|Year : 2012 | Volume
| Issue : 1 | Page : 111-113
Oral doxycycline with topical tacrolimus for treatment of stasis dermatitis due to chronic venous insufficiency: A pilot study
Niteeka Maroo1, Supriyo Choudhury1, Sumit Sen2, Suparna Chatterjee1
1 Department of Pharmacology, IPGMER, Kolkata, India
2 Department of Dermatology, IPGMER and SSKM Hospital, Kolkata, West Bengal, India
|Date of Submission||26-May-2011|
|Date of Decision||12-Aug-2011|
|Date of Acceptance||18-Oct-2011|
|Date of Web Publication||14-Jan-2012|
Department of Pharmacology, IPGMER, Kolkata
Source of Support: None, Conflict of Interest: None
Objectives: Chronic venous insufficiency (CVI) in lower limbs manifest as stasis dermatitis. The anti-collagenase, anti-inflammatory and immunomodulatory effects of doxycycline and the T-cell inhibitory effects of tacrolimus could theoretically modify the disease pathophysiology. This study was undertaken to evaluate the efficacy and safety of four weeks combination therapy of oral doxycycline 100 mg with topical tacrolimus 0.1% for stasis dermatitis associated with CVI.
Materials and Methods: A single-arm, interventional pilot study was conducted on subjects with CVI of C4 to C6 category (CEAP classification: clinical, etiology, anatomical, pathophysiology). Treatment duration was four weeks with fortnightly follow-ups. Primary efficacy was assessed as changes from baseline of pigmentation, erythema, edema, itching and hair loss of the affected area evaluated on Likert scale scores. Secondary efficacy parameters were percentage improvement of the dermatitis area and changes in ulcer dimensions (maximum length and breadth), if present. Safety evaluation included all treatment emergent clinical signs and symptoms reported by the patients and/or observed by the physician.
Results: Out of 19 recruited subjects, 15 completed the study for analysis. Significant (P<0.01) improvement in pain, edema, pigmentation, erythema and exudation were observed. Reduction of ulcer dimensions was also statistically significant (P<0.01). 86.6% showed improvement of the dermatitis area, 6.7% patients failed to show any improvement and 6.7% showed worsening. Adverse effects were observed in only two subjects.
Conclusion: This pilot study suggests efficacy of this combination therapy in controlling features of stasis dermatitis but further studies are needed for validation.
Keywords: Chronic venous insufficiency, doxycycline, MMP inhibitors, tacrolimus, varicose ulcer
|How to cite this article:|
Maroo N, Choudhury S, Sen S, Chatterjee S. Oral doxycycline with topical tacrolimus for treatment of stasis dermatitis due to chronic venous insufficiency: A pilot study. Indian J Pharmacol 2012;44:111-3
|How to cite this URL:|
Maroo N, Choudhury S, Sen S, Chatterjee S. Oral doxycycline with topical tacrolimus for treatment of stasis dermatitis due to chronic venous insufficiency: A pilot study. Indian J Pharmacol [serial online] 2012 [cited 2015 Jul 27];44:111-3. Available from: http://www.ijp-online.com/text.asp?2012/44/1/111/91878
| » Introduction|| |
Chronic venous insufficiency is a common disease entity affecting about 10-20% individuals with a significant impact on quality of life. , The clinical presentation of the disease arises due to altered venous hemodynamics being transmitted to the microcirculation leading to ankle edema, itching, skin changes like pigmentation, stasis dermatitis, hair loss, lipodermatosclerosis and eventually venous ulceration.  The underlying pathological basis of the disease is complex and the suggested hypothesis for primary chronic venous disease is venous hypertension arising due to reflux from pre-existent vessel wall weakness leading to incompetent venous valves. Histological changes in the varicose venous wall like intimal hyperplasia, alternating hypertrophic and hypotrophic segments of smooth muscles with reduced extracellular matrix proteins have been observed. Increased production of proteolytic enzymes like matrix metalloproteases leads to degradation of extracellular matrix proteins and loss of collagen and elastin. Rearrangement and de-differentiation of smooth muscles cells in the intima accompanied with venous inflammation and dysregulated apoptosis are the key pathological features of the disease process. ,, Therefore, combating venous inflammation provides a good pharmacological target for controlling the dermal changes in the disease.
