Gold compounds are contraindicated in patients with all of the following conditions except

Indications

Gold Salts

Jaundice occurring in chrysotherapy has been described for decades [269], although it is likely that early reports of acute hepatic injury may have been secondary to viral hepatitis transmitted unwittingly by contaminated needles or syringes [3,13]. Cholestatic injury, which in some cases may be prolonged and associated with cholangitis progressing to ductopenia, appears to be the most characteristic hepatic lesion associated with gold treatment [270,271]. Immunoallergic mechanisms, which may include eosinophilia and dermatitis, are responsible for the hypersensitivity reaction that is typically seen.

6.2.4 Kidney

Nephropathy after gold treatment has been described in rats: at high doses, tubular necrosis was produced, but at low doses, the histological picture was similar to that seen in humans, with electron-dense deposits and IgG deposits on the basement membrane (Nagi et al., 1971). Similar electron microscopy findings were also reported in rabbits treated for 8 weeks with aurothiomalate (4 mg gold) or fed a “tonic” called gold kushta, which is said to contain gold oxide (a total dose of approximately 8 mg gold/kg b.w.) (Nagi and Khan, 1984).

Proteinuria is relatively frequent in patients treated with gold for rheumatoid arthritis, with frequencies of 1-10% and occasionally as high as 20% being reported. Proteinuria occurs after therapy with all gold preparations, with a peak incidence after 3 months of therapy. Usually the proteinuria decreases after stopping the therapy and subsides within 2 years. However, in approximately one-third of the patients, proteinuria may be severe enough to cause nephrotic syndrome that may last 12-18 months. The severity and duration of proteinuria are not associated with the dose of gold, duration of therapy, peak or mean blood gold levels, or urinary gold excretion. Histologically, the glomerulonephritis is most often (approximately 70%) of the “membranous” type, and less frequently of the “mesangial” or “minimal change” type (Bigazzi, 1999; Francis et al., 1984; Hall, 1988; Wolters et al., 1987). In the membranous type, granular deposits of IgG, and more rarely of IgA and IgM, are present along the capillary loops. In the mesangial type, the deposits are most often of IgM, followed by IgG and IgA. Membranous glomerulonephritis also occurs in rheumatoid arthritis patients treated with penicillamine. The mesangial type is most frequent in patients presenting with proteinuria and hematuria. Mesangial glomerulonephritis also occurs in rheumatoid arthritis patients not treated with gold. In the “minimal change” proteinuria caused by gold, there is no hematuria, in contrast to minimal change nephropathy seen after the use of nonsteroidal analgesic drugs (Hall, 1988). The risk of developing glomerulonephritis was 32-fold in patients with the HLA type DR3 compared to those negative for this histocompatibility antigen (Bigazzi, 1999; Wooley et al. 1980).

Chronic interstitial nephritis has been described in a patient who had received a cumulative dose of 9400 mg aurothioglucose (4700 mg gold) (Cramer et al., 1983).

Gold

Liver

Liver injury is an extremely rare complication of gold therapy [79]. The underlying mechanisms are probably complex and certainly variable. Overdosage can cause centrilobular necrosis and bile stasis. With normal doses intrahepatic cholestasis with an absence of necrosis is more likely, although there can be both bile duct damage and canalicular damage [80]; an immunological mechanism for this disorder has been suggested. Several cases of a severe form of idiosyncratic hepatic necrosis soon after starting chrysotherapy have been described [19,81]. However, most hepatic lesions as a rule resolve rapidly after withdrawal of chrysotherapy, and mild or moderate liver injury of any type is not necessarily a contraindication to gold treatment.

A 62-year-old man with rheumatoid factor positive rheumatoid arthritis developed painless icterus, nausea and vomiting, and discolored stools [82]. He had previously been given methotrexate without effect, and was instead given aurothioglucose 50 mg/week (cumulative dose 160 mg). He reported sweating, fatigue, and myalgia shortly after each gold injection. The liver was tender but not enlarged, and there were no signs of splenomegaly. Liver function tests showed a cholestatic pattern and predominantly conjugated hyperbilirubinemia. All potentially hepatotoxic drugs (aurothioglucose, naproxen, and aspirin) were withdrawn and his dose of prednisone was increased to 15 mg/day. His liver function tests normalized 4 weeks later.

