Nitrendipine-induced subacute cutaneous lupus erythematosus

ARTICLE

Several medicaments have been implicated in the induction of lupus erythematosus (LE) [1]. On the basis of a genetic predisposition, it is supposed that drug-induced formation of autoantibodies may sustain the development of the disease. Drug-induced LE usually resembles systemic LE (SLE), satisfying the American Rheumatism Association (ARA) criteria for diagnosis of SLE. Drug-induced LE differs from drug-induced subacute cutaneous LE (SCLE), the latter being regarded as a distinct syndrome that is frequently unrecognized [2-4]. On the other hand, antiphospholipid antibody syndrome (APS) is characterized by the occurrence of venous or arterial thrombosis, recurrent fetal loss and the presence of lupus anticoagulant (LAC) and/or anticardiolipin antibodies (aCL) [5]. We report the case of a patient affected by the association of drug-induced SCLE, high titer antiphospholipid antibodies and hemiparesis, which occurred after nitrendipine administration.

Case report

In November 2001, a 66 year-old man was admitted to our Institute for the investigation of a slightly painful skin eruption which developed one month before on his trunk and limbs. On admission, the dermatosis presented as annular polycyclic and gyrate, erythematous-violaceous lesions, 2 to 7 cm in diameter; vesiculation and crusting or hemorrhagic erosions were present at the borders (Fig. 1). There was no mucosal involvement and the patient had neither xerostomia nor xerophtalmia. He was apyrexial with a blood pressure 160/90 mmHg. The remaining physical examination was unremarkable without evidence of organomegaly or lymphoadenopathy.

Past medical history revealed pulmonary tuberculosis at the age of 58 years, successfully treated. At the onset of the eruption the patient had been taking nitrendipine (40 mg daily) due to a mild arterial hypertension for about three weeks. He was not taking other drugs and not exposed to sunlight. Laboratory tests showed thrombocytopenia (83 <=> 10⁹/l, normal 140-440) and prolonged activated partial-thromboplastin time (APTT: 57.2 sec, normal 30-43). LAC was detected using various coagulation tests, such as kaolin clotting time, silica clotting time and diluted Russell's viper-venom time; the presence of LAC was confirmed by the prolonged clotting times. Autoimmune screening also demonstrated the following findings: (i) positive antinuclear antibodies (ANA) (titer 1:160) with a fine speckled pattern, as determined by indirect immunofluorescence on Hep-2 cells, (ii) positive anti- Ro(SS-A), La(SS-B), Sm antibodies, as demonstrated by enzyme-linked immunosorbent assay (ELISA), and (iii) positive rheumatoid factor. In addition aCL, and both IgM and IgG, were found at titers 18 IgM phospholipid units (MPL; normal: < 10, low positivity: 10-20, medium positivity: 20-80, high positivity: > 80) and 80 IgG phospholipid units (GPL; normal: < 10, low positivity: 10-20, medium positivity: 20-80, high positivity: > 80), as measured by ELISA. Anti-beta2-glycoprotein I antibodies could not be evaluated. Strongly positive anti-histone antibodies (AHA) were detected by immunoblotting using a commercially available kit (Innogenetics N.V., Gent, Belgium).

Routine serum chemistry abnormalities included C-reactive protein at 2.1 mg/dl (normal < 1) and ferritin at 951.7 ng/ml (normal 22-320). Levels of IgG, IgA and IgM were 1 725 mg/dl (normal 700-1 600), 466 mg/dl (normal 70-350) and 109 mg/dl (normal 34-200), respectively. The liver function tests revealed high serum levels of alkaline phosphatase (423 U/l, normal 98-279), gamma glutamyl transpeptidase (751 U/l, normal 11-50) and aspartate aminotransferase (96 U/l, normal 4-37). Normal or negative results included renal function tests, complement C3 and C4 serum levels, anti-native DNA, anti-platelet, anti-liver-kidney microsomal, anti-mitochondrial, anti-actin and anti-smooth muscle antibodies, serologies for hepatitis B and C, Coxsackie B, Parvovirus and ECHO viruses.
Serologies for CMV, EBV were suggestive of previous infection.

