Penicillamine hypersensitivity

Chan, C.-Y., Baker, A.L. Penicillamine hypersensitivity successful desensitization of a patient with severe hepatic Wilson s disease. Amer. J. Gastroenterol. 1994 89 442-443... 

Hypersensitivity reactions Allergic reactions occur in approximately 33% of patients. They are more common at the start of treatment, and occur as generalized rashes or drug fever. Discontinue treatment and reinstitute at a low dosage such as 250 mg/day, with gradual increases. Administering prednisolone 20 mg/day for the first few weeks of penicillamine therapy reduces the severity of these reactions. Antihistamines may control pruritus. 

In 20-25% of cases, side effects are observed, depending mainly on the dose (hypersensitivity reactions, aphthous lesions, arthralgia, nausea, fever). All in all, treatment of Wilson s disease with penicillamine is considered to be successful and safe. If jrenicill-amine is not well tolerated or if serious side effects are observed (e.g. kidney or bone-marrow damage, polyneuropathy, pemphigus), treatment must be discontinued. Penicillamine usually causes pyridoxin deficiency, so that substitution (25—40 mg/day) is recommended, particularly as chronic liver damage also leads to vitamin Bg deficiency. If necessary, electrolytes and trace elements also have to be substituted. 

Hypersensitivity reactions are frequent early in a course of penicillamine, with urticarial or maculopapular rashes, fever, and lymphadenopathy. Cross-allergy to penicillin can occur. In addition, the use of penicillamine can be complicated by a unique variety of often serious autoimmune reactions, involving the skin, kidneys, liver, lungs, muscles, or other organs. Proteinuria is found in more than 10% of patients and sometimes develops into the nephrotic syndrome. Pemphigus, myasthenia gravis, polymyositis, or a lupus-like syndrome occur in smaller percentages. 

Rhinitis, bronchospasm, and asthma can occur as a manifestation of hypersensitivity to penicillamine (SEDA-5, 248) (61-63) and rarely of the Churg-Strauss syndrome (64). Rhinitis can also be a symptom of peni-ciUamine-induced pemphigus (65). In one patient a large pulmonary cyst developed concomitantly with skin lesions characteristic of the use of large doses of penicillamine (66). Microscopic derangement of the elastic fibers predominated. Although the frequency is uncertain, penicillamine can be associated with recurrent respiratory tract infections, that is secondary to IgA deficiency (67,68) or as part of the yellow nail syndrome (SEDA-9, 223). 

Eosmophilia can occur in up to 25% of patients using penicillamine, but is of little value in predicting serious hypersensitivity reactions (148). 

Several case reports have demonstrated that penicillamine can cause hver damage (SEDA-13, 199) (184), mainly cholestatic hepatitis, often associated with other signs of hypersensitivity such as fever, rash (185), and pulmonary (159,186) or hematological reactions (162). In two children with Wilson s disease, penicillamine was thought to have caused persistence of a pre-existing increase in aminotransferase activity (187). 

A 30-year-old Japanese man with polyarthritis, in whom sodium aurothiomalate for 3 years had been ineffective, was given penicillamine 200 mg/day (188). After 10 days he became febrile and 2 days later jaundiced. A lymphocyte stimulation test against penicillamine was positive, suggesting type IV hypersensitivity. Later on he had a good response to tiopronin, without further adverse reactions. 

A rash or photosensitivity can also occur as part of the penicillamine-induced lupus-like syndrome (248-250). Type II bullous systemic lupus erythematosus (251) and necrotizing vasculitis (46) have been attributed to penicillamine. In one report, a hypersensitivity reaction to penicillamine with a skin rash and fever was associated with low back pain (252). 

In the serum of three patients with acute hypersensitivity reactions to penicillamine, complement-binding antibodies against penicillamine were detected (349). Patients with Wilson s disease are not known to have an abnormal immune status. The striking variability of penicUlamine-induced pathology, including autoimmune reactions such as SLE, is also seen in patients with Wilson s disease, but the proportion of these patients in whom withdrawal is necessary is smaller, about 2-8% (72,79,80,350). 

The National Taiwan University Hospital has reported successful desensitization with prednisolone in a patient with hypersensitivity to penicillamine (377). 

Early hypersensitivity reactions are usually transient, and although there is undoubtedly an increased risk, in patients with a history of previous adverse reactions to penicillamine (or gold), re-exposure may not be followed by a relapse (SEDA-10, 218). In the case of serious complications, such as agranulocytosis, profound thrombocytopenia, polymyositis, or Goodpasture s syndrome, the repeated use of penicillamine carries unacceptable risks. Commencing penicillamine in patients with Wilson s disease can aggravate or even precipitate neurological involvement. 

Kumar A, Bhat A, Gupta DK, Goel A, Malaviya AN. D-penicillamine-induced acute hypersensitivity pnenmoni-tis and cholestatic hepatitis in a patient with rhenmatoid arthritis. Clin Exp Rheumatol 1985 3(4) 337-9. 

