Fig. 20.1
Treatment of Raynaud’s phenomenon (RP)
Treatment Approach
Indications for Drug Therapy
Severe RP that is impacting quality of life despite non-pharmacologic therapy.
Raynaud’s events with signs of ischemia–reperfusion injury that threatens digital tissue.
Recurrent digital ulcers in a patient with secondary RP.
History of digital loss associated with secondary RP.
Most people who have primary RP will not need pharmacologic treatment, but if they do, calcium channel blockers (CCB’s) are usually used first. The dihydropyridine calcium channel blockers are the most studied and are first line prescription treatment, particularly nifedipine. Although not as well studied in randomized clinical trials (RCTs) other drugs in the dihydropyridine class (nicardipine, amlodipine, felodipine) are also effective. Studies of CCBs have shown that these drugs will decrease the frequency of attacks. They do not work in every case and there may have side effects such as hypotension, lightheadedness, flushing, headaches, and peripheral edema that limit their use. If patients tolerate the dose of a CCB but do not obtain benefit, the dose can be increased to tolerance or maximum benefit. It is the author’s opinion that a higher dose of a calcium channel blocker is more effective than lower doses. This view is based on clinical experience in that no RCTs at higher doses have been systematically done. If one calcium channel blocker is not tolerated or ineffective at a higher dose, then switching to another calcium channel blocker or another vasoactive medication class can be tried. There is clinical trial evidence to support the use of several options (see Specific Drugs below) including phosphodiesterase 5 (PDE5) inhibitors, angiotensin II inhibition (losartan), topical nitrate, and selective serotonin reuptake inhibitors (SSRI) drugs (fluoxetine). Many older drugs once used for treatment of RP (alpha blockers such as prazosin; the adrenergic neuron blocker guanethidine or the monoamine transport blocker reserpine) have fallen out of favor because they often cause significant hypotension including intolerable postural hypotension.
A meta-analysis of drug treatment of secondary RP provides evidence that best support s the use of either a CCB or the intravenous administration of the synthetic prostacyclin, Iloprost. The authors of this analysis considered that the data for other treatments was sparse, negative, or conflicting [2]. Most of the objective data providing evidence for drug therapy are from studies in secondary RP in patients with scleroderma (SSc). Indeed, among patients with connective tissue diseases, SSc patients often suffer with the most severe RP and are at risk of digital ulcers or digital loss.
Guidelines from the European League against Rheumatism (EULAR) and EULAR Scleroderma Trials and Research group (EUSTAR) state that in patients with SSc-related Raynaud’s attacks, dihydropyridine-type CCBs, usually oral nifedipine, should be initially considered for RP treatment [3]. In cases with more severe RP then consider intravenous iloprost [3]. Iloprost is approved and available in Europe for treatment of SSc related RP. Experts from the US based Scleroderma Clinical Trials Consortium (SCTC) also start with a CCB, but would in severe RP add a PDE5 inhibitor and then if this combination is not effective consider moving on to an intravenous prostanoid [4] (see Fig. 20.2). This approach is based on the evidence that PDE5 inhibitors seem to work as shown in both in the clinic and in published RCTs. The PDE5 Inhibitors also provide a simpler oral administration; in addition, intravenous iloprost is not available in the USA. Other prostanoids such as the prostacyclin epoprostenol is available for the treatment of pulmonary hypertension but is not FDA approved for the treatment of RP. However, it is an option and can be used in complicated and severe cases. It should be noted that botulinum toxin locally injected is reported in uncontrolled case series to be helpful [5]. It is an option in cases not responding to other traditional agents (see Chap. 22).
Fig. 20.2
RP treatment in systemic sclerosis expert consensus (Treatment of Systemic Sclerosis (SSc) Complications: What to Use when First–Line Treatment Fails. A Consensus of SSc Experts. Semin Arthritis Rheum 2012 Aug;42(1):42–55)
Specific Drugs
Drugs Used for Treatment of RP
Dihydropyridine type calcium channel blockers.
Phosphodiesterase 5 (PDE5) inhibitors.
Prostanoids (PG12, PGE1).
Alpha adrenergic receptor blocker.
Nitrates (nitroglycerin).
Angiotensin H receptor blockers (ARB).
Selective serotonin reuptake inhibitor (SSRI).
Botulinum toxin.
Many different drug therapies have been suggested for treatment in RP. For many of these, the evidence base for their use is weak, in part reflecting the difficulty in mounting clinical trials in RP. This section describes the different drugs and groups of drugs used in patients with RP, and the evidence base for their use.