Radiography and computed tomographic (CT) scans of the chest revealed upper lobe pulmonary infiltrates with a clean cavity in the left lung and numerous calcified nodules, consistent with previous pulmonary tuberculosis. Sonographic examination and CT scans of the abdomen demonstrated liver steatosis. Schirmer test was within normal limits.

A biopsy specimen from a skin lesion showed focal hydropic degeneration of the epidermal basal cell layer and scattered apoptotic keratinocytes with a mild lymphohistiocytic infiltrate in the upper dermis (Fig. 2). Slight mucin deposition was observed in the papillary dermis. Direct immunofluorescence was negative.

Therapy with nitrendipine was discontinued and the patient's cutaneous manifestations markedly abated over two weeks without any treatment. Three days after withdrawal of the drug, while dermatologic features were already improving, the patient was suddenly stricken with left hemiparesis with sensory impairment of the homolateral skin surface. Echocardiography revealed no abnormalities and there was no echographic evidence of previous venous limb thrombosis. Encephalic CT scans revealed a small area of reduced density in the right hippocampus. Supposing a cerebral arterial occlusion, neurologists required the patient's transfer to the neurological department for further investigations, such as magnetic resonance imaging of the brain and echography of the supra-aortic vessels, and starting anticoagulant therapy. However, the patient refused the transfer as well as further instrumental examinations.

After six months, skin lesions have completely resolved, only pigmentary changes persist. Patient's mobility has improved and no other neurological symptoms have occurred. Anti-Ro(SS-A) and La(SS-B) antibodies, AHA and aCL have become negative, while LAC has only decreased; ANA titer has decreased to 1:80. Liver enzyme levels have returned to the normal range and platelet count has raised to 160 <=> 10⁹/l.

Discussion

Lupus-like syndromes may be induced by various causative agents, such as drugs [1], radiation therapy [6], malignancy [6-8], infectious diseases [9, 10], complement deficiencies [11].

Drug-induced LE as a rule presents with clinical features resembling mild idiopathic SLE, with recurrent attacks of fever, pleurisy, polyarthritis, arthralgias and myalgias. Renal and central nervous system involvement is rare and
the skin is often spared. As compared with idiopathic disease, drug-induced LE is associated with the detection of anti-histone antibodies. These, which serve as a useful serologic marker for drug-induced LE, may also be detected in lower frequency in SLE [12]. Thus, considering that drug-related LE usually fulfils ARA criteria for the diagnosis of SLE, unique are the resolution of symptoms and normalization of laboratory abnormalities after withdrawal of the offending drug; furthermore, resumption of the same medicament results in the recurrence of both symptoms and serology.

On the basis of its course, our case fits in well with the diagnosis of drug-induced lupus but differs in the singular clinico-pathologic presentation as annular and bullous SCLE. Alternatively, spontaneous regression of a classic, non-drug-induced SCLE may be considered but seems to be unlikely. SCLE represents a distinct form of cutaneous LE with unique clinical, serologic and immunologic features, first characterized in 1979 by Sontheimer et al. [13]. Two main morphologic varieties of SCLE exist, namely a non-scarring papulosquamous pattern or, less frequently, an annular polycyclic eruption, but overlap forms can occur. In rare cases, vesiculobullae appear at the margins of lesions, as seen in our patient. The laboratory findings include Ro(SS-A) and La(SS-B) antibodies, which are the serum markers of SCLE, whereas AHA to our knowledge have not been reported in non-drug-induced idiopathic SCLE. On the other hand, anti-Ro and anti-La seropositivity has been detected in the majority of cases of drug-induced SCLE [3]. Our patient exhibited both AHA and antibodies against Ro(SS-A) and La(SS-B), which disappeared a few months after discontinuation of the drug. Furthermore, SCLE arose de novo in absence of preexisting symptoms or signs of LE, similarly to previous observations [2, 3, 14].

