Download Porphyria cutanea tarda affecting a rheumatoid arthritis patient

Rheumatology 1999;38:453–456
Porphyria cutanea tarda affecting a rheumatoid
arthritis patient treated with methotrexate:
association or coincidence?
P. Chalem, A.-M. Ghnassia1, Y. Nordmann2 and C. J. Menkes
Department of Rheumatology, Hôpital Cochin, Paris, 11 avenue du Maréchal
de Lattre de Tassigny, 77400 Lagny and 2Centre Français des Porphyries,
Hôpital Louis Mourier, Colombes, France
Abstract
We describe the case of a 44-yr-old woman, suffering from rheumatoid arthritis for 15 yr, who
developed porphyria cutanea tarda while being treated with methotrexate. The cutaneous
lesions healed and the metabolic anomalies improved after a few months, despite continuing
the treatment.
K : Porphyria cutanea tarda, Rheumatoid arthritis, Methotrexate.
T 2. Classification of porphyrias according to their inheritance
The term ‘porphyria’ is used to describe a group of
diseases with very diverse clinical manifestations, but
which share a common feature: abnormalities of porphyrin metabolism. Porphyrins are compounds which are
intermediates in haem metabolism [1].
There is currently no completely satisfactory classification system for porphyria, as the various forms differ
as regards the site of the metabolic dysfunction ( liver
or erythropoietic cells) ( Table 1), the mode of transmission (there are both dominant and recessive hereditary
forms, and acquired or sporadic forms) (Table 2), the
clinical manifestations (cutaneous, abdominal, neurological and psychological ) and the enzyme which is
defective ( Table 3) [1]. However, these taxonomic
difficulties do not prevent satisfactory differentiation
between the major clinical forms. One of these major
Autosomal dominant
Protoporphyria
Porphyria cutanea tardaa
Acute intermittent porphyria
Variegate porphyria
Hereditary coproporphyria
Autosomal recessive
Hepatoerythropoietic porphyria
Congenital erythropoietic porphyria
ALA dehydrase deficiency
aAlso acquired or ‘sporadic’ form.
forms, porphyria cutanea tarda (PCT ), can be identified
by its clinical presentation: cutaneous hyperfragility,
light sensitivity and serous or haemorrhagic blisters
mostly on exposed skin (backs of the hands and face)
with only minimal trauma. PCT is the only form of
porphyria that can be acquired (‘sporadic’ form), and
thus it is not necessarily hereditary. It involves a deficit
in uroporphyrinogen decarboxylase, with accumulation
and excessive elimination of uroporphyrins I and III in
urine, and high levels of isocoproporphyrin in stools.
PCT is often associated with exposure to triggering
factors (particularly alcohol, iron, oestrogens, aromatic
hydrocarbons) and also various diseases including
hepatitis and autoimmune diseases [1].
The autoimmune disease most often reported to be
associated with PCT is lupus erythematosus [2–9]. In
contrast, there have been only three reports of PCT
associated with rheumatoid arthritis (RA) [10–12]. In
the most recent one [12], the onset of PCT was described
as being associated with the start of methotrexate administration. We report an observation which is inconsistent
with this previously suggested causative relationship.
T 1. Classification of porphyrias according to the site of metabolic
dysfunction
Hepatic porphyrias
Acute intermittent porphyria
Variegate porphyria
Porphyria cutanea tarda
Hereditary coproporphyria
ALA dehydrase deficiency
Erythropoietic porphyrias
Congenital erythropoietic porphyria
Protoporphyria
Hepatoerythropoietic porphyria
Submitted 18 February 1998; revised version accepted 31
December 1998.
Correspondence to: C. J. Menkes, Service de Rhumatologie A,
Hôpital Cochin, 27, Rue de Faubourg Saint-Jacques, 75014 Paris,
France.
453
© 1999 British Society for Rheumatology
454
P. Chalem et al.
T 3. Classification of porphyrias according to the clinical manifestations and the defective enzyme
Clinical features
Cutaneous photosensitivity
Neurological dysfunction
Photosensitivity and neurological dysfunction
Disease
Defective enzyme
Congenital erythropoietic porphyria
Porphyria cutanea tarda
Hepatoerythropoietic porphyria
Protoporphyria
ALA dehydrase deficiency
Acute intermittent porphyria
Hereditary coproporphyria
Variegate porphyria
Uroporphyrinogen III synthase
Uroporphyrinogen decarboxylase
Uroporphyrinogen decarboxylase
Ferrochelatase
ALA dehydrase
Porphobilinogen deaminase
Coproporphyrinogen oxidase
Protoporphyrinogen oxidase
Modified from Wyckoff and Kushner [19].
Case report
The patient was a woman, 44 yr old, who had been
suffering from RA for 15 yr (since 1981). The sites
affected, from the onset of the disease, were the minor
joints (metacarpophalangeal, proximal interphalangeal
and metatarsophalangeal ). She was treated, successively,
with gold salts (stopped after 3 months due to a cutaneous eruption), hydroxychloroquine for 18 months
(stopped because of lack of efficacy) and -penicillamine
from 1985 to 1991 (stopped following therapeutic
failure). Since 1991, methotrexate therapy, initially
7.5 mg/week, increased in 1995 to 10 mg/week, has
been effective. She also receives 75–150 mg/day of
indomethacin.
