D-penicillamine Induced Degenerative Dermopathy.

D-penicillamine interferes with elastin and collagen metabolism and produces several cutaneous and multi-systemic side-effects. We present two cases of Wilson's disease who on long-term penicillamine therapy developed drug-induced degenerative dermopathy manifesting as skin fragility over pressure sites and cutis laxa-like changes.

What was known?

Prolonged d-penicillamine administration can produce skin fragility.

Introduction

Penicillamine is a heavy metal chelator, used to treat several heavy metal toxicities including lead, mercury, and copper. It is an important therapeutic modality for several diseases including scleroderma, Wilson's disease, rheumatoid arthritis, and cystinuria.[1] Common side effects of D-penicillamine include gastrointestinal upset, skin rash, stomatitis, dysgeusia, cytopenia, proteinuria due to membranous nephritis, and uncommonly, myasthenic syndrome.[23] Prolonged penicillamine therapy can also produce a spectrum of skin changes.[4] We present two cases with severe degenerative dermopathy due to prolonged penicillamine therapy.

Case Reports

Case 1

A 15-year-old girl presented to the Neurology department of our hospital with behavioral problems, irritability, progressive academic decline and generalized dystonia also affecting speech. She had corneal Kaiser Fleschner (KF) ring. Serum copper was 54 μg/dl (normal – 70-140 μg/dl), serum ceruloplasmin was 0.002 OD/unit (normal – 0.2-0.5 OD/unit), 24 h urinary copper was 87 μg/day (normal – 20-50 μg/day) and MRI brain showed T2 hyperintensities in bilateral globus pallidus and substantia nigra. Liver function test was normal. She was diagnosed to have Wilson's disease and started on d-penicillamine, initially 250 mg/day, which was titrated over months to 3 gm/day along with zinc acetate. Dystonia improved partially and the patient was able to take orally. After two and half years of starting D-penicillamine, she developed tense vesico-bullous lesions filled with clear and hemorrhagic fluid over trauma- prone sites that ruptured in 7-10 days and healed with scarring in 1-2 months. She also complained of increased laxity of skin over these areas as well as all skin folds. On examination, the patient had severe generalized dystonia involving face, jaw, neck, trunk and limbs, with rigidity, and the deep tendon jerks were difficult to elicit. Dermatological examination revealed vesicobullous lesions and erosions symmetrically distributed over shoulders, elbows, hands, knee, and ankles. There was also evidence of scarring, hyperpigmentation and milia over these sites [Figure 1a and b]. There was increased skin laxity in these areas and over body folds (neck, groin, cubital and popliteal fossae). Tzanck smear made from a blister was negative for acantholytic cells or inflammatory cells. Skin biopsy from a lesion over the hand revealed decreased, thickened and fragmented elastic fibers, highlighted on vVG staining (compared to control–normal skin sample) suggestive of elastolysis [Figure 2a and b]. Patient was also evaluated for other side effects of D-penicillamine. Urine was normal without any proteinuria (0.02 gm/24 hour urine). CT chest incidentally revealed bilateral reticulonodular shadows suggesting early diffuse interstitial fibrosis. She had microcytic hypochromic anemia secondary to iron deficiency anemia with serum iron 11 ng/nl (normal – 50-150 ug/dl). Recent 24 hour urine copper was < 5 μg/day and serum copper was 31 μg/dl. Echocardiography was normal. Since the copper stores had significantly reduced, it was planned to decrease the dose of D-penicillamine, continue zinc acetate and keep the patient on follow up. After decreasing the dose to 1.5 gm her skin lesions improved dramatically (70-80%) over a period of 4-6 months.

Figure 1a

Erythematous to hyperpigmented atrophic plaques with milia over dorsa of hands in case 1

Figure 1b

Erythematous scarred plaques topped by milia over shins, feet and knees in Case 1

Figure 2a

Photomicrograph from site of skin fragility showing multiple short, fragmented elastic fibers (black color) in the dermis (vVG stain ×40)

Figure 2b

Photomicrograph from healthy skin (control) showing normal elastic fibres (black colour) between collagen bundles (vVG stain ×40)

Case 2

A 29-year-old man, presented to neurology department with gradually progressive stiffness of all four limbs, action tremors in the upper limbs and history of frequent falls. He had history of jaundice at the age of 14 years which was conservatively managed. On examination, there was no evidence of anemia, jaundice or any sign of hepatic failure but he had inappropriate laughter. His Mini Mental status Examination was 17/24 and KF ring was present. There was generalized dystonia and rigidity of all the limbs and trunk and difficulty in writing because of severe action tremor. Investigations showed serum copper as 25 μg/dl, serum ceruloplasmin of 0.058 OD/unit, and 24 h urinary copper of 71 μg/day. He was diagnosed as Wilson's disease and started on zinc acetate and D-penicillamine, which was gradually increased from 1 to 3 gm/day. There was only partial improvement in the rigidity and dystonia. After 4 years of penicillamine therapy, he developed vesicobullous lesions over trauma-prone area that healed with milia formation and scarring [Figure 3]. Skin biopsy revealed fragmented elastic fibers in the reticular dermis. These features were consistent with penicillamine-induced skin fragility. Investigations toward systemic side-effects of D-penicillamine revealed no abnormality. The dose of penicillamine was decreased to 1 gm/day, skin lesions improved significantly after 6 months.

