Severe Type Ii Hypersensitivity Reaction

Published Date: 02 Nov 2017

1. Case Scenario

The clinical scenario revolves around a 25 year old woman with multibacillary Hansen’s disease (i.e. leprosy). The disease however is additionally complicated by a severe inflammatory reaction known as erthyema nodosum leprosum (i.e. type II hypersensitivity reaction) which requires additional pharmacological therapy in conjunction to treating the primary infection.

1.1 Background

Leprosy is a chronic infectious disease known to be caused by the acid-fast, rod-shaped bacillus Mycobacterium leprae (M leprae).1,2 With references of the disease dating as far back as 1550B.C., leprosy has always been believed to be a fearful disfiguring disease for which no treatment would ever be able to cure.2 Often times, individuals affected with leprosy are subjected to ostracism and abandonment, and are forced to live in segregated ‘leper colonies’ for which unfortunately still do exist today in countries such as India, China and Romania. It wasn’t only until 1873, when Dr. Amauer Hansen of Norway first characterised the causative pathogen, Mycobacterium leprae, interests in the disease and treatment for the disease began pouring in.2,3

1.2 Epidemiology

Globally, leprosy remains as a prevalent issue in regions of South East Asia, South America, Africa, Western Pacific and the East Mediterranean.4 Leprosy for a fact is known to generally manifests in both subtropical and tropical temperate climates and this may be exemplified by countries such as India, Brazil and Indonesia being the top three countries with most number of reported leprosy cases in 2010.2,4 In 2009, 244 796 cases of leprosy have been newly detected globally, and the registered prevalence at the start of 2010 totalled to 211 903 cases, resulting in a global prevalence of registered leprosy cases of just 1.77 per 10 000.4

Humans unfortunately however represent the main carriers for M Leprae. Besides man, only the wild nine-banded armadillos are also known to be hosts of the microorganism.5 Hitherto, no other living organisms are known to be natural hosts of M Leprae. Nevertheless, most individuals are physically resistant to an infection with M Leprae and the disease is rarely ever fatal.2,3 Primary consequence of an infection crucially involves nerve impairment and debilitating sequelae.6

1.3 Microbiology of M Leprae

Over the last two decades, progression into the understanding of the microbiology of M Leprae has helped bridged the gaps of knowledge associated with leprosy. The capability to infect and reproduce M Leprae on mouse footpads has not only overcome the challenge of cultivating M Leprae in cell culture, but it has also provided opportunities for detailed microbiological investigations and clinical studies.7

For the most, M Leprae, a gram-positive and obligate intracellular parasite, is known to exhibit tropism for macrophages and Schwann cells, and is figured to thrive predominantly in regions of lower body temperature (e.g. skin, upper respiratory tract, eyes and peripheral nerves). Predilection for Schwann cells are due vitally to the affinity to the G domain of the 2 chain of laminin-2, which are found in abundance in the basal lamina of Schawnn cells. Evidently, consequences of an infection are cutaneous in nature and at times may involve permanent disability caused by severely impaired nerve function.2,7

Additionally, clinical manifestations of leprosy vary depending upon host immune responses towards M Leprae. The complex mixture of polysaccharides and glycolipids which forms the cytoplasmic membrane of M Leprae represents important targets of host immune responses.7 As such, treatment management will vary depending upon the different clinical manifestations of the disease.2,3,7,8

1.4 Clinical Manifestations

As aforementioned, variability in host immune responses corresponds to diverse clinical manifestations of the disease. Accordingly, based on a classification system designed by the WHO, leprosy may be categorised based on the number of skin lesions present and the presence of bacilli determined via a slit-skin smear examination. Paucibacillary Hansen’s disease on one hand is defined as lesser than six skin lesions without the presence of bacilli on slit-skin smear testing. Multibacillary Hansen’s disease on the other hand, is characterized by six or more lesions with or without positive skin smear results.2,3,8

C:\Users\USER\Desktop\Numerous Lesions.jpg

Figure 1: An example of a multibacillary Hansen’s disease patient with >5 anaesthetic erythematous skin lesions.10

