Procainamide-induced lupus

Binding of nitroso-procainamide to histone proteins may perturb chromatin structure or catabolism, resulting in immunogenic forms of DNA-free histones. In fact, all sera of patients (n = 24) with procainamide-induced Lupus showed IgG and IgM antibody activity against various histone components of chromatin (chromosome subunits)122. The nature of the procainamide adduct to histone proteins still awaits elucidation. 

Kluger J, Drayer DE, Reidenberg MM, Lahita R. Acetylprocainamide therapy in patients with previous procainamide-induced lupus syndrome. Ann Intern Med 1981 95 18-23. 

Rubin RL, Burlingame RW, Arnott JE, Totoritis MC, McNally EM, Johnson AD. IgG but not other classes of anti-[(H2A-H2B)-DNA] is an early sign of procainamide-induced lupus. J Immunol 1995 154 2483-93. 

Type III reactions are caused by tissue injury due to immune complexes. The antigen-antibody complexes are usually cleared by the immune system however, repeated contact with antigens can cause the complex to deposit in tissue and result in tissue injury. Serum sickness is the classic example of a Type III reaction. Medications associated with serum sickness include many antibiotics, phenytoin, salicylates, barbiturates, nonsteroidal antiinflammatory drugs, isoniazid, antisera, hydralazine, captopril, and sulfonamides. Procainamide-induced lupus, described in Chapter 16, is also considered a Type III reaction. 

Kushner W, Jones C, Schmid FR, Askenazi J. Remission of procainamide-induced lupus erythematosus with N-acetylprocainamide therapy. Ann Intern Med 1979 90(5) 799-801. 

Pericarditis and tamponade have been reported as rare complications of procainamide-induced lupus-like syndrome (9). 

Scleritis has been reported as part of a procainamide-induced, lupus-Uke syndrome (19). 

Thymus function in 10 patients with sjmiptomatic procainamide-induced lupus has been compared with that in 13 asymptomatic patients who only developed drug-induced autoantibodies (45). Newly generated T cells were detected in all the subjects. Although there was no overall quantitative difference between the sjmp-tomatic and asymptomatic patients, there was a correlation between the level of T cell receptor rearrangement excision circles in peripheral lymphocytes and serum IgG antichromatin antibody activity in patients with drug-induced lupus. These results support the hypothesis that the thymus is important in the genesis of drug-induced lupus-like syndrome and that the production of autoreac-tive T cells starts in the thymus when procainamide hydroxylamine alters T cell tolerance. 

In procainamide-induced lupus there is an increase in the number of B cells in both blood and pleural fluid to about 80% (normal 10-25%). Concentrations of IL-6 and soluble IL-2R are also increased (46). 

The antinuclear antibody is positive in virtually all cases and the ESR is often raised. Antihistone antibodies are also present in most cases. The prevalence of serum autoantibodies to high-mobility group (HMG) proteins in the serum of patients with drug-induced lupus-like syndrome varies from protein to protein 67% for HMG-14 and/or HMG-17 compared with 21% for HMG-1 and/or HMG-2. Procainamide-induced lupus is also associated with antibodies to the H2A-H2B dimer (55,56). 

Turgeon PW, Slamovits TL. Scleritis as the presenting manifestation of procainamide-induced lupus. Ophthalmology 1989 96(1) 68-71. 

Sherertz EF. Lichen planus following procainamide-induced lupus erythematosus. Cutis 1988 42(l) 51-3. 

Heyman MR, Flores RH, Edehnan BB, Carliner NH. Procainamide-induced lupus anticoagulant. South Med J 1988 81(7) 934-6. 

Kameda H, Mimori T, Kaburaki J, Fujii T, Takahashi T, Akaishi M, Ikeda Y. Systemic sclerosis comphcated by procainamide-induced lupus and antiphosphohpid syndrome. Br J Rhenmatol 1998 37(ll) 1236-9. 

