Review Article: The Role of Non-biological Drugs in Refractory IBD

S. C. Ng; F. K. L. Chan; J. J. Y. Sung
Alimentary Pharmacology & Therapeutics. 2011;33(4):417-427. © 2011

Abstract and Introduction

Abstract


Background Up to one-third of patients with inflammatory bowel disease (IBD) do not respond to, or are intolerant of conventional immunosuppressive drugs. Although biological agents are alternative treatments, they may not be suitable or available to some patients.
Aim To review the evidence for use of nonbiological drugs in the treatment of patients with IBD refractory to corticosteroids or thiopurines.
Methods A literature search was performed using PubMed for English language publications with predetermined search criteria to identify relevant studies.
Results Published evidence from uncontrolled series and controlled clinical trials has been used to produce a practical approach relevant to clinical practice which incorporates the indication, optimal dose, and side effects of various therapies including tacrolimus, methotrexate, thalidomide, tioguanine, mycophenolate mofotil, leucocyte apheresis, nutritional therapy, antibiotics, probiotics, allopurinol, rectal acetarsol and ciclosporin in the treatment of patients with refractory ulcerative colitis and Crohn's disease. Approaches to optimise thiopurine efficacy are also discussed.
Conclusions Patients with IBD refractory to corticosteroids or thiopurines may respond to alternative anti-inflammatory chemical molecules, but the evidence base for many of these alternatives is limited and further trials are needed.

Introduction

The medical management of patients with refractory inflammatory bowel disease (IBD) remains a challenge. Up to one-third of patients with IBD are intolerant of,[1] and a further 10% are unresponsive to thiopurine.[2] Although anti-tumour necrosis factor (anti-TNF) drugs have proven to be effective in patients with Crohn's disease (CD)[3] and ulcerative colitis (UC),[4] only approximately one-fifth of all initially treated CD and UC patients are in remission at 1 year. There is still a large gap in the therapeutic armamentarium of both conditions. Additionally, in many developing countries around the world where the incidence of IBD is increasing,[5,6] funding of anti-TNF agents, if available, is limited to only a small proportion of patients.[7] Patients with active disease in whom surgery may not be appropriate will require ongoing treatment to maintain remission. There is a lack of controlled data comparing different treatment strategies for patients who have failed standard therapies. In patients with refractory disease, methotrexate, tacrolimus, leucocyte apheresis, enteral nutrition, thioguanine(tioguanine) or thalidomide may have a role, but the benefit of anti-bacterial therapy in IBD remains controversial. With recent advances in our understanding of thiopurine metabolism, dose optimisation and therapeutic manipulation to avoid toxicity is possible. In this review, we have discussed the evidence of efficacy, optimal dose, drug monitoring and adverse effects of these anti-inflammatory therapies in the treatment of patients with resistant UC and CD; although subjective, they are based on published experience.

Methods

Search was performed on PubMed of all original research studies and reviews published in English-language journals, with a last cut off publication date of March 2010, using the following keywords alone or in combination: Crohn's disease, ulcerative colitis, refractory, resistant, tacrolimus, methotrexate, thalidomide, tioguanine, mycophenolate mofotil, leucocyte apheresis, nutritional therapy, antibiotics, probiotics, allopurinol, arsenic suppository and ciclosporin enema. Abstracts presented at the Digestive Disease Week (DDW), European Crohn's and Colitis Organisation (ECCO) Meeting, and United European Gastroenterology Week (UEGW), within the last 10 years were also included. In contrast to published guidelines or consensus statements,[8,9] this review is intended neither to be a systematic review, nor an evaluation of the merits of different levels of evidence. It is intended as a selection of the most relevant publications that demonstrate points of therapeutic importance in optimisation of existing treatment regimens, and novel therapeutic approaches, relevant to the treatment of patients with refractory IBD. Double-blind placebo-controlled studies are included when available, but the evidence for most of these drugs has been based on uncontrolled cohort studies, retrospective series and expert review articles. For the purpose of this review, we have defined 'conventional therapy' as 'mesalazine (mesalamine)', corticosteroids or thiopurines. We have included studies exploring the use of alternative drugs in patients with IBD refractory to these standard therapies.

