Iloprost infusion through elastomeric pump in the treatment of Raynaud’s phenomenon and digital ulcers

Abstract

Introduction:

Systemic sclerosis is a systemic autoimmune disease characterized by microangiopathy and fibroblast dysfunction resulting in fibrosis of the skin and internal organs. Raynaud’s phenomenon and digital ulcers are the main clinical features of vascular involvement. Treatment with iloprost is recommended to reduce the frequency and severity of Raynaud’s phenomenon attacks and to heal active digital ulcer. Classical forms of treatment require admission to a ward or day-hospital unit to ensure safety during infusion, causing disruption of the patient’s normal daily life and resulting in significant costs with hospitalization. Nowadays, new portable devices, of which the elastomeric pump is an example, are becoming available in order to avoid hospitalization.

Case reports:

We describe five cases of patients with systemic sclerosis or mixed connective tissue disease and severe Raynaud’s phenomenon/critical ischaemia or active digital ulcers that were successfully treated with iloprost infusion through elastomeric pump without experiencing any side effects. We present our unit’s protocol for ambulatory infusion.

Discussion/conclusion:

Our case reports and a brief review of literature prove that iloprost infusion through elastomeric pump is safe, easy and well tolerated and might even improve patient compliance with treatment. Meanwhile, it may also decrease the economic burden of hospitalization with these patients.

Introduction

Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by microangiopathy and fibroblast dysfunction leading to increased deposition of extracellular matrix resulting in fibrosis of the skin and internal organs. Raynaud’s phenomenon (RP) and digital ulcers (DU) are the main clinical features of vascular involvement. These can be extremely hindering for patients and can cause serious complications sometimes leading to severe infection or amputation. European League Against Rheumatism (EULAR) recommends iloprost (prostacyclin analogue) therapy to reduce the frequency and severity of RP attacks not responsive to common oral vasodilators and to heal active DUs. The standard treatment protocol consists of intravenous infusion of iloprost at a rate of 0.5–2 ng/kg/min (for an average 65-kg adult: 9.8–39 mL/h) for 6 h a day for five consecutive days. Infusion is made through a peripheral line with a syringe pump. The recommendations suggest treatment as an inpatient in a ward or outpatient in a day-hospital unit to ensure safety during infusion due to common side effects as nausea, headaches, hypotension or flushing. Important issues arising with the requirement for hospital setting are the patient’s need to discontinue normal daily activities, including family life and work, and the significant cost of admission to a ward or to the day-hospital unit. Nowadays, new portable devices for infusion are becoming available avoiding the need for hospitalization. The advantages of the elastomeric pump are the ability to maintain infusion while the patient carries on with their normal daily activities and the negligible need of training for management of infusion.

Case reports

We describe five cases of patients with SSc or mixed connective tissue disease (MCTD) and severe RP/critical ischaemia or active DUs that were treated with iloprost infusion through elastomeric pump (Table 1). A standard treatment protocol of two consecutive 5-day infusions was followed for every patient. The patients came to the day-hospital unit in the first day of treatment and were evaluated by a doctor with a complete physical examination and routine bloodwork. Afterwards, the elastomeric pump where the iloprost was held (0.25 mg in 240 mL of saline) was connected to a peripheral catheter in the patient’s forearm (Figure 1). The basic care with the catheter and the pump was explained to the patient. A pouch was provided for carrying the pump. For the first 2 h of treatment, the patient remained in the unit to assess tolerability to treatment. The patient was then discharged, coming back after 5 days to refill the pump with another dose of iloprost for the second and final cycles of treatment, lasting another 5 days. At this point, the patient was fully reassessed, and the system was checked before starting the second cycle of infusion. During the time away from the hospital, the medical team was reachable by phone to solve any problems that occurred.

Table 1.

Summary information of case reports described.

	Case 1	Case 2	Case 3	Case 4	Case 5
Patient	73 years old, female	28 years old, female	62 years old, male	26 years old, female	60 years old, female
Diagnosis	DcSSc	VEDOSS	LcSSc	MCTD	MCTD
Antibodies	ACA	ACA	ACA	Anti-Sm, anti-RNP	Anti-RNP
Current lesions	Digital ulcer with purulent exudate	Critical digital ischaemia	Digital ulcer with surrounding necrosis and loss of pulp tissue	Digital ulcer with small area of necrosis	Permanent cyanosis of the fingers, nose and earlobe; digital ulcer
Current treatment	Daily CCB	Daily CCB and phosphodiesterase-5 inhibitor	Daily CCB and phosphodiesterase-5 inhibitor	Daily CCB	Daily CCB
mRSS	14	0	6	12	0
Other organ involvement	Oesophageal dysmotility; bowel dysfunction	Pulmonary arterial hypertension	None	Oesophageal dysmotility	None
Tolerance to iloprost infusion through elastomeric pump	No side effects	No side effects	No side effects	No side effects	No side effects
Result after 10 days	Healing of digital ulcer	Resolution of critical ischaemia	Healing of digital ulcers	Healing of digital ulcer	Resolution of cyanosis Healing of digital ulcer

DcSSc: diffuse cutaneous systemic sclerosis; VEDOSS: very early diagnosis of systemic sclerosis; LcSSc: limited cutaneous systemic sclerosis; MCTD: mixed connective tissue disease; ACA: anti-centromere antibody; anti-Sm: anti-Smith; anti-RNP: anti-ribonucleoprotein; CCB: calcium channel blocker; mRSS: modified Rodnan Skin Scale.

