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| Year : 1980 | Volume
: 26
| Issue : 4 | Page : 263-6 |
Activation of systemic lupus erythematosus by antitubercular drugs.
Agarwal MB, Anjaria PD, Mehta BC
How to cite this article:
Agarwal M B, Anjaria P D, Mehta B C. Activation of systemic lupus erythematosus by antitubercular drugs. J Postgrad Med 1980;26:263 |
Systemic lupus erythematosus (SLE) is a rare collagen disorder, etiology of which seems to be an interplay between a genetically determined diathesis and various environmental factors acting as activators. Failure to detect such activators in a given case is so common that SLE with any obvious activating or inducing factor becomes a medical curiosity. These factors could be drugs, sunlight, pregnancy, viral infections etc.
About 18 cases of isoniazid activated or induced SLE' are reported in the literature.[1], [3], [7], [13] SLE is also a known complication of para-amino salicylic acid (PAS) therapy.[1] We are reporting a case who developed SLE while receiving antituberculous therapy with streptomycin, Isoniazid and PAS.
A 35 year old, married, female patient was admitted with history of irregular fever, pigmentation of skin over the face and the back, pain in both wrists, ankles and knees joints, myalgia and irratability for two months. She had exertional breathlessness. She gave history of fever and diarrhoea nine months ago for which she was treated at multiple places without any response and finally she was put on antituberculous therapy with streptomycin, isoniazid and PAS for suspected intestinal tuberculosis. Streptomycin was stopped after about 100 injections. Her diarrhoea had stopped but she developed additional symptoms mentioned above. She had not taken any contraceptives at any time. Her examination revealed mild pallor, generalised lymphadenopathy, thickening and greyish discolouration of skin over the face, extremities and back [Fig. 1], patchy alopecia of scalp and arthritis affecting wrists and ankles joints. She had a firm hepatomegaly of 4 cms. Spleen was not palpable and there was no free fluid. She had clinical evidence of pericardial effusion. This was confirmed by X-ray chest, ECG and echocardiagraph. X-ray chest revealed a diffuse enlargement of the cardiac shadow. [Fig. 2], ECG showed generalised inversion of T waves and echocardiography revealed free posterior pericardial effusion. Rest of the systemic examination including blood pressure and fundus was normal.
Investigations revealed hemoglobin 9.5 gm.%, PCV 32%, Reticulocyte count 6%, total WBC count 12000/cmm. with P. 60%, L. 38%, E. 1% and M. 1%. Platelet count was 2,70000/ c.mm. ESR was 80 mm. at the end of one hour. Urine examination was normal; BUN was 14 mgm.%, serum creatinine 1.2 mgm.%, Blood Sugar 72 mgm.%, Total protein 6.2 gm.%, albumin 1.78 gm.%, Globulin 4.42 gm.%, alglobulin 0.29 gm.%, a-2Globulin 1.04 gm. %, B-globulin 0.77 gm. %, y-globulin 2.32 gm. orb IgG, IgM, IgA were raised. Coomb's test was negative (both direct and indirect), cold agglutinins and cryoglobulins were absent. Serum VDRL and RA tests were negative. L.E. cell preparations were repeatedly positive. Liver biopsy and kidney biopsy were both normal while lymph node biopsy revealed infiltration with atypical lymphocytes, plasma cells and eosinophils. Bone marrow revealed 7% plasma cells. Serum complement C3 level was normal.
In the absence of any evidence of active tuberculosis and presence of findings suggestive of SLE, the antitubercular drugs were taken off. Patient was treated with prednisolone 60 mg./day. She showed marked improvement in two weeks. Her fever subsided, bone pains and myalgia decreased, joint movements became painless, lymph nodes reduced in size, liver became impalpable and pericardial effusion disappeared with cardiac size returning to normal both clinically and on X-ray. The ECG showed upright T waves while echocardiagraph showed no evidence of fluid in the pericardial space. There was no evidence of flaring up of any tuberculosis over next six months. Other investigations repeated at the end of 6 months revealed that Hb had increased to 13.8 gm% with normal reticulocyte count and ESR had dropped to 20 mm. at end of one hour. Her LE cell preparations became negative, but /globulin had still remained high with elevated IgG levels. Patient is at present without steroids for the last 3 months and is symptom free.
Spontaneous SLE (S-SLE), according to Harvey et al,[6] was first described by Kaposi, a dermatologist, in 1872. Syndrome with clinical, laboratory and histopathological features indentical with those of S-SLE have occurred after administration of a number of drugs.[7] These drugs could act in two ways[1] i.e. (i) Due to their peculiar pharmacological properties which are dose related e.g. hydralazine, procainamide, anticonvulsants and isoniazid etc. and (ii) as a hypersensitivity reaction which is rare and not dose related e.g. sulfonamide, methyldopa, oral contraceptives, PAS etc.
For a definite diagnosis of SLE, the criteria laid down by "American Rheumatology Association” must be satisfied.[5] Presence of facial erythema, alopecia, arthritis without deformities, pericardial effusion and strongly positive LE cell preparations at more than one occassion confirm the diagnosis of SLE in the present case. Pericardial effusion was unlikely to be of tuberculous origin as it occurred while patient was on antituberculous therapy and it responded to steroid therapy. In addition, LE cells are unknown in tuberculosis. There was no definite evidence of intestinal tuberculosis for which patient was given antitubercular drugs. Whether patient had S-SLE from beginning and drugs had aggravated it or the whole picture was induced by drugs alone, is difficult to conclude.