Main Stream Evidence-based Drug

Methotrexate. Methotrexate is effective in IBD but the mechanisms by which methotrexate reduce inflammation remain unclear. Putative pathways include the inhibition of cellular proliferation, downregulation of inflammatory mediators and the induction of apoptosis.[10–12] In UC, the only double-blind, placebo-controlled trial from Israel compared low-dose oral methotrexate 12.5 mg weekly to placebo in 67 active UC patients. There was no significant difference in the induction or maintenance of remission between the two groups, although the lack of benefit may relate to the lower dose of methotrexate used.[13] In contrast, uncontrolled studies with small sample size, varying doses or route of adminstration have shown that methotrexate is effective in maintaining remission in patients with steroid-dependent UC intolerant of thiopurines.[14,15] In a retrospective study, 23 patients intolerant or resistant to thiopurines were treated with subcutaneous methotrexate 20–25 mg weekly. Remission was achieved in 11 patients and symptomatic improvement in three patients.[16] A recent retrospective series from London showed that two-thirds of UC patients refractory to and intolerant of thiopurines responded to oral methotrexate.[17] In a randomised comparative trial of low-dose oral methotrexate (15 mg/week) vs. mercaptopurine (MP, 1.5 mg/kg/day) vs. 5-aminosalicylate (ASA) in 72 steroid-dependent patients (half had UC), remission rates at 30 weeks was 79%, 58% and 25% for methotrexate, MP and 5-ASA respectively.[18] More comparative studies with different doses and different routes of administration are required in UC before any definite conclusions can be drawn.[19] Two well-designed controlled trials have confirmed the efficacy of parenteral methotrexate in steroid-dependent or steroid-refractory, thiopurine-naïve CD patients.[20,21] The benefit of methotrexate in patients with CD who have failed thiopurines has only been subjected to one small uncontrolled study.[17]

Practice points and adverse effects: Data supporting the use of methotrexate for the induction and maintenance of remission in refractory UC have been based on small retrospective series. Although the exact dose and route of administration for treating such patients are unclear, most series have achieved a benefit with parenteral methotrexate 25 mg weekly (with weekly folic acid) for 3 months followed by oral methotrexate 15 mg weekly. Methotrexate, intramuscularly or subcutaneously, is effective in steroid-dependent or -refractory CD patients. The benefit of methotrexate in CD patients who have failed thiopurines, and vice versa, is less clear. The onset of peak of methotrexate is achieved after 12 weeks of treatment. Main adverse effects include bone marrow suppression and liver toxicity. Monitoring of complete blood count and liver function tests at regular intervals (approximately three monthly) is recommended. In patients with persistently abnormal liver function tests of unknown cause, methotrexate should be discontinued and liver biopsy should be performed due to the risk of hepatic fibrosis. Methotrexate is not suitable for women of child bearing age and it is contraindicated in pregnancy due to embryo-toxicity.[22]

Alternative Anti-inflammatory Molecules

Tacrolimus. Tacrolimus is a calcineurin inhibitor. It has similar mechanisms of action to ciclosporin by inhibiting the production of interleukin (IL)-2 and T lymphocyte activation.[23] Several uncontrolled series have shown that it is effective in the treatment of patients with UC, including those who are intolerant or refractory to conventional immunomodulators.[24–29] The only controlled trial of tacrolimus in UC from Japan randomised 20 steroid-refractory UC patients into each of the following arm: high trough level (10–15 ng/mL whole blood), low trough level (5–10 ng/mL whole blood) and placebo. At the end of 2 weeks, significantly more patients in the high trough (68%) and low trough groups (38%) responded compared with placebo (10%).[30] Twenty percent of patients achieved clinical remission and 79% of patients had mucosal healing.[30,31] In the medium term, oral tacrolimus is effective in UC patients resistant to conventional therapy, including some who are refractory to anti-TNF drugs. Half of those with UC achieved remission at a median follow-up of 5 months.[32] In a study of 14 patients with severe steroid-refractory UC, 64% of patients were in remission at about 6 months.[29] In a German study of 31 patients with steroid-refractory IBD, 65% achieved remission at 1 year.[33,34] In a long-term prospective study from Japan, cumulative colectomy-free survival was 62% at 65 months. Colectomy-free survival was significantly higher in patients who have responded to tacrolimus within 30 days than those who have not.[35] These data are important in helping to predict patients who will eventually require a colectomy. Rectal tacrolimus is effective in patient with refractory distal colitis. In a study of 19 patients with refractory left-sided colitis or proctitis, three-quarter of patients responded after 4 weeks of tacrolimus enema (2–4 mg) or tacrolimus suppository (2 mg).[36] A randomised placebo-controlled study of tacrolimus enema in distal UC is currently in progress in Australia.

