|CONTINUING MEDICAL EDUCATION
|Year : 1990 | Volume
| Issue : 5 | Page : 354-363
Immuno pharmacology of drugs used in leprosy reactions
B K Girdhar
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Girdhar B K. Immuno pharmacology of drugs used in leprosy reactions. Indian J Dermatol Venereol Leprol 1990;56:354-63
|How to cite this URL:|
Girdhar B K. Immuno pharmacology of drugs used in leprosy reactions. Indian J Dermatol Venereol Leprol [serial online] 1990 [cited 2020 May 27];56:354-63. Available from: http://www.ijdvl.com/text.asp?1990/56/5/354/3573
Leprosy disease per se is a chronic almost completely silent infection, even when the host-lepromatous patient is loaded with multiplying M. leprae. This silent course, however, is often punctuated by episodes of acute problems, which are responsible for the morbidity associated with this infection. These episodes in general have been called `reactions'. It is now well known that such events can occur in almost all types of patients across the spectrum. Further, these reactions, on basis of the pathogenesis can be grouped into two main types, one due to changes (more often increase) in cellular hypersensitivity and the other due to immune complex formation,,. The former are seen among borderline patients, infact can occur although from subpolar tuberculoid to subpolar lepromatous end of spectrum, whereas the later type of reactions occur mainly in BL and LL cases more often among the smear positive than in the smear negative ones. What precipitates these immunologic changes and thus the clinical manifestations is exactly not known. The alterations in load of antigens, their recognition and the immunological responses to these are considered to be important in this regard. These can be brought about by physiological factors like pregnancy, puerperium, physical and psychological stresses , infections-both acute and chronic, vaccination procedures etc. Therefore, management of reactions really begins with finding, if any of the precipitating cause is present.
In a very large proportion of cases no apparent precipitating factor can be found. In the past, it had been considered that specific drugs were responsible for precipitation of reactions as the reactions occurred more often following initiation of therapy than among the untreated patients. Hence, therapy use to be discontinued when reactions appeared. However, it is now agreed that basic treatment must continue unchanged even during such episodes.
Our attempts at treating and preventing occurrence of reactional episodes is based on preventing immunological phenomenon that lead to tissue damage. This involves blocking effects secondary to immune complex formation and deposition and reducing the hypersensitivity component in the two types of reactions. Several drugs have been used for the purpose. These include
| Steroids|| |
These are mainstay in treatment of reactions in leprosy. These compounds are able to suppress all types of reactions and are able to prevent practically all the sequelae of reactions. Their mechanism of action, as an anti-inflammatory agent, to-date remains controversial as there are contradictory reports on every score. However, one thing appears to be clear that these drugs exert powerful suppressive effect on inflammation and hypersensitivity reactions. Further, these compounds have no significant inhibitory effect of cellular or humoral immune status unless used in very large doses and/or over long duration of periods as is in transplantation surgery. When used in moderate doses, these compounds can suppress lymphocyte functions directly or by altering the circulation kinetics of effector lymphocytes or their regulatory cells.
Steroids cause inhibition of both the early and late phenomenon of inflammation. The early changes include oedema, capillary dilation, influx of leucocytes and the phagocytic activity. The later events of inflammation, which occur after several hours like capillary and fibroblast proliferation, too are inhibited. Associated with these effects are the decrease in chemotaxis of both polymorphs and monocytes, inhibition of plasminogen activation etc. These compounds appear to inhibit release of prostaglandins in several tissues in animals and mouse,. This appears to be on account of reduced availability of prostaglandin synthetase and phospholipase-A. This effect of steroids appears to be confined to synovium in human and is not seen in other tissues.
Though, the above mechanisms appear to be involved in preventing the tissue damage in reactions, effect of steroids on lymphocytes appear to be more important. Steroids have been shown to cause preferential depletion of T cells more so those with Fc receptors for IgM i.e., the B helper T cells. This may result in normalization (restoration) of disturbed helper suppressor T cell ratio as has been found during E.N.L.. These compounds have been found to prevent and control adjuvant arthritis possibly due to redistribution of T cells. It is now more or less established that steroids have an inhibitory effect on most of the lymphocyte effector functions, resulting in decrease in cellular hypersensitivity as evidenced in studies in allergic contact dermatitis. The mechanism of inflammation subsidence appears to be decreased infiltration with lymphocytes with consequent reduced lymphokine liberation.