Mild and transient abnormalities in serum aminotransferase and alkaline phosphatase activities have been reported during therapy with auranofin (0.4%). This is noteworthy, since almost all patients were taking acetylsalicylic acid or other non-steroidal anti-inflammatory drugs, which also can cause increases in transaminases. There has been a report of two cases of toxic hepatosis in patients taking auranofin [83].

10.15.3.2 Drugs That May Promote an Allergic, Inflammatory, Cytotoxic, Ulcerative, or Inflammatory Reaction in the Colon

Use of gold compounds, known as chrysotherapy, for treatment of rheumatologic and other collagen vascular diseases is often complicated by mild diarrhea. In addition, a number of reports have documented that chrysotherapy may precipitate the development of acute colitis manifest by severe watery diarrhea, hematochezia, and abdominal pain and tenderness, accompanied by skin rash, leukocytosis with eosinophilia, anemia, and hypoproteinemia from enteric losses of protein owing to an exudative colitis (Jackson et al. 1986; Teodorescu et al. 1993). Colonoscopy and mucosal biopsy may demonstrate a diffusely ulcerated colonic mucosa with an inflammatory infiltrate of polymorpholeukocytes and eosinophils (Marcuard et al. 1987; Teodorescu et al. 1993). The mechanism by which gold causes colitis is unknown but may be related to direct mucosal toxicity from the drug or to an immune-mediated hypersensitivity. The diagnosis should be suspected in patients who are receiving or have just completed chrysotherapy. The colitis may resolve spontaneously after the drug is discontinued. Treatment with steroids, antibiotics, and chelating agents may facilitate recovery (see Table 4) (Marcuard et al. 1987; Teodorescu et al. 1993).

Table 4. Drugs that can cause cytotoxic, inflammatory, or allergic colitis

NSAIDs are widely used as anti-inflammatory and antipyretic medications and can produce a wide spectrum of colonic injury manifest by (1) diarrhea or constipation with normal-appearing mucosa (Schwartz 1981); (2) exacerbation of inflammatory bowel disease, especially ulcerative colitis and proctitis (Gibson et al. 1992; Hovde and Farup 1992; Stamm et al. 1994); (3) development of discrete mucosal ulcerations presenting with pain and/or hemorrhage (Stamm et al. 1994); and (4) formation of colonic strictures and mucosal diaphragm-like luminal obstructions, particularly in the small intestine and ascending colon (Gargot et al. 1995; Halter et al. 1993; Robinson et al. 1995). NSAIDs have also been suggested as a cause for collagenous colitis, a condition characterized by watery diarrhea and normal mucosal appearance at colonoscopy, but the presence of a thickened layer of collagen below the epithelial surface detected by mucosal biopsy (Riddell et al. 1992).

Development of colonic complications has been reported during oral treatment with many of the NSAIDs including ibuprofen, piroxicam, naproxyn, mefenamic acid, and diclofenac sodium. Administration of NSAIDs by rectal suppository has also been associated with proctitis (Gibson et al. 1992). Delayed-release oral preparations, particularly diclofenac, have been associated with severe mucosal injury and stricture formation in the right colon probably resulting from the release of high concentrations of the medication onto the colonic mucosa when passage through the colon of the sustained-release formulation is delayed (Halter et al. 1993). The mechanisms responsible for NSAID-induced colon injury are not well defined but may be related to the fact that inhibiting cyclooxygenase decreases the synthesis of certain prostaglandins that have mucosal protective properties. An in-depth discussion of this is presented in Chapter 10.11. NSAID-induced inhibition of fatty acid oxidation in colonic epithelial cells has also been suggested as a mechanism for colonic injury (Roediger and Millard 1995). In addition, ischemia may play a contributing role, as has been suggested for some cases of NSAID-induced colitis (Carratu et al. 1993). Thus, local mucosal blood flow, epithelial cell metabolism, and mucosal membrane permeability may all be adversely affected by NSAIDs and result in impairment of the intestinal barrier to invasion by luminal bacteria and enhanced absorption of their toxic products.