Classical features of leprosy nonetheless include skin lesions, weakness, numbness, and even eye pain or visual impairment Figure 1. If left untreated, the disease may result in permanent damage to the skin, nerve, limbs or eyes.2,3,8 In this case of a 25 year old female diagnosed with multibacillary Hansen’s disease, the patient may firstly present with numerous anaesthetic skin lesions (>5) with symmetrical distributions (Figure 1). The skin lesions may additionally exhibit hypopigmentation or erythema, and may be easily confused for other dermatological conditions (e.g. dermatitis, tinea corporis and psoriasis).3

Appreciably, the enlargements of certain peripheral nerves (e.g. ulnar, median and posterior tibial nerve) as in Figure 2 are also hallmark signs of leprosy due to the tropism and subsequent multiplication of M Leprae within Schwann cells.7,8 Damage afflicted from the accumulation of M Leprae within Schwann cells may also result in other distinct signs of leprosy. For example "clawing" of the hands or foot is commonly reported cases distinct of leprosy.3 In particular cases of the multibacillary form of the disease, leonine facies (i.e. lion-like appearance) may also be manifested (Figure 3).3,9

C:\Users\USER\Desktop\Enlargement of Vein.jpg

http://www.stanford.edu/class/humbio103/ParaSites2006/Leprosy/snsx_files/image013.jpg

Figure 2: An example of the enlargement

of the peripheral nerve.10

Figure 3: An example of a multibacillary

Hansen’s disease patient with a

characteristic ‘leonine facies’.9

1.5 Immunologic Reaction

Additionally, in this case, the patient’s disease condition is further complicated by a severe type II hypersensitive reaction (i.e. erythema nodosum leprosum) towards the M Leprae antigen. Additional treatment secondary to a primary regimen must be considered.8,12,13,14

Depending upon the class of the disease (i.e. paucibacillary or multibacillary), immunologic reactions towards the antigens produced by M Lepreae may manifest either as a type 1 (reversal), or type 2 (i.e. erythema nodosum leprosum) reaction. These reactions tend to vary in severity, occur acutely and may also punctuate the course of infection even during or after completion of drug therapy. Patients whom are afflicted with the multibacillary form of the disease are likelier (i.e. 11 – 50 % risk) to experience the erythema nodosum leprosum (ENL) form of reaction.12

In short, ENL reactions are characterized by elevated levels TNF-α and interferon-γ, and immune responses are induced in response to accumulation of extravascular immune complexes formed from M Leprae antigens. Patients suffering from an ENL reaction may present clinically with fever, arthralgia, malaise or acute new appearances of small, tender erythematous subcutaneous nodules.12 In severe cases, hypotension and tachycardia may ensue and are considered to be importantly life threatening.13 Accordingly, ENL reactions are to be treated promptly to avoid long-term permanent nerve impairment.14

2 Treatment

Literature with relevance to treating leprosy, and all information associated with alternative anti-leprotic treatment options were attained via SUPrimo, the University of Strathclyde Library’s integrated search service. The search service utilises various literature databases including Elsevier Science Direct (http://www.sciencedirect.com/) and also PubMed (http://www.ncbi.nlm.nih.gov/pubmed).

For the most, the first line treatment option for leprosy comprises of the WHO-recommended multidrug therapy (i.e. dapsone, clofazimine and rifampicin); although, treatment algorithms may vary between continents (e.g. America, Europe and Asia). Under the WHO, costs for the components of the multidrug therapy for patients whom suffer from leprosy are levied by the organisation. However, this is capped to only a year’s supply. Critically, depending on the initial individual bacterial indices of leprotic patients, treatment durations may need to be lengthened to ensure therapeutic success (i.e. complete patient sterilisation).