Whereas due to very varied modes of action, steroids are able to suppress inflammation in all tissues, they also produce serious side effects. All these are too well known. Of these, steroid dependence is particularly important. This is more common among E.N.L. patients. Each subsequent episode requires higher steroid dose and withdrawal of steroids results in repeated attacks of reactions.
| Thalidomide|| |
It is the other important anti-reaction drug. This potent and fast acting anti-reaction compound is not only able to control practically all the manifestations,, including neuritis in E.N.L. reactions but also permits withdrawal of steroids in steroid dependent cases. The drug is not effective in borderline reactions. Its mechanism of action has been investigated by several groups of workers. The results available thus far can be summarized as under
i. Its anti-reaction and teratogenic effects go hand in hand, as evidenced from investigation of its analogues.
ii. Effect of complement derived chemotactic factors is reduced by thalidomide, resulting in reduced or non recruitment of polymorphonuclear leucocytes into the lesions as has been seen in carragennon induced rat paw oedema model.
iii. The drug has been found to reduce IgM response in animals and in E.N.L.patients. This has been attributed to decrease in T helper cell activity. However, some doubt has been expressed with regard to IgM involvement in E.N.L. reactions.
iv. Recently, it has been shown that thalidomide significantly reduced T helper cell numbers with relative increase in suppressor cells. Indeed, during E.N.L. reaction a relative increase in helper cell population is found and subsidence of reaction helper, suppressor ratio comes down. This is possibly the most important way by which thalidomide exerts its effect in E.N.L.
v. Other modes of action which may play some role include, lysosomal stabilizing action (limited to liver cells only) as also modulating effect on defective monocyte function. These modes of action possibly result in reduced release of antigens and improvement in chemotaxis and superoxide release.
Like steroids, it is a boon for patients getting repeated E.N.L. It is particularly useful in weaning and withdrawing steroids in steroid dependent patients. However, there are several problems with this drug. These include teratogenicity and a state of thalidomide dependence requiring drug to be continued till smear negativity i.e. for several years. Fortunately, no serious metabolic or other side effects are observed. Teratogenicity associated with the drug limits its use in males or menopausal women only. Of the other problems occasional sensory neuropathy needs to highlighted.
| Clofazimine|| |
It is basically an antileprosy drug. This drug has been found to have a special role in management of E.N.L.,. Its mechanisms of anti-inflammatory action is not well understood. The possible ways include
i. The drug may result in decrease in neutrophil mobility with consequent decreased influx of PMN into the inflammed area. Associated with this is the ability of drugs to stimulate PMN and macrophage membrane associated oxidative metabolism,. This may result in presentation of altered antigens to the lymphocytes, resulting in decrease in antibody formation with consequent control and prevention of reactions.
ii. In contrast to decrease lysosomal activity or decrease in lysosomal enzymatic release with other anti-inflammatory drugs, clofazimine appears to increase the synthesis of these enzymes as also phagocytic capacity,. These effects may result in increased or relatively complete digestion of antigens by the macrophages. Ingested antigens are possibly degraded to much less antigenic forms.
iii. A recent report suggests that clofazimine might act by stimulating synthesis of PGE 2 by PMN monocytes and macrophages. High levels of PGE 2 are known to have immunomodulatory effect on T cell proliferation and antibody production. Further, this prostaglandin or its poorly metabolized analogues have been found to prevent adjuvant arthritis, a some what closely related problem
iv. Regarding its effect on cellular immunity, there are conflicting reports. Some suggest that, with the addition of clofazimine there- is reduction in mitogen induced lymphocyte transformation, whereas, other studies indicate that the drug potentiates C.M.I. Exactly, in line is the controversy regarding its - usefulness in borderline reactions. One school of workers find it effective in type I reaction while others have observed no such effect
However, it is agreed that the drug is very slow to act taking several weeks for its full effect indicating the need to add other drugs for management of acute/subacute manifestations. The drug has only a limited role in neuritis since it takes too long for any significant effect. The usefulness of the drug lies in its being primarily an anti-leprosy drug, being helpful in management of chronic recurrent E.N.L. as also in withdrawing steroids in steroid dependent cases. It limitations include pigmentation, ichthyosis and G.I.T. deposition especially as the drug is required to be used in high doses and for long periods in patients with repeated reactions.