Klimas NG, Patarca R, Perez G, Garcia-Morales R, Schultz D, Schabel J, Fletcher MA. Case report distinctive immune abnormalities in a patient with procainamide-induced lupus and serositis. Am J Med Sci 1992 303(2) 99-104. 

Genetic polymorphisms of xenobiotic-metabolizing enzymes may result in expression of inactive enzymes or enzymes with a reduced or increased metabolic activity (Daly, 1995). For example, the incidence of hydralazine- and procainamide-induced lupus is higher or the disease starts earlier in individuals with the slow acetylator phenotype caused by mutant NAT-2 alleles than in individuals exhibiting the fast-acetylator phenotype (Woosley et al., 1978 von Schmiedeberg et al., 1999). 

The rate of drug metabolism, which is in part under genetic control, may be of importance. The population with low levels of hepatic acetyltransferase activity seems at greater risk of developing the hydralazine-induced lupus syndrome (Perry et al. 1970), but this does not hold for procainamide-induced lupus. Genetic factors have also been implied in pseudoallergic reactions, such as aspirin intolerance (Lockey et al. 1963). 

It is difficult to derive an overall figure for the incidence of procainamide-induced lupus erythematosus, mainly due to the difficulty of accurately diagnosing some of the early clinical signs which often cause the patient to stop taking the drug. But in one series more than 10% of patients taking procainamide developed severe lupus erythematosus and another 10% developed a milder form of the syndrome (Fakhro et al. 1967). In the series by Hope and Bates (1972) 3 out of 61 patients who had taken procainamide for more than 4 weeks were found to have the full lupus syndrome, and another 3 had some features of the condition. 

More significantly, procainamide can be complexed to DNA in vitro. Blom-GREN and Vaughan (1968) showed that procainamide, in the presence of a photoactive molecule and visible light, bound to DNA to produce a highly antigenic complex. It has been postulated that such a complex may be involved in the pathogenesis of procainamide-induced lupus. 

The fact that procainamide can be photocomplexed to DNA in vitro is an interesting observation. If a procainamide-DNA complex is the form of the complete antigen in vivo, then the antibodies should have limited cross reactivity with native DNA. This, indeed, appears to be the case no antibodies to native DNA have been found in patients with procainamide-induced lupus (Blomgren and Vaughan 1970 Koffler et al. 1971). Moreover, it would be expected that, if the mechanism for procainamide lupus is centered around a drug DNA complex and no similar complex is demonstrable for hydralazine, DNA antibodies might be likely to occur in patients with hydralazine lupus. Hahn et al. (1972) and Blau (1973) have reported DNA antibodies in hydralazine-treated patients, but the data are not sufficiently definitive to be conclusive. 

Bareis RJ (1974) Procainamide induced lupus erythematosus. SD J Med 27 19-20 Barzel US (1967) Quinidine sulfate induced hypoplastic anaemia and agranulocytosis. JAMA 201 325-327... 

Blomgren SE, Condemi JJ, Vaughan HJ (1972) Procainamide induced lupus erythematosus. 

Kosowsky BD, Taylor J, Lown B, Ritchie RF (1973) Long term use of procainamide following acute myocardial infarction. Circulation 47 365-366 Ladd P (1962) Procainamide induced lupus erythematosus. N Engl J Med 267 1357-1358 Lesne M (1972) Des are radioimmunoloigique de la gitaloxine et de la gitoxine. Arch Int Pharmacol Ther 199 206-208... 

Smaha, L. A. and Wanamaker, J. L. (1975) Three cases of procainamide induced lupus syndrome. Guthrie Bull, 45, 65. 

Chose, M. K. (1975) Pericardial tamponade. A presenting manifestation of procainamide induced lupus erythematosus. Amer. J. Med., 58, 581. 

Sunder, S. K. and Shah, A. (1975) Constrictive pericarditis in procainamide induced lupus erythematosus syndrome. Amer. J. Cardiol, 36, 960. 

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