2.1 Components of the Multidrug Therapy

Prior to the introduction of the multidrug therapy (MDT), dapsone (diamino-diphenylsulphone) was initially thought of to be the long awaited cure for leprosy. Dapsone was first used as a monotherapy but it required patients to be on long term, often lifelong treatment due its slow bactericidal activity. Years after its introduction however, over and uncontrolled use led to the emergence of dapsone-resistant strains.15 Globally, primary and secondary resistance rates soared to as high as 50% and 19% respectively.16 In response to the alarming threat to leprosy control, in 1982 treatment for leprosy was revolutionised with the advent of MDT. The concept of combining several drugs was ideally aimed at limiting the development of antibiotic resistant pathogens. Since then, approximately 11.5 million individuals have been treated with MDT.4

Therapeutic effectiveness in the context of treating leprosy however is determined by measuring rate of relapses following successful completion of a scheduled course of treatment.3 Rate of relapses since the introduction of MDT was discovered to be only 0.06% among multibacillary afflicted patients globally, thus proving the therapeutic efficacy of MDT.6 Since then, MDT has been the mainstay first-line regimen for the treatment of leprosy.8

Table 1: Recommended MDT according to the WHO and National Hansen’s Disease Program (NHDP) for treatment of multibacillary Hansen’s disease.

WHO

NHDP

Dapsone 100mg/day

Rifampicin 600mg/month

Clofazimine 100mg/month

for 12 months

Dapsone 100mg/day

Rifampicin 600mg/day

Clofazimine 50mg/day

for 24 months

2.2 Dapsone

Dapsone, which represents the first component of the MDT, exhibits structural similarities to sulphonamides. It is known to target dihydropteorate synthase, a key enzyme involved in the folate biosynthesis pathway in M Leprae.17

In a study conducted in 1975 utilizing mouse footpad models, Louis Levy18 detected a pertinent interval between the growth curves attained from passages from control and dapsone-treated mice. A 99.4% elimination rate of viable M leprae with the use of dapsone as a singular therapy was observed and the growth curves comparing treated and control mice exhibited an average 78 day delay between both groups, with the bacilli from the treated mice lagging behind. Appositely, dapsone was concluded to have exhibited both bacteriostatic and bactericide effect.18 Despite the fact however, in comparison to the efficacy of rifampicin, dapsone was only considered to be weakly bactericidal against M leprae.8 For the most, it is used in combination with rifampicin and clofazimine crucially to prevent the emergence of resistant strains.8,17,18

Missense mutation within codons 53 and 55 of the folP1 gene encoding dihyropteorate synthase has been implicated in the emergence of dapsone resistant strains. Patients whom are likely to relapse after either dapsone monotherapy or MDT would most likely display mutant folP1 genes rather than rpoB genes (i.e. rifampicin resistant genes).19

Additionally in certain cases, patients lacking glucose-6-phosphate-dehydrogenase (G6PD) started on dapsone therapy may exhibit methaemoglobinemia and hemolysis. Adverse events as such limits the use of dapsone and thus requires patients to be screened for G6PD deficiency prior to starting therapy. 17

2.3 Rifampicin

Rifampicin on the other hand, which represents the key component of MDT, is known to be the most bactericidal antileprotic agent available.2,18 Numerous studies at most have highlighted its potent and rapid activity against M Leprae 20,21,22 . A study conducted by Levy et al23 for example demonstrated no viable bacilli via mouse footpad tests just after 4 days of a single 600mg dose of rifampicin. Additionally, a study by Ji et al24 established that rifampicin was more bactericidal when compared to any combination of new antileprotic agents (e.g. clarithromycin-minocyclin-ofloxacin, clarithromycin-minocyclin and dapsone-clofazimine).

Rifampicin essentially acts on the β-subunit of the DNA dependent RNA polymerase encoded by rpoβ.19 It is never used as monotherapy due to the risk of rapid development of resistant strains.2,19 Depending on the treatment algorithm by WHO or NHDP (Table1), rifampicin may be taken on a monthly basis or even a daily basis.2 Crucially however, it was noted that patients are less likely to relapse if prescribed rifampicin on a daily basis. 20

Adverse effects with the use of rifampicin commonly include hepatoxicity, malaise and rash. Patients may at times also experience a reddish discolouration of the urine but it is nevertheless harmless.2,3

Clofazimine

Clofazimine crucially represents the third and last component of the MDT. Despite an unestablished mechanism of action to date, the antibacterial activity of clofazimine has been attributed to both its lipophilic and anti-inflammatory properties.3, 25 For the most, the highly lipophilic property of clofazimine enables it to accumulate in the skin and nerves, the similar sites whereby M Leprae resides.25 Additionally, the anti-inflammatory properties of clofazimine has been hypothesised to reduce the occurrences of harmful erythrosum nodum leprosum(ENL) reactions. 26

