Introduction

The most common area of side effect manifestations provoked by medication is given in the most extensive organ we have in our body, which is the skin, in up to 30% of the total of these complications,¹,² and range from rash, dermatitis, different types of purpura, angioedema, and blisters to necrosis, such as skin ulcers or more severe: epidermolysis.

According to the world data, the greatest number of skin drug-related side effects (SDRSE) is mainly due to antibiotics, followed by nonsteroidal anti-inflammatory drugs.

However, antihypertensive drugs are not complication-free. Institutions such as the Drug Adverse Reaction Committee of the National Healthcare Board of Denmark report that in the SDRSE in this case, antihypertensive drugs have a skin complication rate varying from 10% to 60%³.

Among the most common SDRSE of such drugs, one may find angioedema, urticaria, pruritus, vasculitis, exanthematous pustulosis, bullous rash, erythroderma, photosensitivity, and eczema, and inter alia; being the angiotensin-converting enzyme inhibitors (ACEI) and antihypertensive drugs the ones that the most commonly provoke these issues.

More SDRSE publications have been submitted by angiotensin II receptor blockers (ARBs)⁴ as well as reports of more severe skin complications, such as the exhibition of ulcers from the oral mucosa⁵ or severe pustular vasculitis with the use of these medications, although they have been only single-case reports⁶-⁹. Nonetheless, there are no reports in the references mentioning that ARBs or ACEI are responsible repeatedly in a series of cases showing skin ulcers.

In this trial, the objective was to determine the risk factors for skin ulcers, being the results that caused this paper.

Materials and methods

A retrospective, observational, case-designed, and control-in-patient trial was performed from the San Luca Centro Vascular Medical Unit, located in Queretaro, Qro., Mexico, where such patients were assisted from July 14, 2005, to December 31, 2020. The inclusion criteria were the presence of cutaneous ulcers in any part of the skin, a detailed arterial and venous examination were performed on these subjects. Non-inclusion criteria were ulcers in a prone position; rheumatological disease, cancer, and a chronic venous disease are based on the CEAP classification¹⁰ and patients with the absence or decrease of distal pulses, ankle/arm ratio < 1 or > 1.4,¹¹ and with abnormal foot and ankle blood Doppler waveform. Those patients who had an incomplete registration of the parameters aforementioned were withdrawn.

The control group was comprised patients with similar characteristics in age, sex, and pathological antecedents, but who did not have any ulcerous injuries of any kind on the skin.

Statistical analysis was performed by bivariate analysis with a Chi-squared test for the “p” value and the determination of odds ratio (OR) and confidence interval (CI 95%) using the EpiInfo software, version 7.2.2.6.

Results

The total universe as of December 31, 2020, in the vascular center was 6799 patients, out of which 69 (1.01%) were detected with skin ulcers from unknown etiology.

In the case group, 78% (n = 54) were women and 22% (n = 15) were men; the age range was 32–90 years, with a 70.3-year average, 88.4% (n = 61) patients were taking some medication previously and 11.6% (n = 8) were not. In their pathological antecedents, patients exhibited one or more of these diseases: high blood pressure 84.05% (n = 58); diabetes mellitus 44.92% (n = 31); heart failure 4.34% (n = 3); and various diseases 20.28% (n = 14).

Progression time of ulcers varied from 7 to 2160 days; the areas affected were the following: hands 1.4% (n = 1) and lower limb under the knee 98.6% (n = 68), with exhibition in neither thigh nor another part of the body; one-sided 73.9% (n = 51) and two-sided 26.1% (n = 18). Symptomatology in all skin ulcers in the lower limbs was always similar, being quite painful, and pain increased in decubitus or whilst lifting the limb, and involved only the skin and subcutaneous cellular tissue.

A significant difference was obtained in patients who exhibited skin ulcers and treatment with ARBs-type antihypertensive medication (losartan, telmisartan, irbesartan, valsartan, and candesartan were the drugs prescribed) versus the control group, with p ≤ 0.02 and OR 2.24 with CI 95% (1.1–4.5) (Table 1).

There were no significant differences among the other variables, such as sex, age, substance abuse, high blood pressure, diabetes mellitus, or any other degenerative chronic diseases, or with the other types of antihypertensive/glucose-lowering drugs, or miscellaneous medication (Table 2).

Discussion

During the search for similar antecedents, no literature was found in the important sources of medical information (Medline, PubMed, and Google Academic) that reported ARA II as a risk factor for severe skin lesions, only one case reports. This work provides information to be considered as such and improve the diagnosis and adjust the integral management of such an issue, and it could shorten long periods of unsuccessful treatment of ulcers of up to 6 years of progression without showing any healing in this series reported (Fig. 1).

Figure 1 Female patient with a superficial and quite painful skin ulcer, treated with telmisartan and previously treated as a venous ulcer. 

The mechanism of ulcer formation turns out to be unknown; nevertheless, more recent studies demonstrate an inflammatory stimulating effect for greater bradykinin accumulation in receptors not blocked by ARBs¹². In addition, not only does the renin-angiotensin system (RAS) regulate blood pressure at a kidney level, but also plays a local physiological role in other organs, such as the brain, heart, and also in the gastrointestinal tract, such as the liver, pancreas, and bowel, which explain the side effects such as nausea, vomiting, and diarrhea from using ACEI and ARBs¹³. Skin is not free from this physiological regulation. Stecklings demonstrated a very comprehensive review since the mid-1990s, the unequivocal role of angiotensin II receptors in this organ in modulating cellular proliferation¹⁴ influencing the growth and regeneration of skin, a condition that may influence the lack of cicatrization with the blockade of such receptors. Ulcers may also be provoked, like in other medications, such as DPP4-type glucose-lowering drugs¹⁵ and hydroxyurea,¹⁶ by secondary vascular inflammatory processes (vasculitis) to circulating autoimmune complexes¹⁷.

This report may be considered to be a watershed recognizing the role of ARBs as a risk factor in this severe complication and helping encourage to study this more comprehensively, even with histopathological diagnoses, to be able to explain more precisely the mechanism of the injury.

We consider this is one of the first works in demonstrating the relationship in such a risk factor for skin-ulcer formation in the lower limbs, a situation that can be considered in the clinical practice, and to weigh this possibility whenever these drugs are prescribed and also consider to stop and/or change to another type of antihypertensive drugs different than those that influence the RAS as we face the presence of such ulcers not exhibiting any apparent explanations or causes.

Conclusions

ARBs-type drugs are a risk factor for the presence of skin ulcers. This complication should be considered in hardly controlled skin ulcers that do not have any apparent causes.