Enteric-coated and wax matrix-containing potassium chloride (KCl) tablets can cause ulceration in the stomach, proximal intestine, and possibly the colon (Carratu et al. 1993; Leijonmarck and Raf 1985). The mucosal damage appears to result from local release of high concentrations of potassium, which cause focal vasospasm and ischemia of the underlying mucosa. Intestinal ulceration from KCl tablets is most frequently encountered at areas of luminal narrowing or stricture, which hinder passage of the sustained-release formulation. Patients who sustain KCl intestinal damage may present with abdominal pain, acute or chronic gastrointestinal bleeding and perforation, or intestinal obstruction.

Microencapsulated, high-dose formulations of pancreatic enzymes have been described as causing fibrosing colonopathy and colonic obstruction in young patients with cystic fibrosis (Pettei et al. 1994; Smyth et al. 1994). The condition is characterized by a proliferative fibroblastic process in the colon submucosa, which leads to a long, fusiform segmental narrowing of the lumen. This complication has been most frequently reported in children with pancreatic insufficiency from cystic fibrosis, who take large amounts of pancreatic enzymes orally to facilitate fat digestion and control steatorrhea. The high-dose concentrated enzyme products were initially welcomed as a way to enhance treatment by diminishing the number of pills containing lipase, amylase, and protease that had to be ingested each day. However, shortly after introduction of these high-dose formulations and widespread clinical use, fibrosing colonopathy was reported (Smyth et al. 1994). Generally, greater than 2 mg kg−1 of enzymes, equivalent to about 6000 or more lipase units kg−1per meal was the dosage level associated with colonic mucosal damage (Borowitz et al. 1995). Most children who developed fibrosing colonopathy were under 12 years of age, had a history of meconium ileus with distal ileal obstruction, and often had prior ileocolonic surgery (Campbell et al. 1994; Oades et al. 1994; Pettei et al. 1994; Smyth et al. 1994). Patients with the condition usually present with crampy abdominal pain and distention. Barium X-ray of the colon or endoscopy demonstrates a fusiform colonic stricture involving the right colon. Once established, the stricture does not regress and usually requires surgical resection.

The exact cause for the fibrosing colonic reaction remains unclear. It has been suggested that undissolved minitablets or microspheres containing the enzymes pass to the distal small intestine and colon and dissolve there releasing large amounts or high concentrations of lipase, amylase, and proteases that caused the damage to the bowel wall (Mac Sweeney et al. 1995). It is also possible that chemicals used to coat or protect the enzymes against inactivation by gastric acid play a role in causing the tissue reaction. However, evidence for any one specific factor remains inconclusive. Studies including intestinal lavage and subsequent analysis of the fluid for inflammatory cells and cytokine mediators released into the lumen have demonstrated evidence for the presence of subclinical mucosal inflammation in some, although a minority of cystic fibrosis children taking high-dose pancreatic enzyme replacement (Croft et al. 1995). This test may prove to be useful for identifying those persons at increased risk of developing fibrosing colonopathy. The best approach to prevent this complication, however, appears to be to use doses of pancreatic enzyme preparations that contain no more than 20 000 units of lipase per dose and to administer the lipase in the recommended range of 500–2500 lipase units kg−1 (Cappell and Simon 1993) per meal (Borowitz et al. 1995). Further clinical experience is needed to confirm this recommendation.