Clofazimine, if used singularly, even at 600mg monthly as demonstrated by Jamet et al27, was only partially effective in eliminating M Leprae. Thus, similarly to dapsone, it is to be used a combination therapy to prevent the emergence of resistant M Leprae strains3,27. A commonly noted side effect with the use of clofazimine includes a reddish-brown discolouration of the skin and conjunctiva, both of which are reversible upon discontinuation of therapy. 3

2.4 Multidrug Therapy (MDT)

Overall, over the last 3 decades, responses towards MDT have been relatively satisfactory. The use of dapsone, rifampicin and clofazimine in combination was considerably tolerable and were devoid of major interactions.28 The bactericidal activity of MDT crucially became the benchmark in determining the effectiveness of newer combination regimens. Relapse rates, as previously mentioned were relatively low.6

Recommended treatment durations however vary between regimen algorithms(Figure 1).2 As per WHO, a 12 dose regimen was thought to be minimally sufficient. However, this was based due to monetary limitations. Conversely, as per the National Hansen’s Disease Ppogram(NHDP), a 24 month duration treatment was considered sufficiently intensive.29 Sales et al30 described no significant differences in decline of bacillary levels between the 12 and 24 dose multidrug regimens. Katoch31 however, in her review associated increased rates of relapses due to an insufficient reduction in bacilli index (BI) after 12 months of therapy. Controversially, various sources have even recommended treatment durations till smear-negatives are achieved; however this depends very much on the initial BI count prior to initiation of therapy. In some cases patients may require up to 5-6 years to achieve smear negatives.31,32

As in this case, an intensive 24 month therapy of MDT or till smear negatives are achieved may be the suitable first line treatment option for this patient to ensure total bacterial eradication. As per the NHDP, 100mg of dapsone, 600mg of rifampicin and 50mg of clofazimine is to be each taken daily for 24 months.32

3 Alternative Regimens

If the patient however is contraindicated to any of the components of the standard MDT drugs (i.e. rifampicin or dapsone), other antileprotic agents must be considered. Alternative treatment options include combinations of ofloxacin, minocyline and clarithromycin. At the very most, each agent has exhibited bactericidal activity against M Leprae, but these effects despite being used in combination are nonetheless incomparable to that displayed by rifampicin.3 These regimens include both ROM and COM(Figure2).

Table 2: Alternative treatment regimens

ROM

COM

Rifampicin 600mg/monthly

Ofloxacin 400mg/monthly

Minocycline 100mg/monthly

supervised for 2 years

Clarithromycin 2000mg/monthly

Ofloxacin 800mg/monthly

Minocylcline 200mg/monthly

≥ 2 years or till smear negatives are achieved

In short, minocycline is the only member of tetracycline class active against mycobacteriaceae. It functions by binding to the 30s and 50s ribosomal subunits and consequently inhibiting protein synthesis. Clarithromycin alternatively, is an erythromycin derivative also known to inhibit protein synthesis by binding into to the 50s ribosomal subunits. Ofloxacin on the other hand is the recommended alternative to rifampicin by WHO. It functions by inhibiting DNA gyrase, thus interfering with cell replication.2,19

3.1 Rifampicin + Ofloxacin + Minocycline

ROM primarily consists of rifampicin, ofloxacin and minocycline. ROM may be represented as a 2nd line treatment option or an alternative regimen for patients whom are contraindicated to the dapsone component of MDT.33 In various studies utilizing mouse footpad tests and clinical trials, the simultaneous use of ofloxacin and minocycline exhibited greater bactericidal activity than both dapsone and clofazimine used in combination.24,33,34,35

In a study by Villahermosa et al36 assessing the effectiveness of ROM (n=10) against the effectiveness of the WHO-MDT (n=11) amongst multibacillary afflicted patients, both groups exhibited similar significant reductions in mean BI levels (p<0.05). ROM of which was given for 24 consecutive monthly observed doses of rifampicin(600mg), ofloxacin(400mg) and minocycline(100mg) displayed histological improvements similar to those treated with the WHO-MDT and were generally well tolerated by patients. All MDT-treated patients however additionally developed clofazimine induced skin discolouration. Crucially however, despite displaying promising outcomes, the treatment size in this study was small and may not warrant for similar outcomes in a larger population size.36 Moreover, the cost of a ROM regimen quadruples the cost of a standard WHO-MDT regimen.36