In perianal fistulising CD, one controlled trial has shown that oral tacrolimus was superior to placebo, although fistula healing was not different between the two groups.[37] In luminal CD, the benefit of tacrolimus has only been demonstrated in small uncontrolled studies.[28,33,34,38–40]

Practice points and adverse effects: Tacrolimus is an effective alternative therapy for patients with refractory UC and luminal and perianal fistulising CD. Response is superior in patients with UC than those with CD.[33,34] It has a rapid onset of action usually within 2 weeks, therefore it can also be used as a bridge to thiopurine. Start 0.1 mg/kg/day oral tacrolimus in two divided doses, and measure serum trough levels at 2 weeks, followed by every 6–8 weeks and aim for trough level of 5–10 ng/mL. Consider dose reduction or cease treatment if renal impairment develops. Common side effects of tacrolimus include hypertension, paraesthesia, tremor and headache. Hypomagnesaemia, renal impairment (usually reversible), hyperglycaemia or gastrointestinal disturbances may be present in about half of the treated patients.[30] The more predictable oral bioavailability and better side-effect profile makes tacrolimus more favourable compared with ciclosporin.[41] Opportunistic infection is an important consideration,[42] and standard prophylaxis with co-trimoxazole has been recommended by the ECCO in patients on triple immuno-immunomodulators with one of these being a calcineurin inhibitor or an anti-TNF agent.[43]

Thalidomide Thalidomide has re-emerged as a potent anti-inflammatory and immunosuppressive drug. The effects of thalidomide relate, in part, to the down-regulation of TNF-α, and the inhibition of angiogenesis.[44] It also inhibits NFκB activity, and suppresses IL-12.[45,46] Several uncontrolled studies have shown that thalidomide is effective in patients with refractory luminal and fistulising CD, and those with oral and upper gastrointestinal CD. In an open-label study of 12 male patients with steroid-dependent luminal CD treated with low-dose thalidomide (50–100 mg each night), 70% of patients responded and 20% were in remission by 3 months. The onset of action may be as rapid as 2 weeks.[47] In a separate study from Chicago using higher doses of thalidomide (200–300 mg each night), three-quarter of patients responded at 1 month, and 40% were in remission at 3 months.[48] In both these studies, most of the patients were naïve to biological drugs. In a retrospective series from St Mark's Hospital London, 25 treatment-resistent CD patients received a median dose of thalidomide 100 mg each night and 75% and 60% with luminal and fistulising disease respectively, responded at 12 months. Half of those with fistulising disease achieved healing. Most patients have failed azathioprine, MP, methotrexate, and some have also failed anti-TNF drugs.[49] In patients who have responded to infliximab, thalidomide can be used as a bridging therapy to maintain remission.[50]

Practice points and adverse effects: In uncontrolled studies of luminal and fistulising CD, thalidomide is effective and has steroid-sparing properties. Response and remission rates are 70% and 20% respectively. Efficacy usually occurs within 4 weeks. Long-term use is often limited by toxicity in particularly peripheral neuropathy. Start with a dose of 25–50 mg nocte, and increase to 100 mg if tolerated. Baseline nerve conduction study can be performed if available locally although no studies have evaluated the significance of abnormal baseline nerve conduction study on clinical outcome. Side effects of thalidomide include teratogenicity, drowsiness, peripheral neuropathy and rash. Peripheral neuropathy has been reported in up to 50% of patients, and in most patients it is mild and reversible. The incidence of neuropathy is related to the total cumulative dosage, and most cases of neuropathy occur after 40–50 g of thalidomide. Patients are required to use strict contraceptive measures whilst on thalidomide and must not conceive during, or up until at least 6 months after stopping the drug (manufacturer's recommendation).