Drug-induced SCLE has been linked to a variety of drugs [3, 12, 14-20]: thiazides, angiotensin-converting enzyme inhibitors and calcium channel blockers are the most commonly reported agents. Among calcium channel blockers, nitrendipine had never previously been associated with development of SCLE. Sunlight exposure is sometimes necessary in triggering the development of SCLE [14], whilst our patient's rash was not photosensitive.

About the potential pathogenetic mechanism of the disorder, we hypothesize that nitrendipine triggered an acute antibody-dependent cellular cytotoxic reaction directed against the dermo-epidermal junction structures.

The finding of LAC, aCL, prolonged APTT and thrombocytopenia represents another important characteristic of our patient, as these are the classic laboratory markers of APS. The term APS was introduced to describe patients with LAC and aCL and at least one of the following clinical criteria: venous or arterial thrombosis, recurrent fetal loss or thrombocytopenia [21]. Arterial occlusion is a common clinical feature of patients affected by APS; large cerebral arteries are particularly involved, this involvement leading to stroke or transient ischaemic attacks [22]. International criteria for the diagnosis of APS have recently been revised and at present include only vascular thrombosis and/or complications of pregnancy, in association with aCL and/or LAC [5]. APS may arise as a primary disease or may be associated with other diseases, most frequently SLE [23]. On the other hand, antiphospholipid antibodies alone have also been detected in other autoimmune disorders [24], in several carcinomas and in Behçets' disease; it is noteworthy that the aforesaid antibodies can be found also in drug-induced LE [21, 25]. In view of the rarity of marked extracutaneous disease both in classic SCLE and in drug-induced SCLE, the occurrence in our patient of hemiparesis is also noteworthy. However, due to the patient's examination refusal, it could not be ascertained whether the hemiparesis depended on arterial brain occlusion or on other causes, such as the presence of atherosclerotic plaques or an arterial aneurysm. Thus, a diagnosis of secondary APS may only be suspected in our patient.

CONCLUSION

In conclusion, nitrendipine was thought to have caused the cutaneous eruption because of its prior ingestion, the resolution of the skin lesions and normalization of immunological parameters after the cessation of therapy, and the fact that it was the sole prescribed drug in our patient.

REFERENCES

1 - Pramatarov KD. Drug-induced lupus erythematosus. Clin Dermatol 1998; 16: 367-77.

2 - Callen JP. Drug-induced cutaneous lupus erythematosus, a distinct syndrome that is frequently unrecognized. J Am Acad Dermatol 2001; 45: 315-6.

3 - Bonsmann G, Schiller M, Luger TA, Ständer S. Terbinafine-induced subacute cutaneous lupus erythematosus. J Am Acad Dermatol 2001; 44: 925-31.

4 - Crowson AN, Magro C. The cutaneous pathology of lupus erythematosus: a review. J Cutan Pathol 2001; 28: 1-23.

5 - Levine JS, Branch DW, Rauch J. The antiphospholipid syndrome. N Engl J Med 2002; 346: 752-63.

6 - Wallach HW. Lupus-like syndrome associated with carcinoma of the breast. Arch Intern Med 1977; 137; 532-5.

7 - Chtourou M, Aubin F, Savariault I, Chabot P, Manchet G, Montcuquet P, Humbert P. Digital necrosis and lupus-like syndrome preceding ovarian carcinoma. Dermatology 1998; 196: 348-9.

8 - Strickland RW, Limmani A, Wall JG, Krishnan J. Hairy cell leukemia presenting as a lupus-like illness. Arthritis Rheum 1988; 31: 566-8.