The management of dermatitis associated with CVI poses challenges and surgery is the mainstay of treatment for severe cases. Other non-pharmacologic measures like leg elevation and compression bandaging are recommended for most cases. The role of pharmacotherapy though limited has been advocated for selected cases mainly to control the dermal changes associated with the disease. The role of pentoxifylline, topical steroids have been debated and recently some naturally occurring plant products like micronized purified flavonoid fraction and oxyrutein have shown promising results in recent studies. 
Since venous inflammation is an important factor underlying the disease process, we explored the role of oral doxycycline and topical tacrolimus as an alternate treatment option based on some preliminary study reports suggesting their effectiveness. ,
Doxycycline, a tetracycline group antibiotic, is reported to have matrix metalloproteinase inhibitory, anti-collagenolytic and anti-inflammatory properties,  while tacrolimus, a macrolide antibiotic with additional immunosuppressant, anti-inflammatory activity in stasis dermatitis, was evaluated as a combination therapy to determine whether they could modify the disease progression. This study was therefore undertaken to evaluate the efficacy and safety of four weeks combination therapy with oral doxycycline 100 mg with topical tacrolimus 0.1% for stasis dermatitis associated with CVI.
The primary efficacy was assessed as changes from baseline of pigmentation, erythema, edema, itching and hair loss of the affected area. Secondary efficacy parameters were percentage improvement of the dermatitis area and of maximum length and breadth of ulcers, in those subjects who had varicose ulcers. Safety assessment was also done by evaluating all treatment emergent adverse effects (clinical signs and symptoms) reported by the subject and/or by the physician.
| » Materials and Methods|| |
After taking approval from institutional ethics committee, the study was performed in Department of Dermatology of IPGMER and SSKM Hospital. The study was a post-marketing, single arm, pilot study. Male and female subjects of age >18 years, who were willing to sign informed consent form and practice contraception, were assessed for other inclusion criteria. Patients with clinical diagnosis of chronic venous insufficiency and belonging to clinical grade C4 to C6 of CEAP criteria  were enrolled. Any patient presenting with venous ulceration due to causes other than chronic venous insufficiency or with history of rheumatologic or collagen vascular disorders were excluded. Patients who had been treated with pentoxifylline, oral or topical steroids or any growth factors used in treatment of venous ulcers within two months prior to enrolment were also excluded.
Patients were treated with oral doxycycline 100 mg once daily and topical tacrolimus 0.1% ointment which was applied in periulcer area twice daily for four weeks along with the standard conservative treatment as leg elevation and compression bandaging. Patients were evaluated at fortnightly intervals for the following efficacy parameters-pain, pruritis, erythema and hair loss on a 10-point Likert scale. Edema and pigmentation were evaluated on 4-point and 6 point Likert scales respectively. Exudation was evaluated as none, mild, moderate and severe-rated as 0-4. Improvement in dermatitis area was measured as percentage improvement of maximum diameter from baseline to study end values. In subjects with bilateral disease (n=9), the leg which showed lesser degree of improvement was taken for analysis of results. Maximum length and breadth of ulcer area where present (n=9) was also measured and compared from baseline to study end. Safety parameters were assessed as those complained by patients and/or observed by physician.
Statistics analysis was done using Graphpad Prism software version 5. Nonparametric variables (efficacy scores) were analyzed using Friedman's ANOVA and Dunns post hoc test was. P values less than 0.05 were considered significant.
| » Results|| |
During the study period, a total of 19 patients were recruited while 15 patients were considered as "evaluable" subjects as they had baseline and two post-baseline visit data. Baseline demography and disease characteristics are presented in [Table 1].
Primary efficacy parameter analysis is shown in [Table 2]. Improvement in pain, edema, erythema, pigmentation and pruritus was highly significant (P<0.01) as compared to baseline scores. Improvement in exudation was also significant (P= 0.013) but there was no statistically significant (P=0.09) improvement in hair loss. Secondary efficacy parameters i.e changes in dermatitis area are shown in [Table 3] and changes in ulcer dimensions are depicted in [Table 4]. Results reveal that 80% of the evaluable patients had 15-35% improvement. In 60% of patients who had varicose ulcers, there was a highly significant reduction (P<0.01) of maximum length and breadth of the ulcers from baseline dimensions. Safety analysis shows that out of the 19 recruited patients only 2 reported adverse events-one of burning sensation on tacrolimus applied area which was mild and recovered gradually and another patient had angioedema after taking doxycycline and this patient was withdrawn from the study.
|Table 3: Percentage change in maximum diameter of dermatitis area at study end compared to baseline|
Click here to view
| » Discussion|| |
The combination therapy of oral doxycycline and topical tacrolimus has been shown to be effective in reducing the symptoms and dermal manifestations of chronic venous insufficiency of leg. Though the reduction of pain and edema can also be attributed to the conservative measures which were adopted uniformly by all patients, the reduction of pruritus, erythema, pigmentation and improvement in dermatitis area and ulcer dimensions can be attributed only to the treatment given.