The patient was hospitalized and administered methylprednisolone i.v. therapy, 500 mg/day for 3 days, for
major inflammatory episodes in 1988, 1989 and 1994.
Hand and feet X-rays showed erosions of the metacarpophalangeal and metatarsophalangeal joints.
Rheumatoid factor was positive (ELISA IgM anti-IgG:
200 IU/ml, Rose–Waaler titre: 64).
She had been taking oral contraception (norgestrel
0.50 mg + ethinyloestradiol 0.05 mg/day) for 20 yr.
In August 1996, she noticed the appearance of vesicles
and bullous lesions on the backs of her hands and face,
followed by superficial erosions with the development
of crusts and a small number of hypopigmented and
atrophic scars.
The clinical signs suggested PCT, and the diagnosis
was confirmed by assaying urinary porphyrins: the uroporphyrin concentration was 334 nmol/mmol of creatinine (normal: <10), or 3607 nmol/l (normal: <50);
5-aminolaevulinic acid, porphobilinogen and coproporphyrin levels were normal. The porphyrin concentration
in stools (229 ng/g dry weight) was slightly higher than
normal (<200 nmol/g) and erythrocyte counts were
normal. Liver investigations revealed normal values:
aspartate amino transferase 23 IU/l, alanine amino
transferase 41 IU/l, alkaline phosphatase 58 IU/l,
gamma glutamyl transferase 34 IU/l and 5∞ nucleotidase
2 IU/l. Serum iron was normal (94 mg%).
As PCT is known to be associated with systemic lupus
erythematosus, we tested ANA serology, which was
positive (1:500, speckled pattern). Anti-double-stranded
(ds) DNA, anti-ENA and anti-Scl-70 were all negative.
Oestro-progestational contraception was halted imme-
diately upon diagnosis, but methotrexate and indomethacin treatments were continued. The evolution of
the skin disease was favourable, and the bullous lesions
disappeared within a few weeks.
Porphyrin assays 3 months after the first such assays
revealed that the concentration of uroporphyrins had
declined to 259 nmol/nmol of creatinine (1245 nmol/l ).
Six months after the first assay, the porphyrin levels
were normal. To date, after 24 months of follow-up,
there has been no further episode of cutaneous lesions,
despite the continuation of methotrexate therapy.
Discussion
Our patient presented a well-known risk factor for PCT:
taking oestro-progestational contraceptives [13]. In spite
of this, the case raises two questions. First, was RA
involved in the development of the metabolic abnormality and, second, was methotrexate therapy in any way
responsible?
As noted previously, the association between PCT
and systemic lupus erythematosus seems to be evident
in view of the numerous papers published. However,
the association with other autoimmune diseases, including RA, is not as obvious as that with lupus [10–12,
14, 15].
In 1972, Eales and co-workers [10] described a 64-yrold woman who had been suffering from RA for 40 yr
and Felty syndrome. She developed PCT during her last
3 yr of life, with recurrent blisters and erosions on the
sun-exposed skin surfaces with minimal trauma. There
was no family history of cutaneous porphyria. Clinical
examination revealed hepatomegaly; however, no abnormal findings were revealed either by enzymology or
hepatic biopsy. The patient eventually died as a result
of a severe pulmonary infection, certainly related to the
persistent neutropenia and the multiple portals of infection located in the porphyric skin lesions. At autopsy,
there was hepatic congestion, focal fatty changes, slight
portal fibrosis and minimal siderosis; under ultraviolet
light, there was evidence of widespread fluorescence, a
characteristic finding indicating the presence of porphyrins. Liquid chromatography showed the presence of
7- and 8-carboxyl porphyrins.
In the same year, Nyman [11] reported a male patient,
49 yr old, suffering from PCT, bronchial cancer and
RA. There was a family history of porphyria. Moreover,
Porphyria cutanea tarda and methotrexate
this patient presented a risk factor for developing PCT:
he was a chronic alcoholic. However, the diagnosis of
RA was questionable, and the author also suggested
that polymyalgia rheumatica was a possible diagnosis;
it could also have been a paraneoplastic syndrome.
Thus, these two former reports do not demonstrate
any relationship between PCT and RA. More recently,
O’Neill and co-workers [12] published a third paper,
where they report the case of a 69-yr-old woman
suffering from RA for >20 yr and who had been
administered several types of treatment, each discontinued because of either lack of efficacy or side-effects.
She developed a sporadic form of PCT 2 weeks after
starting methotrexate (total dose 15 mg). In her past
medical history, there were no risk factors for PCT
(exposure to oestrogens, hydrocarbons or excess alcohol
intake). The authors concluded that the methotrexate
treatment had caused the PCT [12].