A number of other drugs have been incriminated as causing acute colitis, but the number of case reports for each is small. However, the evidence for a causal effect is reasonably convincing for α-methyldopa, flucytosine, sulfasalazine, and mesalamine. α-Methyldopa, used to treat hypertension, has been reported in rechallenge cases to cause a watery or bloody diarrhea, a macular rash, hepatomegaly, and leukocytosis with eosinophilia, suggesting a hypersensitivity or allergic process (Borkowsky and Brisbane 1976; Troster and Sullivan 1989). Flucytosine, used to treat systemic fungal infections, has been reported to cause abdominal pain, diarrhea, and colonic mucosal ulceration (White and Traube 1982). Salicylates are rarely associated with colon toxicity but patients have been reported who developed bloody diarrhea, abdominal pain, nausea, vomiting, and skin rash with eosinophilia, again suggesting a hypersensitivity reaction (Chakraborty et al. 1987; Rutherford et al. 1984). Of note, sulfasalazine that contains sulfapyridine and 5-amino salicylic acid has been used for years as a mainstay for treatment of idiopathic ulcerative colitis and occasionally rheumatoid arthritis. There is good evidence from case reports that sulfasalazine can occasionally worsen symptomatic ulcerative colitis and reactivate quiescent disease (Schwartz et al. 1982; Shanahan and Targan 1987). A similar toxic effect can also occur with the newer 5-amino salicylate preparation mesalamine, suggesting that the adverse effect is likely related to the amino salicylate moiety (Kapur et al. 1995).

Other drugs about which case reports have appeared suggesting colon toxicity but for which the evidence is less convincing include carbamazepine (Anttilla and Valtonen 1992), rifampin (Tajime et al. 1992), isoretinonin (Martin et al. 1987), penicillamine (Houghton et al. 1987), and cyclosporine A (Murphy et al. 1993). Two of the H2 receptor blockers, cimetidine and ranitidine, have also been the subject of isolated reports of colon mucosal toxicity that resolved following withdrawal of the drugs (Beaugerie et al. 1995; Collins 1982).

Antirheumatic Drugs

Peripheral neuropathy is a well-recognized complication of gold treatment in patients with rheumatoid arthritis, occurring in 0.5 to 1 percent of patients. Motor involvement is prominent, with inconspicuous sensory symptoms. The onset may be abrupt and the progression rapid, so that in some cases the condition mimics the Guillain–Barré syndrome, particularly in patients who develop facial diplegia and have elevated cerebrospinal fluid protein levels.148 A sensory or mixed peripheral neuropathy has been reported in patients with rheumatoid arthritis treated with the recently introduced disease-modifier leflunomide.149

Chloroquine may cause a mild sensorimotor neuropathy as well as a more severe proximal myopathy in some cases. A neuropathy may also occur rarely in patients treated with d-penicillamine, but this is less common than the myasthenic syndrome that may occur in patients on long-term treatment with this drug. There has also been a report of the Guillain–Barré syndrome developing in a patient on d-penicillamine.148 A mixed sensorimotor neuropathy may develop in patients treated with colchicine for long periods and is usually associated with a proximal myopathy.150

Antirheumatic Drugs

Peripheral neuropathy is a well-recognized complication of gold therapy in rheumatoid arthritis. Motor involvement is usually prominent and sensory symptoms are inconspicuous. The onset may be abrupt and the progression rapid, and in some cases may mimic Guillain–Barré syndrome, particularly in patients who develop facial diplegia and elevated cerebrospinal fluid protein levels. A sensory or mixed neuropathy has also been reported in patients with rheumatoid arthritis treated with leflunomide.

Chloroquine may cause a mild sensorimotor neuropathy or more severe neuromyopathy. A neuropathy may occur rarely in patients treated with d-penicillamine, and Guillain–Barré syndrome has been reported to occur. A mixed sensorimotor neuropathy sometimes develops in patients treated with colchicine for long periods and is often associated with a proximal myopathy.

Several types of neuropathy have been described with the TNF-α inhibitors etanercept and infliximab, including Guillain–Barré syndrome, Miller Fisher syndrome, chronic inflammatory demyelinating neuropathy, multifocal motor neuropathy with conduction block, mononeuritis multiplex, and axonal sensory or sensorimotor polyneuropathy. The pathogenesis is thought to involve a T-cell and humoral immune attack against peripheral nerve myelin antigens, inhibition of axonal signaling functions, and vasculitis-induced ischemia. Adalimumab may also be associated with a peripheral neuropathy; multifocal motor neuropathy with conduction block and acute bilateral phrenic neuropathy have been reported.