9 - Segev A, Hadari R, Zehavi T, Schneider M, Hershkoviz R, Mekori YA. Lupus-like syndrome with submassive hepatic necrosis associated with hepatitis A. J Gastroenterol Hepatol 2001; 16: 112-4.

10 - Berman A, Reboredo G, Spindler A, Lasala ME, Lopez H, Espinoza LR. Rheumatic manifestations in populations at risk for HIV infection: the added effect of HIV. J Rheumatol 1991; 18: 1564-7.

11 - Dragon-Durey MA, Quartier P, Fremeaux-Bacchi V, Blouin J, de Barace C, Prieur AM, Weiss L, Fridman WH. Molecular basis of a selective C1s deficiency associated with early onset multiple autoimmune diseases. J Immunol 2001; 166: 7612-6.

12 - Hess E. Drug-related lupus. N Engl J Med 1988; 318: 1460-2.

13 - Sontheimer RD, Thomas JR, Gilliam JN. Subacute cutaneous lupus erythematosus. Arch Dermatol 1979; 115: 1409-15.

14 - Reed BR, Huff JC, Jones SK, Orton PW, Lee LA, Norris DA. Subacute cutaneous lupus erythematosus associated with hydrochlorothiazide therapy. Ann Intern Med 1985; 103: 49-51.

15 - Fernandez-Diaz ML, Herranz P, Suarez-Marrero MC, Borbujo J, Mannaro R, Casado M. Subacute cutaneous lupus erythematosus associated with cilazapril. Lancet 1995; 345: 398.

16 - Toll A, Campo-Pisa P, Gonzalez-Castro J, Campo-Voegeli A, Azon A, Iranzo P, Lecha M, Herrero C. Subacute cutaneous lupus erythematosus associated with cinnarizine and thiethylperazine therapy. Lupus 1998; 7: 364-6.

17 - Wollenberg A, Meurer M. Thiazid-Diuretika-induzierter subakut-kutaner Lupus erythematodes. Hautartz 1991; 42: 709-12.

18 - Nousari HC, Kimyai-Asadi A, Tausk FA. Subacute cutaneous lupus erythematosus associated with interferon beta - 1a. Lancet 1998; 352: 1825-6.

19 - Miyagawa S, Okuchi T, Shiomi Y, Sakamoto K. Subacute cutaneous lupus erythematosus lesions precipitated by griseofulvin. J Am Acad Dermatol 1989; 21: 343-6.

20 - Crowson AN, Magro CM. Subacute cutaneous lupus erythematosus arising in the setting of calcium channel blocker therapy. Hum Pathol 1997; 28: 67-73.

21 - Stephens CJM. The antiphospholipid syndrome. Clinical correlations, cutaneous features, mechanism of thrombosis and treatment of patients with the lupus anticoagulant and cardiolipin antibodies. Br J Dermatol 1991; 125: 199-210.

22 - Asherson RA, Khamashta MA, Gil A, Vazquez JJ, Chan O, Baguley E, Hughes GR. Cerebrovascular disease and antiphospholipid antibodies in systemic lupus erythematosus, lupus-like disease, and the primary antiphospholipid syndrome. Am J Med 1989; 86: 391-9.

23 - Alarc—n-Segovia D, DelezE M, Oria CV, Sanchez-Guerrero J, Gomez-Pacheco L, Cabiedes J, Fernandez L, Ponce de Leon S. Antiphospholipid antibodies and the antiphospholipid syndrome in systemic lupus erythematosus. Medicine 1989; 68: 353-65.

24 - Marzano AV, Berti E, Gasparini G, Caputo R. Lupus erythematosus with antiphospholipid syndrome and erythema multiforme-like lesions. Br J Dermatol 1999; 141: 720-4.

25 - Drouvalakis KA, Buchanan RR. Phospholipid specificity of autoimmune and drug induced lupus anticoagulants; association of phosphatidylethanolamine reactivity with thrombosis in autoimmune disease. J Rheumatol 1998; 25: 290-5.