Pertinently, in a recent systemic review 37 assessing several studies (n=6) utilizing ROM against MDT, it was made known overall that ROM was as effective as MDT in reducing BI levels in patients (proportion change: -4%, 95% CI -31% to 23%). Similarly, no major interactions were identified and that ROM was generally well accepted.37

3.2 Clarithromycin + Ofloxacin + Minocycline

In a study by Xiong et al38 assessing the combination of clarithromycin, ofloxacin and minocycline (COM) via mouse footpad test, administration of a single dose of the three drug combination eliminated 98.4% of viable M. Leprae, approximately similar to that produced by a single dose of rifampicin (i.e. 99.4%).38

Likewise, in a study by Ji et al39 assessing the administration of a single monthly dose of COM (i.e. 2000 mg of clarithromycin, 200mg of minocycline and 800mg of ofloxacin) in MB afflicted patients (n=10), a similar degree of bactericidal activity as to that of the mouse model was observed. In the same study, patients treated with COM demonstrated improvements in morphological indices similar to those treated with ROM (n=10) but most however also suffered from mild to moderate gastrointestinal disturbances due to the use of clarithromycin. Gastrointestinal disturbances however subsided within a few hours after administration. The fact that the patients however only received a single dose of COM may not even be sufficient to suggest the need for the discontinuation of therapy due to clarithromycin.39 More importantly, because most studies have only experimented with a single dose in 1 month, appropriate treatment duration with COM for the treatment of MB has yet to be suggested.

Thus, assumingly if the patient is started on COM, it would be most advisable that she should be on a prolonged treatment (≥ 2 years) or till smear negatives are obtained, although as aforementioned, there is no evidence to support this suggestion.

4. Treatment of Severe Type 2 Hypersensitivity Reaction

Depending upon the type of immunologic reaction (i.e. reversal or ENL), treatment options vary among one and another. Ultimately, treatment management for ENL reactions are aimed at reducing both elevated TNF-α and interferon-γ levels.2,40,41 Recommended treatment options include the use of either thalidomide 400mg once daily or pentoxifylline 1.2g daily as a singular therapy.41

4.1 Thalidomide

Among both treatment options suggested, thalidomide crucially is known to be more potent than pentoxifylline for the management of severe ENL reactions.41 First reported in 1965, Sheksin41 demonstrated efficacious thalidomide activity against ENL. The S- enantiomer of thalidomide was thought to be responsible for the activity against ENL by suppressing TNF-α release from peripheral blood mononuclear cells, although other mechanisms may also contribute to its anti-inflammatory activity.41,42

Numerous studies have demonstrated efficacious thalidomide activity against ENL. In a randomised double-blind double-dummy study (n=22) by Villahermosa et al.43 for example, the activity of thalidomide 300mg daily was compared to 100mg given daily initially for a week, with both doses subsequently tapered throughout the treatment duration of 6 weeks. By week 7, patients started on the higher dose group (n=12) exhibited lesser occurrences of ENL when compared to the lower dose group (P=0.02), and several patients whom started on the lower dose thalidomide redeveloped lesions soon after stopping treatment. Accordingly, Villahermosa et al. concluded by recommending the use of thalidomide with a higher starting dose (e.g. 400mg) and slower dose reductions in for the treatment ENL reactions. Participants in this study however consisted only of men and thus the outcomes wouldn’t be able to be generalized to occur similarly in women.43

Separately, in a review by Walker et al40, the authors reported a study similarly conducted by Sheksin et al44 in 1969 with significant thalidomide activity given at 400mg daily to women in the management of ENL relative to placebo. The full original article by Sheksin et al44 as reported however was irretrievable and thus questions the credibility of the study.