4.12.2 Clinical Studies

Bureau, Barriere, Nicolas, and Leroux (1962) described two cases of erythroderma induced by gold treatment of rheumatoid arthritis. In the first case, a pruritus starting some time after initiation of gold therapy in a 53-year-old man rapidly developed into erythroderma on hands, trunc, and face after administration of total 0.9 g gold over 2 months. A 10 days i.v. EDTA chelation course, total 5 g EDTA, mobilized extensive amounts of gold into urine paralleled by rapid healing of the skin lesions. The second case, a 76-year-old female, had a rapid, serious and painful aggravation of her rheumatoid arthritis. She then received 6 injections of 0.2 g Aurotioprol (“allochrysine”) followed 3 months later by weekly injections of 0.1 g Aurotioprol. After 5 injections in the second course she rapidly developed a generalized pruritus worsening to a vesiculobullous edematous erythroderma over most of the body, requiring hospitalization. She received 2 daily i.v. EDTA infusion of 0.5 g EDTA for 5 days, then 1 infusion per day for 6 days. She experienced rapid healing of her erytherma paralleled with extensive mobilization of gold in urine.

Davis and Barraclough (1977) monitored serum and urinary gold levels during chelation with DPA in 18 patients treated with gold salts for rheumatoid arthritis. DPA did not increase urinary gold excretion statistically significantly. Serum gold levels in chelated and unchelated patients fell at similar rates. Analysis of protein binding of gold salts in vitro indicated high affinity between gold and albumin and low levels of unbound gold even at very high gold levels suggesting that only small amounts of gold are available for chelation by DPA, which is considered an unreliable chelator of gold in vivo and its use in gold poisoning remains speculative.

Thompson, Pegelow, Singsen, Powars, and Hanson (1978) described development of severe neutropenia in five children receiving gold injections for treatment of systemic onset juvenile rheumatoid arthritis within eight weeks after starting therapy in four patients, and 24 weeks after start in the fifth. In two children leukopenia preceded neutropenia. One child died from septicemia. In the four surviving children neutropenia resolved within 1–2 weeks. BAL chelation in one child did not appear to influence the recovery.

Perry and Jacobsen (1984) described a patient treated with therapeutic doses of gold for presumed rheumatoid arthritis. The patients developed encephalopathy, generalized muscle fasciculations, and peripheral neuropathy. BAL chelation resulted in remission of the symptoms.

Dubowitz, Hughes, Lane, and Wade (1991) described a case of gold induced neuroencephalopathy in a 56 y old man starting 5 months after starting AuTM therapy (50 mg injection weekly) for rheumatoid arthritis. The patient presented anorectic after loosing 20 kg, with painful paraesthesia in hands and feet, muscle waisting and fasciculations. He was confuse and disoriented and these conditions rapidly worsened. Gold induced polyneuropathy and neuroencephathy was diagnosed and gold therapy was discontinued. The patient was chelated with BAL, 150 mg × 2 daily for 2 days, 150 mg daily for 6 days. His condition improved and he was discharged after 10 days, alert and with appetite.

Reproductive system

Gigantism of the breasts, probably induced by bucillamine, has been reported [16].

After attempts with chrysotherapy and lobenzarit, a 24-year-old woman was given bucillamine 300 mg/day and a glucocorticoid, predonine, for rheumatoid arthritis. After 10 months she noticed bilateral breast enlargement, which over 6 months progressed to extreme proportions, the left breast ultimately reaching as far as her pubis. The skin of the breasts was thin and erythematous, with marked dilatation of the superficial veins. The nipple areola complexes were elongated and poorly defined from the surrounding skin. There were no abnormalities of prolactin, sex hormones, growth hormone, or TSH (but the values were not stated). Bilateral total mastectomy was performed and the nipple-areola complexes were removed from the resected tissue and grafted on to the breasts after insertion of a tissue expander. The breast tissue removed from the right side weighed 5 kg and that from the left side 7 kg. Histologically there was increased fibrosis and duct dilatation and no malignancy.

This reaction, attributed here to bucillamine, is a rare but well-established adverse reaction to penicillamine. Although the patient had also taken isoniazid for pulmonary tuberculosis, that was unlikely to have played a part, since the breast enlargement started earlier and progressed after the isoniazid had been withdrawn.