| Antimony Compounds|| |
These drugs have been used for over two decades and continue to be used in some parts of the world even today. Both tri and pentavalent compounds have been found useful in patients with mild to moderate E.N.L. particularly in relieving bone and joint problems. Their mode of action has not been elucidated as no significant work is available in the literature in this regard. Pentavalent antimonials (such as sodium antimony gluconate) are more effective and less toxic than the commonly used trivalent preparations. The use of these drugs is restricted on account of parentral route of administration and several serious toxic effects such as anaemia, cardio and nephropathy.
| Chloroquine|| |
Following an incidental observation that anti-malarial compounds were useful in management of E.N.L., chloroquine and to less extent amodiaquines have been widely used in some parts of the world,. Their effect in suppressing E.N.L. appears to be, on account of their anti-inflammatory properties. These include lysosomal membrane stabilization, inhibition of prostaglandin synthetase with consequent reduced PG synthesis and decreased inflammatory damage. The drug has also been found to suppress complement activation, platelet aggregation, and enhances fibrinolytic activity. The relevance of observation of chloroquine inhibiting mitogen induced lymphocyte transformation is not clear.
Whereas, the drug is easily available, cheap and effective against mild episodes of both borderline and E.N.L. reactions, its side effects pose some limitations. These include G.I. disturbances, skin rashes and visual problems. The drug is contraindicated in pregnancy due to its damaging effect on foetus.
Apart from their analgesic and antipyretic effect, salicylates reduce the symptoms and signs of inflammation and act in practically all the ways as chloroquine does. Even though, their action is very mild, these are very useful for symptomatic relief of pain and fever.
During the past several years search for other drugs effective in suppressing reaction has continued. Several non-steroidal antiinflammatory drugs (NSAD), immunosuppressive agents, anti metabolities and other diverse agents have been screened. Some of the important observations are mentioned.
| Cyclosporin-A (CsA):|| |
With the understanding that, in the active lesions of E.N.L., a consistent increase in T helper suppressor ratio is found and that following subsidence, whether with thalidomide or steriods, this transitory increase is reversed, workers have attempted to use other drugs which have this as one of their modes of action. CsA was first tested in vitro using peripheral blood mononuclear cells from E.N.L. patients. It was found that lepromin induced Con A suppression of suppressor cells was reversed, with predominant effect on adherent cells.
Following this, clinical studies in 3 E.N.L. patients, by the same group of workers, have indeed found it to be useful when given in dose of 100 to 200 mg. daily. The limiting factors being G.I.T. symptoms observed in all the 3 treated patients. This effect was attributed to earlier prolonged clofazimine administration.
| Colchicine|| |
Of late this drug has received some attention in treatment of E.N.L. reaction. The drug has been shown to suppress Arthus reaction in rabbits despite deposition of immune complexes. This was considered to be on account of its suppressing the PMN chemotaxis. Other studies have indicated that in addition to immuno-regulatory action, the drug is able to restore T cell balance, an abnormality that appears with onset of E.N.L.
Whatever the mechanism of action the reports are contradictory with regard to its efficacy. Whereas, Sarojini and MashnaSharma et al and Kar and Roy found it useful, Standley and others were not able to reduce the dose of steriods with addition of colchicine in patients with recurrent E.N.L. Beneficial effect on joint and nerve pains has also been reported with its use.
| Topical steroids|| |
Work in BT has shown that granulomas in sensitized animals contain short lived replicating steroids sensitive T cells and these get affected with steroids. Based on this topical steriods have been used by Srinivasan et al in 6 BT patients in reaction. A good clinical response in a week's time with use of fluocinolone acetonide (0.025%) under occlusion was observed. Histology also showed a very dramatic decrease in oedema with more compact granuloma and less dilated lymphatics.
| Levamisole|| |
Some reports are available in the literature, wherein levamisole has been used in E.N.L. cases. The results have not been encouraging. The possible consideration for its use was its ability to restore T cell numbers to normal. Enhanced in-vitro responses to both PHA and Con A has also been observed with this drug.
| Zinc|| |
This compound has been reported to have inhibiting effect on neutrophil chemotaxis and complement mediated reactions. The drug has been found to be useful in management of E.N.L. Of the 8 patients treated with oral zinc by Mathur et al, 7 were more or less controlled and in them steriods could be withdrawn completely with reduction in weekly dose of clofazimine and better tolerance of DDS.