Tiopronin can cause fever, with or without a rash (3). In a patient with a prior hypersensitivity reaction to penicillamine, there was no cross-hypersensitivity to tiopronin (26). 

Habib GS, Sallba W, Nashashibi M, Armali Z Penicillamine and nephrotic syndrome. Eur Intern Med 2006 17 343-8. PIrmohamed M Genetic factors in the predisposition to drug-induced hypersensitivity reactions. Aaps 2006 8 E20-6. 

Captimer treatment of patients with cystinurie in whom treatment with penicillamine had sufficient result or who were hypersensitive to pencillamine... 

Rats, in particular BN rats, have been frequently used to study drug hypersensitivity, but again to only very limited number of drugs (Balazs, 1987). D-penicillamine has been studied most extensively in BN rats (Donker et al., 1984 Tournade et al., 1990 Seguin et al., 2003, 2004 Masson and Uetrecht,... 

Manfredi R, Calza L (2007) Safety issues about nevirapine administration in HIV-infected pregnant women. J Acquit Immune Defic Syndr 45 365-368 Maniar JK, Shah SR, Verma R, Kamath R, Gupte P, Maniar A (2006) Nevirapine-induced fulminant hepatitis. J Assoc Physicians India 54 957-961 Martin AM, Nolan D, James I, Cameron P, Keller J, Moore C, Phillips E, Christiansen FT, Mallal S (2005) Predisposition to nevirapine hypersensitivity associated with HLA-DRB 1 0101 and abrogated by low CD4 T-cell counts. AIDS 19 97-99 Mary Ann Liebert, Inc. (2001) Antiviral briefs. AIDS Patient Care and STDs 15 103-104 Masson MJ, Uetrecht JP (2004) Tolerance induced by low dose d-penicillamine in the Brown Norway rat model of drug-induced autoimmunity is immune-mediated. CRT 17 82-94... 

However, in these studies, no serious attempts were made ot assess the antibodies specific for penamaldate and penicillamine determinants, which are precisely those which could be expected. Benzylpenicilloic acid, when applied to guinea pig skin, seems able through whatever immunochemical mechanism to induce contact hypersensitivity (Levine 1960 a). 

Penicillamine is a chelating agent which binds copper, mercury, zinc, and lead. It has been used to treat poisoning from these chemicals and also for disorders of copper metabolism such as Wilson s disease and primary biliary cirrhosis. Penicillamine has been tried in scleroderma and arthritis. Hypersensitivity reactions are common. About 20%-30% of the patients show hypersensitivity reactions suchs as morbilliform exanthema, urticaria, purpura, anorexia, lymphadenopathy, leukopenia, and thrombocytopenia (Meyboom 1975 Balme and Huskisson 1977). More severe skin symptoms associated with penicillamine therapy are Stevens-Johnson syndrome, pemphigus, myasthenia gravis, cholestatic jaundice (Barzilai et al. 1978), nephropathy (Lange 1978) and lupus-like syndrome (Harpey et al. 1972). 

Respiratory Hypersensitivity pneumonitis has been attributed to penicillamine [47 ]. 

D-Penicillamine is used in the treatment of rheumatoid arthritis. Several types of pulmonary toxicities have been described with this agent. A pulmonary-renal syndrome similar to Goodpasture s syndrome has been rarely described and is fatal in 50% of the cases. Hemoptysis and hematuria are present in an acute fashion and warrant prompt discontinuation of the drug. Anti-glomerular basement membrane antibodies are not found and the role of plasmapheresis in undetermined. Treatment with corticosteroids or immunosuppressive agents may be of benefit (21). Bronchiolitis obliterans with or without organizing pneumonia has also been reported, but is also described with rheumatoid arthritis. Hypersensitivity pneumonitis and the subacute onset of pulmonary fibrosis have been... 

A major review discussed cutaneous adverse effects associated with penicillamine [67 ]. It has been associated with toxicity in patients with histocompatibility antigens DRl, DR3, DR4, Al, C4QO, BW35 and B8. Autoimmune and immediate hypersensitivity reactions are associated with patients with altered immunity such as rheumatoid arthritis of scleroderma. Cutaneous adverse effects occur in 25-50% of patients, causing withdrawal in 10% of patients. This review provides a comprehensive analysis of dermal toxicities associated with penicillamine. A second review discussed eosinophilic fasciitis [68 ]. 

A study compared the efficacy and side effects associated with n-penicillamine (n=58) versus allicin (n=59) treatment for blood lead concentration in 117 workers [69 ]. The frequency of side effects was significantly higher in patients administered D-penicillamine (250 mg, three times daily) in a study comparing this compound with allicin (1200 gg, three times daily) after 10 days. Both treatments reduced serum lead, but the frequency of side effects was higher in the D-penicillamine group. D-Penicillamine was associated with hypersensitivity (n=5), GI complications (n=6), headache (n=4), somnolence (n = 1), chest pain (n=1) and dizziness (n=1). 

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