Mycophenolate Mofotil. Mycophenolate mofotil (MMF) selectively inhibits lymphocyte proliferation.[51] It has been used to treat patients with thiopurine-refractory IBD, but its efficacy has not been supported by controlled trials.[52–55] In a series from the UK, 17 of 70 patients with resistant UC and CD were maintained in remission with MMF for a mean duration of 33 months.[52] At 5 years follow-up, approximately one-fifth of patients achieved steroid free remission, one-fifth discontinued treatment due to side effects, and half required an escalation in medical therapy or surgery because of failure of the therapy.[55] Gastrointestinal toxicity, usually manifested as diarrhoea, is the most common side effect of MMF.[56] The induction of colitis with histological features similar to those associated with intestinal Graft vs. Host disease has been reported in patients treated with MMF.[57] There is currently no convincing evidence of the efficacy of MMF in the treatment of IBD, and its use in this condition should be confined to trial settings.

Arsenic Suppository/Ciclosporin Enema. In patients with proctitis or distal UC refractory to topical 5-ASA, a combination of oral corticosteroids with rectal 5-ASA or immunomodulators, can be used. Experimental therapies such as arsenic (acetarsol) suppositories[58] or ciclosporin enemas[59,60] may have a role in very resistant cases.[61,62] In a small prospective open-label study, ten patients with intractable proctitis were treated with arsenic suppositories 250 mg twice daily for 4 weeks. Nine of ten patients achieved symptomatic and sigmoidoscopic improvement within 2 weeks. Side effects were minimal and arsenic levels dropped rapidly when acetarsol was withdrawn.[58] The mechanism of action of arsenic is unclear. Open trials of ciclosporin enemas for refractory distal UC have shown favourable results although a placebo-controlled study of ciclosporin enema 350 mg daily vs. placebo in 40 patients with mild to moderately active distal UC have shown no difference in symptom improvement after 4 weeks of treatment.[63] In patients with resistant proctitis, acetarsol suppositories or ciclosporin enemas may enable some patients to achieve remission prior to the consideration of surgery.

Tioguanine. An active metabolite of azathioprine and MP, tioguanine, has been considered as an alternative therapy in patients who were intolerant of azathioprine or MP. In one study of 40 patients (10 with UC) with thiopurine-refractory disease, tioguanine 40 mg was given for a median of 34 weeks. Disease remission was achieved in 44%, 73% and 89% of patients at 3, 6 and 12 months respectively.[64] The GETAID group assessed the safety and efficacy of tioguanine in 49 patients with active CD intolerant or resistant to azathioprine or MP. The probability of clinical remission without corticosteroids or infliximab at 6 and 12 months was 46% and 79% respectively.[65] Larger controlled trials are warranted to further evaluate both the short- and long-term safety and efficacy in this subgroup of patients as well as in a broader spectrum of IBD patients.

Practice points and adverse effects: Recommendations from the European tioguanine working party have suggested that in selected patients who are intolerant of, or who have failed, other immunosuppressive therapies, and in those where surgery is considered to be inappropriate, low-dose (25 mg daily) tioguanine with close monitoring of metabolite levels and liver function tests, may have a role. Treatment with tioguanine must be discontinued in patients with overt or histologically proven hepatotoxicity.[66] Liver biopsies should be performed after 6–12 months of treatment and followed up every 3-yearly accompanied by gastroduodenoscopy, to monitor for potential complications of nodular regenerative hyperplasia and veno-occlusive disease.[67,68] Hepatic nodular regenerative hyperplasia appears to be dependent on the level of 6-tioguanine nucleotide (6-TGN).[69,70] The drug tioguanine is not recommended as a treatment in IBD by the American guidelines due to insufficient data to predict the risks of hepatotoxicity.[8]

Leucocyte Apheresis. Leucocyte apheresis involved the removal of leucocytes from the circulation,[71,72] through an absorptive system of cellulose acetate beads (Adacolumn; Otsuka Pharmaceuticals, Tokushima, Japan) or a polyester fibre filter (Cellsorba; Asahi Medical Company, Oita, Japan).[73] Earlier observational studies in UC have shown response rates varying between 21% and 90%,[74] most likely secondary to variable study design, heterogenous patient populations and a different definition of clinical outcome.[75–79] The largest definitive randomised, double-blind, sham-controlled trial of apheresis (Adacolumn Apheresis System; JIMRO Ltd, Takasaki, Japan) in patients with moderate to severely active UC involving patients from North America, Japan and Europe, has shown no difference in the clinical remission, clinical response, endoscopic remission and endoscopic response rates between the active and sham arm after 9 weeks of treatment.[80] A recent open-label randomised prospective study, however, has shown that twice weekly apheresis appeared to be more effective than one weekly session; significantly more patients responded, mean time to response was significantly reduced, but side effects were not increased.[81]

Practice points: Leucocyte apheresis is a relatively safe procedure but the precise positioning of this approach in the treatment of UC is uncertain at present and its use will vary according to geography, availability and patient preference. Positive results from large open series have not been matched by controlled data. Technical issues such as the need for continuous adequate venous access and the cost argue against the general use aimed at long-term remission. It is more widely used in Japan than in other countries. Further efficacy studies are required to assess the optimal frequency of treatments and there is also a need for head-to-head comparisons with established drugs.