| Antimetabolites|| |
These cytotoxic agents exert antiinflammatory effect by decreasing both humoral and cellular responses. There are only anecdotal reports suggesting their usefulness of E.N.L. The drugs have not found favour on account of several side effects as a part of their anti-proliferative action. A recent study has found combination of azathioprin and steriods better than the latter alone.
| Trepterygium wilferdin hook - A Chinese Herb|| |
This herbs has been reported to be effective in both type I and type II reactions, with efficacy of 96.6% and 98% respectively The herb is also effective in suppressing neuralgia.
| Plasmapheresis|| |
This method has been employed in treatment of both type 1 and type II, reactions and involves replacement of plasma of the patient with sterile albumin solution. It has been suggested that the type I reaction is on account of appearance of some plasma factors that augment LTT response of lymphocytes of these patient to PHA stimulation. The removal of `this' immunostimulatory factor results in beneficial effect by reducing the hypersensitivity response. In a clinical study a net decrease of T4 : T8 ratio was observed in the second course of plasmapheresis. It has also been found effective in E.N.L. type of reaction,. Its possible mechanism includes dilution of I.C. and/or free antigens and antibodies.
Non-steroidal anti-inflammatory drugs have also been tried in reactions of leprosy. None of them have been found to be particularly useful in suppressing or preventing reactions per se. Some do relieve symptoms by their analgesic and antipyretic effects
There are suggestions in the literature that drugs like DFS, and gangliosides have beneficial role on nerves in patients and/or experimental mouse infection. Though, their effect on nerve damage, during reactions, is not known, they need to be tried as adjunct in management of patients in reactions.
| Clinical management of reactions|| |
It is now well established that the drug of choice in borderline (reversal) reactions is steroids. This drug has to be administered without delay at the earliest evidence of painful neuritis and/or suddenly appearing or progressive nerve deficit a manifestation more likely to be on account of hypersensitivity reaction occurring within the nerves. Steroids are usually required to be given in moderate doses (20-30 mg prednisolone equivalent per day) and for long periods and then be tapered off. Various schedules have been recommended regarding dosing and length, of treatment. Instead of generalizations patients need be treated on individual basis.
In a large proportion of patients, the reactions are confined to skin, while in few others both the nerve and skin lesions get affected. For all the latter cases and where swelling and oedema of skin lesions is gross, steriods as mentioned above, are required. But when the reactions are mild with only skin manifestations short courses of chloroquine may suffice.
Splinting of nerves, physical therapy and symptomatic treatment to relieve pain by giving analgesic, emperical use of diuretics to relieve oedema etc. are important aspects of treatment.
Mild cases of E.N.L., respond to simple measure like rest, aspirin and chloroquine. Moderately severe cases often require steriods or antimony compounds, if available. Patients with neuritis, orchitis, uveitis or those having severe pustulating E.N.L. need be given steriods together with supporting drugs for symptomatic relief. In contrast to reversal reaction, high initial dose and rapid tapering appears to be more suitable way of management. When prolonged administration of steriods is required once a day or alternate day steroid therapy has been found to be more beneficial.
In patients with repeated reaction, or those in whom attempts to withdraw steroids precipitate the reactions, thalidomide is the treatment of choice, starting the drug with high doses (300 to 400 mg per day in divided doses) and reducing it gradually. Thalidomide, if available, is preferred to steroids in all patients with E.N.L. as this drug has comparatively fewer side effects and is able to control all symptoms. Clofazimine regimens have an added advantage in such patients, with clofazimine dose increased during the initial 4 to 6 weeks when used for reaction. Since clofazimine takes more than a month to exert its anti inflammatory effect, other anti-reaction drugs must be added in the initial stages of management.
On the whole, it has been found that the treatment of leprosy hardly has any effect on the reaction or its outcome. Therefore, in order to prevent emergence of resistance, it is advocated that basic anti-leprosy drugs must be continued even during reactions, unless the latter is life threatening.
To conclude, though several compounds have been investigated/applied in the management of the two types of reactions in leprosy, only a few are actually available for field application and for treatment of hospitalized patients. Other drugs either give equivocal response, or are too toxic and expensive. The advances in understanding of immunopathology are opening up new horizons for investigations of other immunomodulatory drugs. Though, the problem of lack of precise methods of testing the drugs for their modes of activity, exists, many drugs are becoming available for the purpose of ameliorating patients morbidity.
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