The pathogenesis of this disease condition involves shear stress on capillary wall of veins exerted by reduced blood flow thus causing inflammation and cytokine release. This leads to various symptoms like itching, heaviness, edema and inflammation activates the extracellular matrix remodelling which ultimately leads to more severe features of disease including venous dermatitis, lipodermatosclerosis and venous ulcer.  This extracellular modelling is mediated by matrix metalloproteinases. There is upregulation of MMP1, MMP2 and MMP13. , Combination of drugs used in this study act on different steps and helps to alleviate symptoms while also limiting disease progression.
Tacrolimus exerts anti-inflammatory activity while doxycycline modifies matrix metalloproteinases and tissue inhibitor of metalloproteinase 1. Since our study was a single arm, pilot study, we compared the results of our study with two previous published case reports, , the first one evaluated the effects of topical tacrolimus monotherapy while the second on combination therapy of topical tacrolimus with oral doxycycline. ,
The first case study was on a 81-year-old patient of acute stasis dermatitis which was treated with topical 0.1% tacrolimus ointment twice daily for 5 days and complete healing was achieved.  The second published study was on a long-standing venous stasis ulceration case in a 71-year-old lady which was non-responsive to leg elevation, local wound care, and was intolerant to compression stockings. After two weeks of treatment with 0.1% topical tacrolimus with 100 mg of doxycycline hyclate twice daily, the ulcers showed marked improvement and at two months, the ulcerations were nearly completely re-epithelialized. 
Due to logistic and financial constraints, this study had some limitations like absence of control arm, small sample size, limited study duration, evaluation of post-treatment effect on disease progression and finally systemic laboratory adverse events were not assessed.
This combination may be a novel option for short-term treatment of stasis dermatitis. A randomized controlled trial with a larger sample is needed to validate and establish the efficacy and safety of this combination.
| » References|| |
|1.||Bradbury AW. Epidemiology and aetiology of C4-6 disease. Phlebology 2010;25:2-8. |
|2.||Rabe E, Pannier F. Societal costs of chronic venous disease in CEAP C4, C5, C6 disease. Phlebology 2010;25:64-7. |
|3.||Worley CA.'It hurts when I walk': Venous stasis disease-differential diagnosis and treatment. Dermatol Nurs 2006;18:582-3. |
|4.||Lim CS, Shalhoub J, Gohel MS, Sheperd AC, Davies AH. Matrix metalloproteinase in vascular disease-A potential therapeutic target? Curr Vasc Pharmacol 2010;8:75-85. |
|5.||Perrin M, Ramelet AA. Pharmacological treatment of primary chronic venous disease: Rationale, results and unanswered questions. Eur J Vasc Endovasc Surg 2011;41:117-25. |
|6.||Raffetto JD, Khalil RA. Mechanisms of varicose vein formation: Valve dysfunction and wall dilation. Phlebology 2008;23:85-98. |
|7.||Gohel MS, Davies AH. Pharmacological treatment in patients with C4, C5 and C6 venous disease. Phlebology 2010;25:35-41. |
|8.||Dissemond J, Knab J, Lehnen M, Franckson T, Goos M. Successful treatment of stasis dermatitis with topical tacrolimus. Vasa 2004;33:260-2. |
|9.||Mackelfresh J, Soon S, Arbiser JL. Combination therapy of doxycycline and topical tacrolimus for venous ulcers. Arch Dermatol 2005;141:1476-7. |
|10.||Nordström D, Lindy O, Lauhio A, Sorsa T, Santavirta S, Konttinen YT. Anti-collagenolytic mechanism of action of doxycycline treatment in rheumatoid arthritis. Rheumatol Int 1998;17:175-80. |
|11.||Pascarella L, Schönbein GW, Bergan JJ. Microcirculation and venous ulcers: A review. Ann Vasc Surg 2005;19:921-7. |
|12.||Herouy Y, Mellios P, Bandemir E, Dichmann S, Nockowski P, Schöpf E, et al. Inflammation in stasis dermatitis upregulates MMP-1, MMP-2 and MMP-13 expression. J Dermatol Sci 2001;25:198-205. |
[Table 1], [Table 2], [Table 3], [Table 4]