Nutritional or Anti-bacterial Therapy

Enteral Nutrition. In paediatric or adolescent CD, enteral therapy has been used as a primary therapy to induce and to maintain remission in CD, but it is used less in adults with CD partly due to poor compliance. Three meta-analyses of randomised-controlled trials have assessed the role of enteral nutrition as a primary therapy in adults with CD. These studies have shown that enteral nutrition is effective to induce remission in 50–70% of patients with active CD; enteral and parenteral nutrition are both equally effective to achieve remission, and elemental diet is as effective as polymeric diet.[82–84] Cochrane systematic reviews have shown that enteral nutrition is less effective than corticosteroids for the induction of remission in CD.[85,86] Enteral nutrition is also effective to support nutritional status prior to surgery, or to correct malnutrition in short bowel syndrome or patients with stenosis and in patients with active CD. Total parenteral nutrition can be considered as an adjunctive therapy in very severe cases where enteral nutrition is not tolerated or standard drug therapy is not effective or in hospitalised patients with complex fistulising disease. More palatable oral feeding regimens with improved nutritional compositions may have a potential to improve compliance.

Antibiotics/Probiotics. Ciprofloxacin and metronidazole, although commonly used, have limited evidence in luminal CD apart from being used to treat perineal disease and sepsis.[87] Metronidazole was not more effective than placebo for the induction of remission in active CD,[88] and ciprofloxacin showed similar efficacy to mesalazine in active CD.[89] Evidence from large controlled studies have shown that anti-mycobacterial therapy is not effective for the induction or maintenance of remission in CD.[90–92] There is currently no convincing evidence to support the use of antibiotics as a primary treatment in refractory IBD, apart from its use to treat septic complications or as an adjunctive treatment to steroids or mesalazine. There is also no evidence to suggest that probiotics are effective in active CD.[93] Recent studies have shown that a high-dose probiotic combination added to existing treatment may be effective to induce remission in active UC.[94,95] A meta-analysis has shown that probiotic treatment was more effective than placebo in maintaining remission in UC.[96]

Optimising Thiopurine Efficacy

Further understanding of the metabolism of azathioprine to its effective and toxic metabolites has led to several newer approaches in the use of thiopurines in IBD. MP and its pro-drug azathioprine, mediate their effects predominantly by the inhibition of proliferation and induction of T-cell apoptosis. Azathioprine is metabolised to MP, then to the active metabolite, 6-TGN. The therapeutic effect of thiopurine correlates best with the concentration of 6-TGN.[97] An alternative pathway of metabolism is mediated by the enzyme thiopurine methyltransferase (TPMT) which metabolises MP to 6-methyl-mercaptopurine (6-MMP). Excess levels of 6-MMP have been associated with hepatotoxicity. Patients with low TPMT levels are at increased risk of myelotoxicity with standard doses thiopurine. In patients with normal TPMT levels careful monitoring for toxicity is still required as most of these patients can potentially develop myelotoxicity.[98] Traditional dosing strategy for starting thiopurine has been weight-based or, sometimes, empirically selected. The use of standard weight-based regimen does not guarantee the achievement of efficacy or the avoidance of toxicity.

Azathioprine Dose Escalation. Approximately 40% of patients will not respond to 2 mg/kg/day dose of azathioprine or equivalent doses of MP.[99] Increasing the dose of azathioprine up to 2.5 mg/kg is beneficial but the benefit of dose escalation above this level is less. In a prospective study of 40 patients with chronic active IBD and recurrent flares despite standard dose azathioprine, 11 patients responded at a median of 6 months when their azathioprine dose was increased from a median 2.02–2.72 mg/kg/day.[100] The measurement of 6-TGN and 6-MMP can also be used to guide increasing doses of thiopurines whilst avoiding hepatotoxicity.[97] There are currently no controlled data comparing the efficacy of weight-based empirical dose escalation vs. dosing guided by the measurement of metabolite.