Figure 1.

Elastomeric pump.

Elastomeric pump filled with the iloprost solution and connected to a patient through peripheral catheter.

Case 1

A 73-year-old woman had a diagnosis of diffuse cutaneous SSc (positive anti-centromere antibodies (ACAs)) with previous fingertip auto-amputation for gangrene, a modified Rodnan Skin Scale (mRSS) of 14, oesophageal dysmotility and bowel dysfunction but no pulmonary or cardiac involvement. She presented with a de novo DU with purulent exudate in the right index finger despite daily therapy with oral vasodilators. She was treated with iloprost infusion through elastomeric pump according to protocol experiencing no side effects and resulting in complete healing of the active DU (Figure 2).

Figure 2.

Before and after 10-day iloprost infusion through elastomeric pump in patient 1.

Before: patient with active digital ulcer with purulent exudate on the tip of the second right finger. After: same patient after 10-day treatment with iloprost infusion through elastomeric pump revealing healing of the digital ulcer.

Case 2

A 28-year-old woman with very early diagnosis of SSc (severe RP, puffy fingers, positive ANAs with anti-centromere pattern and scleroderma pattern in the capillaroscopy), mRSS of 0 and pulmonary arterial hypertension developed critical digital ischaemia of the right index finger refractory to oral vasodilators. The capillaroscopy showed active scleroderma pattern. She was treated with iloprost infusion through elastomeric pump according to protocol, being able to maintain professional activity as normal. She reported no side effects of treatment. There was resolution of the critical ischaemia and capillaroscopic improvement with the treatment performed (Figure 3).

Figure 3.

Before and after 10-day iloprost infusion through elastomeric pump in patient 2.

Before: patient with critical digital ischaemia of the second right finger and active scleroderma pattern on the capillaroscopy. After: same patient after 10-day treatment with iloprost infusion through elastomeric pump revealing cure of the digital ischaemia and improvement of the capillaroscopic changes.

Case 3

A 62-year-old man with limited cutaneous SSc (positive ACAs), mRSS of 6 and no internal organ involvement presents with a DU with surrounding necrosis and loss of pulp tissue in the fourth left finger and in the right index finger, despite daily treatment with oral vasodilators. He was treated with iloprost infusion through elastomeric pump according to protocol, after which the ulcers healed. He was able to maintain normal activity throughout the treatment and reported no side effects.

Case 4

A 26-year-old woman with MCTD (positive anti-Smith (anti-Sm) and anti-ribonucleoprotein (anti-RNP) antibodies), mRSS of 12, oesophageal dysmotility but no pulmonary or cardiac involvement, severe RP and previous fingertip auto-amputation for gangrene developed a new ulcer with a small area of necrosis on the second right finger. She requested treatment with iloprost infusion through elastomeric pump since she could not afford to miss work. This resulted in healing of the ulcer while the patient maintained normal activity and reported no side effects.

Case 5

A 60-year-old woman had a diagnosis of MCTD (positive anti-RNP antibodies) with severe RP, small ulcers on the fingertips of both hands and no skin thickening (mRSS = 0) or internal organ involvement. The capillaroscopy revealed an early scleroderma pattern. She developed permanent cyanosis of the fingers of the right hand, nose and earlobe and a DU on the first right finger despite optimized therapy with oral vasodilators. The capillaroscopy showed active scleroderma pattern. She was treated with iloprost infusion through elastomeric pump with complete resolution of the cyanosis and ulcers and improvement of the capillaroscopic changes. She was able to maintain normal professional activity throughout the treatment and reported no side effects.

Discussion/conclusion

Iloprost is considered the mainstay of treatment for severe RP not responding to common oral vasodilators or active DUs. Its administration is usually performed in hospital setting leading to problems with patient’s acceptance (having to defer normal daily activities including family life and work) and costs with admissions for treatment. Infusion through elastomeric pump can solve both these issues as there is no need for hospitalization, and patients can continue with normal daily life.

Considering efficacy, small group studies^1–3 and our own case reports proved that treatment with iloprost through elastomeric pump (slower rate of infusion: 2 mL/h for 24 h/day and longer courses of treatment: 10 days) is equally effective in treating severe RP/critical digital ischaemia and active DUs.

A common concern with this type of infusion is about safety of treatment outside hospital setting. It has been proven that the iloprost solution as enough stability and does not modify its physical–chemical properties during long-term infusions. ⁴ Also, since the elastomeric pump provides a constant and continuous slow rate release (2 mL/h), there are much less side effects, allowing for a safer and better tolerated treatment. Furthermore, this type of pump needs very little maintenance and is very easy to use, so the patient needs little training for its management. ⁵ In fact, in the past few years, small portable devices have been routinely, safely and successfully used in oncology and anaesthesiology.

Economically, it has been established that this kind of infusion allows us to decrease costs by saving the value of hospital admission to the ward or to the day-hospital unit (at least five episodes in consecutive days are mandatory). Also, the price of the drug is the same whether the infusion is made through a syringe or elastomeric pump, but the latter allows savings on maintenance costs, cleaning materials and health-care professional time.^3,5

In summary, this alternative form of iloprost infusion appears to be safe, easy and well tolerated and might improve patient compliance while decreasing the economic burden of hospitalization. It should be considered a valid alternative to the classic form of iloprost infusion although larger randomized trials could be helpful in standardizing protocols.