The suspicion of drug induced SLE (D-SLE) can be made if the drug was given prior to the occurrence of syndrome; the syndrome regresses on its withdraw' and if recurrence occurs on rechallenging with the suspected drug. Such rechallenge is always dangerous and also non-ethical. Perry[9] had a unique opportunity to rechallenge11 patients of D-SLE with hydralazine. Clinical and laboratory manifestations of SLE occurred in most of them. No such trials have been carried out with isoniazid.[1]
Various factors are known to favour a diagnosis of D-SLE over S-SLE, but none is diagnostic. None of the serological and immunological tests can differentiate between S-SLE and D-SLE., The important differences are as follows (i) Kidneys are rarely involved in D-SLE.[1] (ii) SSLE is more common in males and in old age[2] but this is probably due to the fact that this is the group commonly receiving antihypertensive drugs. (iii) Pleuropulmonary complications are more common in hydralazine and procainaide induced SLE [2] (iv) Anemia and leucopenia are rare in D-SLE., (v) D-SIYE is said to be reversible in a large number of cases.
The incidence of D-SLE is about 3-4% of all cases of SLE, the commonest drug being hydralazine.[7] First description of hydralazine induced SLE was in 1954.[10] Isoniazid is a rare drug to do so but antinuclear antibodies are found in about 20% of cases treated with Isoniazid.[1] Cases of Isoniazid induced SLE have usually received about 150-900 mgs/day of Isoniazid for a variable period of 6-8 months. LE cell phenomenon on PAS therapy is on record but a fully developed collegen diseases is not yet described.[12]
The mechanism of D-SLE is hypothesised in multiple reports. These mechanisms can be summarised as (i) The dose related D-SLE is produced by drugs acting on cellular membrane with release of macromolecules in altered form or in immunological amount [4] (ii) Most of the drugs producing dose related SIX are aromatic compounds and even a poor immunogen can be made more immunogenic by addition of simple aromatic substitutes.[11] (iii) Isoniazid is known to increase collagen deposition.[8] (iv) Slow acetylaters get isoniazid and hydralazine induced SLE more often. This is due to the longer and stronger action of drugs over nucleoproteins rendering them more autoantigenic.[1] (v) drugs are said to lower the normal defence mechanisms sufficiently to allow a viral infection to manifest[4] and this infective hypothesis may explain the full recovery seen in some cases of D-SLE.
Awareness of D-SLE helps in early detection of the disease in the patients who are receiving drugs known to produce SLE. Such knowledge has important prognostic and therapeutic applications as the drug causing it needs withdrawl and prognosis is better in D-SLE than in S-SLE.
We thank Dr. C. K. Deshpande, Dean, K.E.M. Hospital and Seth G.S. Medical College, for permission to publish this case.
| 1. | Alarein-Segovia, D.: Drug induced lupus syndrome. Mayo Clin. Proc., 44: 664-681, 1969.  |
| 2. | Alarein-Segovia, D. and Alarecin, D. G.: Pleuropulmonary manifestations of systemic lupus erythematosus Dis. Chest., 39: 7-71, 1961. |
| 3. | Bickers, J. N., Buechner, H. A., Hood, B. J. and Alvaraz-Chiesa, G.: Hypersensitivity reaction to anti-tuberculosis drugs with hepatic lupus phenomenon and myocardial infarction. New Eng. J. Med., 265: 131-132, 1961. |
| 4. | Blomgran, S. E.: Drug-induced lupus erythematosus. Semi. Hemato., 10: 345349, 1973. |
| 5. | Coben, A. S. and Canoso, J. J.: 'Editorial', Criteria for the classification of SLE status 1972. Arthritis and Rheumatism, 15: 540-543, 1972. |
| 6. | Harvey, A. M., Shulman, L. E., Tumulty, P. A., Conley, C. L. and Schoenirch; E. H.: Systemic lupus erythematosus: Review of the literature and clinical analysis of 138 cases. Medicine (Baltimore), 33: 291-296, 1954. |
| 7. | Lee, S. L., Rivoro, I. and Siegal, M.: Activation of systemic lupus erythematosus by drugs. Arch. Int. Med., 117: 620-626, 1966. |
| 8. | Martyn, T. W. and Compbell, J.: Isoniazid and wound healing. Canad. Med. Ass. J., 88: 229-235, 1963. |
| 9. | Perry, H. M.: Late toxicity to hydralazine resembling systemic lupus erythematosus or rheumatoid arthritis. Amer. J. Med., 54: 58-72, 1973. |
| 10. | Perry, H. M. and Schroeder, H. A.: Syndrome simulating collagen disease caused by hydralazine (Aprasoline). J. Amer. Med. Assoc., 154: 670-673, 1954. |
| 11. | Sela, M. and Arnon, R.: Studies on the chemical basis of the antigenecity of protein. Biochem. J., 75: 91-102, 1960. |
| 12. | Simpson, D. G. and Walker J. H.: Hypersensitivity to Para-aminosalicylic acid. Amer. J. Med., 29: 297-306, 1960. |
| 13. | Zingale, S. B., Minzer, L., Rosenberg. B. and Lee, S. L.: Drug induced lupus like syndrome. Arch. Int. Med., 112: 6366, 1963. |
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