In two other reports, Malina et al. [16 ] and Dopfer
et al. [17] suggest a link between the administration of
methotrexate and PCT. However, the causative association described in these reports is unlikely. In one case,
methotrexate had been administered to a patient with
psoriatic erythroderma a long time (7 yr) before the
onset of porphyria [16 ]. The other case was a 6-yr-old
girl with a family history of porphyria who developed
PCT after bone marrow transplantation for chronic
myelogenous leukaemia; she had received methotrexate
and also cyclophosphamide [17], a drug which is liable
to reveal porphyria [13].
A detailed review of the mechanisms by which drugs
can trigger porphyria is beyond the scope of this paper.
However, it is important to underline some aspects of
hepatic porphyrin metabolism and its drug-induced
disturbances.
The biosynthesis of porphyrins involves eight enzymes
and occurs in both mitochondria and cytoplasm [1, 18,
19]. The condensation of succinyl coenzyme A and citric
acid, mediated by the enzyme ALA synthase, allows the
synthesis of d-aminolaevulinic acid (ALA). This is the
first and, at least in the liver, the rate-limiting step in
the synthesis of porphyrins. ALA synthase is directly
inhibited by the final product, haem [18]. Because this
biosynthetic pathway is complex, it is convenient to
divide it into four separate steps: (1) formation of the
pyrrole rings; (2) assembly of macrocyclic tetrapyrrole;
(3) modification of the peripheral side chains; (4) oxidation of protoporphyrinogen IX to protoporphyrin IX
and the insertion of iron to form the haem molecule
[19]. Thus, porphyrins are composed of four pyrrole
rings and are the intermediate chemical compounds in
the haem biosynthetic pathway.
The liver is a major site of haem production: it
synthesizes 15–20% of total body haem, half of which
is used in the synthesis of cytochromes P-450 [18]. The
liver is also important in the excretion of porphyrins;
this can result in liver damage caused by porphyrin
accumulation in certain types of porphyrias (e.g. PCT )
[18, 20]. Because porphyrins are secreted in bile, various
hepatocellular or cholestatic liver diseases are associated
455
with increased urinary levels of porphyrins. However,
this phenomenon is not characterized by clinical manifestations of porphyria [18].
There are a wide variety of porphyria-related drugs,
most of which are thought to induce cytochrome P-450
and thus to increase the demand for hepatic haem
biosynthesis, thereby increasing the rate of formation of
porphyrins. A deficit or abnormal function in one
enzyme of this metabolic pathway will cause the excessive accumulation and excretion of porphyrins and
porphyrin precursors [13]. As previously noted, PCT
involves a deficit in uroporphyrinogen decarboxylase
activity with accumulation of uroporphyrins I and III.
In sporadic PCT (as in our patient), only the hepatic
enzyme is involved; red cell haem metabolism remains
normal in such cases [1].
There are three pathways for methotrexate metabolism, none of which appear to be related to porphyrins
or haem products. First, methotrexate can be inactivated
by intestinal bacteria; this inactivation accounts for
<5% of the total dose. Second, the drug is metabolized
by aldehyde oxidase to 7-hydroxy-methotrexate, a less
active metabolite. Third, methotrexate and 7-hydroxymethotrexate are transformed to polyglutamate derivatives, which exhibit a more powerful and prolonged
activity [21–23]. Therefore, hepatic methotrexate metabolism does not involve cytochromes P-450; current
theory does not indicate how this drug could be able to
induce porphyrias.
Experiments in animal models (especially in rats and
chick embryo) are useful to demonstrate the ability of
a drug to induce porphyrin synthesis. The correlation
between the experimental findings and clinical evidence
is good: indeed, drugs known to induce porphyria are
found to be associated with a rise in porphyrin biosynthesis in chick embryo; on the other hand, harmless
drugs in patients with porphyria usually give negative
results in models. Experimental tests demonstrated that
methotrexate has no effect on porphyrin metabolism
[13]. Some authorized and unauthorized drugs in
patients with hepatic porphyrias are listed in Table 4.
Another matter of interest is whether liver disease
related to methotrexate can induce disturbances in porphyrin metabolism. Porphyrin excretion does not appear
to have been measured in patients with methotrexate
hepatotoxicity; thus, secondary porphyrinuria, attrib-
T 4. Drugs and hepatic porphyrias
Authorized
Acetylsalicylic acid
Cyclosporin
Diclofenac
Indomethacin
Ketoprofen
Methotrexate
Naproxen
Piroxicam
Tenoxicam
Unauthorized
Mephenamic acid
Choroquine
Cyclophosphamide
Danazol
Ibuprofen
Oestrogens
Paracetamol
Progestin
456
P. Chalem et al.
uted to methotrexate-related advanced liver disease, has
not yet been reported [24–28].
In conclusion, PCT seems to be a disease only fortuitously associated with RA. Methotrexate, at least at the
doses used in rheumatology and despite its effects on
the liver, does not appear to be contraindicated in
patients with PCT; there is, therefore, no reason to
avoid its use. In our patient, the metabolic anomaly and
the cutaneous lesions disappeared despite continuing
methotrexate therapy.
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