Considerably, in a randomised double-blind trial comparing the efficacy of thalidomide (300mg daily) against pentoxifylline (1.2g daily) (n=44), by week 4, thalidomide-treated patients exhibited a 95% overall improvement rate (i.e. reduction in axillary temperature, regression in cutaneous lesions, lymph nodes and oedema) when compared to a 62.5% overall improvement in pentoxifylline-treated patients.41

The recommended dose for the management of severe ENL is 400mg once at night. Common occurrences of drowsiness are an issue with the use of thalidomide and neuropathy in particular cases may be a limiting factor to the use of thalidomide.40 Doses should be tapered cautiously from 400mg to 100mg, and regular assessments involving ENL responses and nodule regressions are required.40,41 Despite the fact however, as it is known infamously for its teratogenic properties, thalidomide should be used with caution in women of childbearing potential.40 As such, despite displaying efficacious activity, thalidomide should be considered as a 2nd line treatment option instead for the patient in this particular case.

4.2 Pentoxifylline

For the most, pentoxifylline is considered as the safer alternative to thalidomide for use in women of childbearing potential.41 Despite displaying lesser and somewhat slower activity as compared to thalidomide, pentoxifylline is known similarly to be capable of inhibiting the release of TNF- α and thus relieving patients of ENL syndromes. In an open label study involving 15 multibacillary type patients, following treatment with 1200mg pentoxifylline given once daily for a total of 2 months, 13 patients’ significant decreases in TNF- α were exhibited by the end of week 8.45 Similarly, in an open label study conducted by Carsalde et al46 (n=15), within a week of pentoxifylline treatment, 11 patients displayed rapid improvements of systemic symptoms and neuritic pain within a week, and by the end of week 3, approximately half of all participants exhibited complete cure while the other half displayed significant clinical improvements. Subsequently, 5 patients whom abruptly discontinued pentoxifylline treatment relapsed shortly within 2 to 3 months but those who were tapered down slowly exhibited no relapse. Vitally, no significant adverse events were reported and pentoxifylline was generally well accepted by patients.46

As such, the recommended dose for the management of ENL using pentoxifylline is 1.2g daily and side effects may include nausea, vomiting or agitation. Unless a patient is refractory towards pentoxifylline, thalidomide should then be considered instead.45,46

5 Treatment Plan

Treatment of ENL

Treatment of Infection

NHDP-MDT

Dapsone 100mg/daily

Rifampicin 600mg/daily

Clofazimine 50mg/daily

for 2 years or till smear negatives are achieved

Pentoxifylline 1.2g/daily

+

1st Line

refractory or

contraindicated to pentoxifylline

relapse or

contraindication to dapsone

Thalidomide 400mg/daily

Reduce doses by 100mg to 100mg/daily fortnightly or according to control

*avoid in pregnancy

ROM

Rifampicin 600mg/monthly

Ofloxacin 400mg/monthly

Minocycline 100mg/monthly

supervised for 2 years

2nd Line

contraindication to rifampicin

COM

Clarithromycin 2000mg/monthly

Ofloxacin 800mg/monthly

Minocylcline 200mg/monthly

≥ 2 years or till smear negatives are achieved

3rd Line

Figure 4 – Treatment plan for the 25 year old female multibacillary Hansen’s disease with severe ENL reactions. Recommended doses for the MDT-regimen are according to the NHDP algorithm and treatment for ENL is started with pentoxifylline.

Accordingly, the treatment plan for the 25 year old female patient in this case is presented in Figure 4. First-line treatment options include both the NHDP based MDT regimen and pentoxifylline. On completion of the 2 year therapy or till smear negatives are achieved, yearly follow-up sessions should be in place. Relapses on average may occur after a 5 to 10 year remission period and follow-ups should be conducted by an expert leprologist.(2) Unless relapse has been truly established, M Leprae rifampicin-sensitivity testing should be carried out prior to initiating ROM. COM should only be initiated if rifampicin resistant strains are established or that the patient is contraindicated to the medication. Pentoxifylline on the other hand should be initiated together along with the multidrug regimen. Unless refractory, thalidomide should be initiated with caution. Prior to the dispensing of thalidomide, pregnancy tests are to be carried out to ensure safe and effective usage of the medicine. Additionally, for both regimens, the patient should be advised on the importance of adherence and on the side effects most likely to be encountered (e.g. urine discolouration induced by rifampicin or skin and conjuctive discolouration induced by clofazimine) Ultimately, compliance is key to ensuring the emergence of resistant strains and to ensure complete patient sterilisation.