Allopurinol in Thiopurine Nonresponder. One-third of patients does not respond to, or are intolerant, of thiopurines due to side effects. Failure to respond to thiopurines can relate to noncompliance, inadequate dosing, or the preferential metabolism of the drug to the metabolite 6-MMP, resulting in inadequate amounts of the active metabolite 6-TGN. Allopurinol, a xanthine oxidase inhibitor, has been used to shunt the metabolism of MP towards 6-TGN. In a retrospective series of 20 patients with IBD who have failed to respond to azathioprine or MP, and who have high 6-MMP levels, allopurinol 100 mg daily was added to reduced doses of azathioprine or MP. As a result, 6-TGN levels increased, 6-MMP levels reduced, corticosteroid requirement decreased, and aminotransferase levels normalised.[101,102] Long-term follow-up of this cohort up to 3 years showed sustained response and no adverse effects.[103] Allopurinol cotherapy with low-dose azathioprine or MP can also alleviate hepatotoxicity. Of 11 IBD patients treated, nine patients were in long-term remission at a median of 42 months with normal liver function tests.[104] In a larger retrospective study of 41 patients from the UK who had adverse reaction to thiopurines, clinical remission was achieved in 78% at a median follow-up of 41 weeks.[105]

Practice points and adverse effects: Combined azathioprine-allopurinol therapy can help to improve thiopurine efficacy in initial nonresponders and to normalise liver dysfunction in patients who develop hepatotoxicity. Prospective studies are in progress to confirm the efficacy of this strategy in thiopurine-refractory IBD patients. Checking TPMT prior to starting azathioprine has become routine in most hospitals. When co-prescribing azathioprine and allopurinol, start allopurinol 100 mg daily and reduce the dose of azathioprine or MP to one-quarter of the original dose. Monitor blood count weekly for at least 4 weeks followed by three monthly thereafter. Monitor thiopurine metabolites to guide therapy. There also appears to be ethnic variations in key enzymes involved in thiopurine metabolism which should be considered. For instance, South East Asian women have lower TPMT activity than men.[106] Figures 1 and 2 illustrate proposed therapeutic strategies for patients with refractory UC and CD.

Figure 1.
Therapeutic strategy for patients with refractory ulcerative colitis.



Figure 2.
Therapeutic strategy for patients with refractory luminal and fistulising Crohn's disease.

Other Novel Therapies

Further understanding of the pathogenesis of IBD has led to novel therapies including helminths,[107,108] heparin, anti-adhesion molecules, anti-cytokine therapy, gene therapy and autologous stem cell transplant. In a phase one study of 12 active refractory CD patients, 11 of 12 patients achieved sustained clinical remission at 18 months after successful autologous haemopoietic stem cell transplant.[109,110] Advances in delivery systems have also enabled patients to achieve improved response. For instance the Multimatrix (MMXTM) technology can augment the targeting of existing and new drugs including heparin, budesonide and mesalazine to the intestine, thereby increasing response and remission rates for those drugs.[111]

In general, many of the anti-inflammatory entities discussed above have been used for nonlicensed indications and can be associated with significant side effects. It is imperative that, akin the use of biological drugs, patients are selected carefully, treatments are initiated in expert hands, the risk–benefit ratios of therapy are discussed, and patients are monitored closely for adverse effects during therapy. Failure to respond or worsening symptoms are indications for surgical intervention.

Conclusions

CD and UC are chronic diseases without a pharmacological cure that usually require regular, indefinite therapy to maintain remission. The management of patients with IBD refractory to standard conventional therapies remains a clinical challenge. An expanding array of treatment options is available to clinicians although not all these drugs have been subjected to controlled studies. Ultimately, when treating patients with refractory IBD, the decision on the next therapeutic option should be guided by local availability and a combined decision between the clinician and the patient, weighing the risks and benefits of the drug. In some patients surgery should be considered. As new therapies continue to be added to the treatment armamentarium, and improved strategies of existing and novel therapies continue to evolve, the future of management of these patients appears to be promising.

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Excellent, informative article, thanks David!

Dusty.

Glad you found it interesting, Dusty.

You know you have a nasty condition when Thalidomide & arsenic suppositories are seriously discussed as alternative therapies.

Yeeeeeesh....