Figure 3

Hemorrhagic vesicles and scarring over bony prominences with overlying milia in upper limb in Case 2

In both cases, this adverse-event to penicillamine yielded a score of 9 on the Naranjo adverse drug reaction (ADR) probability scale (definite ADR if score ≥ 9). It was a ‘certain ADR’ according to WHO-UMC causality category and a level 4 ADR on the Hardwig's Severity Assessment scale.[567]

Discussion

Our cases were striking examples of penicillamine-induced degenerative dermopathy, first described by Sternleib and Scheinberg in 1964 in a patient of Wilson's disease.[4] Both cases developed drug-induced skin fragility over bony prominences and pressure sites manifesting as hemorrhagic blisters, scarring, and milia formation while one case also had associated cutis laxa-like changes.

Long term administration of D-penicillamine has been shown to produce a dermopathy in 20 to 33% of patients in addition to hematological, immunological, and other organ system involvement.[2] The incidence of side effects ranges from 30 to 60% and the rate of drug withdrawal due to side effects may go upto 30%.[23] Cutaneous side effects can be classified into four distinct groups; acute sensitivity reactions (e.g. acute urticaria), a toxic-metabolic effect on connective tissue or degenerative dermopathy (penicillamine-induced skin fragility, cutis laxa, elastosis perforans serpiginosa-EPS, anetoderma, pseudoxanthoma elasticum-PXE), autoimmune skin manifestations (e.g. pemphigus, lupus erythematosus and dermatomyositis) and those due to unknown mechanisms (e.g. lichen planus, hypertrichosis).[4] At high doses, penicillamine interferes with elastin and collagen metabolism which manifests as: Cutis laxa, anetoderma, PXE, ecchymosis, and lymphangiectasis.[8910] D-penicillamine binds directly to the aldehyde precursors which are essential for elastin and collagen cross-linking and inhibits copper-dependent enzyme lysyl oxidase, that catalyses the cross-linking reaction.[11] It, however, has no effect on mature, insoluble collagen, therefore explaining the long period before dermopathy sets in. The precise amount of penicillamine required to produce elastic fiber damage is unknown, but it has been estimated that a minimum of 1 g daily for more than 5 years is necessary to induce these changes.[12] However, a study by Dalziel et al., showed that elastic fiber damage occurred in rheumatoid arthritis patients receiving low-dose penicillamine therapy (0.25 to 1 g daily), even after as little as 1 year of treatment.[13]

Our cases developed skin fragility and cutis laxa-like changes after 3-4 years of treatment. They did not have features of EPS, which presents as pink to red keratotic annular plaques on the neck, axillae and ante-cubital fossae, PXE which manifests as small yellowish papules coalescing to form plaques over neck, or any systemic side effects of D-penicillamine, which occurs due to damage to elastic fibers in various organs including upper and lower respiratory tract, joint capsules and blood vessels.[1213]

The characteristic histopathology of penicillamine-induced elastic fiber damage is that of thickened elastic bundles with prominent lateral protrusions giving the so-called ‘bramble-bush’ appearance with or without calcification of elastic fibers, and sometimes granulomatous inflammation. Transepidermal elimination of elastic fibers may occur that manifests clinically as EPS.[14] In both our cases vVG stain on skin biopsies demonstrated thickened and fragmented elastic fibers.

Improvement in dermatologic manifestations requires stoppage or reducing the dose of D-penicillamine.[4] These patients can be started on zinc acetate and trientine (a chelating compound for the removal of excess copper from the body) for Wilson's disease since no skin changes occur with these agents. As with most cases of penicillamine-induced degenerative dermopathy, our patients’ lesions improved significantly on reduction of penicillamine dose. It can be envisaged that early intervention will help minimize further widespread penicillamine-induced elastolysis.

In conclusion, prolonged use of high-dose penicillamine is associated with elastic tissue damage that can manifest in the skin as cutaneous fragility, milia and purpura, as illustrated in these cases. Early recognition of penicillamine-induced skin changes is important since these abnormalities may not be restricted only to the skin, but may be markers of more widespread, multi-systemic involvement.

What is new?

D-Penicillamine-induced degenerative dermopathy can manifest as a combination of manifestations of skin fragility over bony prominences and pressure areas and cutis laxa-like features, as was seen in one of our case.

Stoppage of D-penicillamine can significantly improve the features of degenerative dermopathy.