited]

1. Stoll T, Bruhlmann P, Fontana A, et al. Systemic sclerosis

(scleroderma): etiology and pathogenesis - where are we today? Schweiz

Med Wochenschr 1994; 124 (5): 193-203

2. Haustein UF, Ziegler V, Herrmann K. Chemically-induced scleroderma.

Hautzart 1992; 43 (8): 469-74

3. Biasi D, Carletto A, Caramaschi P, et al. Scleroderma induced by

chemical agents. Description of a case and review of the literature.

Recenti Prog Med 1995; 86 (4): 155-8

4. Akesson A, Blom-Bulow B, Scheja A, et al. Long term evaluation of

penicillamine or cyclofenil in systemic sclerosis. Results from a

two-year randomised study. Scand J Rheumatol 1992; 21 (5): 238-44

5. Steen VD, Medsger Jr TA, Rodnan GP. D-Penicillamine therapy in

progressive systemic sclerosis. Ann Intern Med 1982; 97: 652-6

6. Miyagawa S, Yoshioka A, Hatoko M, et al. Systemic sclerosis-like

lesions during long term penicillamine therapy for 's disease. Br

J Dermatol 1987; 116 (1): 95-100

7. Dawkins RL, Zilko PJ, Carrano J, et al. Immunobiology of

D-penicillamine. J Rheumatol 1981; 8 Suppl. 7: 56

8. DF, Skaehill PA. Drug-induced lichen planus. Pharmacotherapy

1994; 14 (5): 561-71

9. Wilhelm KP, Wolff HH. Penicillamine-induced elastosis perforans

serpinginosa. Hautzart 1994; 45 (1): 45-7

10. Burge S, T. Penicillamine-induced pseudo-pseuso-xanthoma elasticum

in a patient with rheumatoid arthritis. Clin Exp Dermatol 1988; 13:

255-8

11. Manohar MB, Boldy DA, RL, et al. Penicillamine-induced changes in

elastic tissue of the upper respiratory tract. J Laryngol Otol 1993;

107 (1): 62-4

12. Gebhart W, Bardach H. The 'lumpy-bumpy' elastic fiber. Am J Dermatol

1988; 113: 630-5

13. Dalziel KL, Burge SM, Frith PA, et al. Elastic fibre damage induced by

low dose D-penicillamine. Br J Dermatol 1990; 123: 305-12

14. Bernstein RM, Hall MA, Gostelow BE. Morphea-like reaction to

D-penicillamine therapy. Ann Rheum Dis 1981; 40: 42-3

15. Voskuyl AE, Zwinderman AH, Westedt ML, et al. Factors associated with

the development of vasculitis in rheumatoid arthritis: results of a

case-control study. Ann Rheum Dis 1996; 55 (3): 190-2

16. Kolsi R, Bahloul Z, Hachicha J, et al. Dermatopolymyositis induced by

D-penicillamine in rheumatoid polyarthritis. Apropos of 1 case with

review of the literature. Rev Rheum Mal Osteoartic 1992; 59 (5): 341-4

17. Chappel R, Willems J. D-Penicillamine-induced myositis in rheumatoid

arthritis. Clin Rheumatol 1996; 15 (1): 86-7

18. EA, Hull RG, AL. D-Penicillamine and polymyositis: the

significance of the anti Jo-1 antibody. Br J Rheumatol 1993; 32 (12):

1109-10