Calcium Channel Blockers (CCBs) (Table 20.1)
Table 20.1
Tips for RP treatment with CCBs
• If a patient needs treatment, usually a dihydropyridine calcium channel blocker (CCB) is prescribed |
• First: nifedipine ex. As needed 10 to 30 mg a day and increasing if needed to long acting (XL) to max of 90 mg daily |
• Next: an alternative dihydropyridine CCB |
– Nicardipine, amlodipine, felodipine |
• Long acting drugs are usually better tolerated |
• However, short acting CCBs may be considered when an outdoor activity that precipitates RP is to be undertaken |
• If, the drug is tolerated and efficacy is not obtained then the dose can be increased |
• Treatment goals include: |
– Reducing the frequency of attacks |
– Reducing the severity of attacks |
– Reducing the duration of attacks |
• Clinical trial data support mostly the first two treatment possibilities |
• CCBs may cause orthostatic hypotension and many people with primary RP are young women and have normal to low blood pressures |
• Side effects of calcium channel blockers include hypotension, flushing, peripheral edema, and headache |
Calcium Channel Blocker (CCB)
Use an extended release dihydropyridine class of a CCB.
Expect a 30 % reduction in number of attacks in 2–4 weeks on initial treatment with a CCB.
If tolerated but benefit not achieved, then increase the dose because higher doses are likely to improve severity of RP.
The first line drug treatment for RP is from the dihydropyridine class of calcium channel blockers (CCBs). Calcium channels enable activator calcium to enter smooth muscle cells and initiate constriction (or vasospasm). There are meta-analyses to evaluate evidence for the treatment of RP with CCBs. The trials reviewed often included both primary and secondary RP (mostly patients with scleroderma) making the measured outcomes reasonably generalizable to the various populations of patients with RP [6, 7]. Usually the response to treatment is blunted in the subset of patients with secondary RP compared to primary RP; especially among patients with SSc. Many trials are small, use low doses of medications, were of short duration and most use a crossover design with the potential problem of having a significant crossover effect. The crossover effect especially occurs when the study patients do not return to baseline status at time of the second treatment period is started.
Most of the convincing data supporting the use of nifedipine or other drugs used in RP comes from Randomized Clinical Trials (RCTs). Meta-analyses are used to collate these data. Most of the RCTs included in published meta-analyses were small; the number of people included in each RCT with primary Raynaud’s phenomenon ranged from 3 to 130 (8 RCTs included 21 people or fewer with primary Raynaud’s). There are also biases in these trials. For example, if the trial included subjects with both primary and secondary RP, the meta-analysis can be biased if the randomization was not stratified by subgroups. These reviews often included RCTs with a withdrawal rate of up to 35 %. The analysis also noted that many of the included RCTs were of short duration (median 2 weeks, range 1−10 weeks) and used relatively low doses of agents such as nifedipine.
A meta-analysis compared calcium-channel blockers as a group versus placebo in primary RP [7]. The meta-analysis included for review a RCT if a subset of people with primary RP could be identified separately and their outcome assessed independently, or if >75 % of people had primary Raynaud’s. Most RCTs compared a CCB to placebo, but some compared the CCB to other drugs. The meta-analysis of primary RP included 18 eligible trials (of 31 that were found) consisting of 13 RCTs comparing nifedipine to placebo, two of nicardipine, two of nisoldipine, and one of diltiazem. Eleven were crossover studies and two were parallel. It found that calcium-channel blockers as a group significantly reduced the frequency and the severity of attacks compared with placebo. The frequency of ischemic attacks were reduced by 3–5 attacks per week overall and six attacks less for nifedipine. The severity [measured on a 10-cm visual analog scale]: was reduced by 1.4 overall and 1.8 for nifedipine alone. The severity of RP was reduced by 1/3 by CCBs; a clinically relevant change.
Another meta-analysis review the experience in scleroderma related RP [6]. Five of the six RCTS of calcium-channel blockers versus placebo in SSc tested nifedipine and one compared nicardipine to placebo. The average quality score of the studies included in the analysis was 4.2 out of 5; so the trial quality was good overall. Nifedipine was usually studied at 10–20 mg TID. The reduction in the frequency of RP attacks over a 2-week period was 8.3 attacks overall and 10.2 attacks per week for nifedipine. The severity of attacks decreased significantly for all CCBs versus placebo (three trials) and for nifedipine versus placebo (two trials) with an approximate reduction of 2.3 cm on a 10 cm visual analog scale (VAS) or a 35 % improvement compared to placebo [6]. Therefore, the evidence from several small clinical trials of CCBs for RP in patients with SSc appear to lead to significant clinical improvement in both the frequency and the severity of ischemic attacks (see Figs. 20.3 and 20.4).
Fig. 20.3
Treatment of RP in scleroderma with calcium channel blockers: frequency of attacks. (Data based on Thompson A, et al. Arthritis Rheum 2001;44:1841–7)
Fig. 20.4
Treatment of RP in scleroderma with calcium channel blockers: severity of attacks. (Data based on Thompson A, et al. Arthritis Rheum 2001;44:1841–7)
Nifedipine
There were 12 trials from the meta-analysis that compared nifedipine to placebo in primary RP containing 215 subjects [7]. The doses were mainly from 5 to 20 mg three times daily; and one trial used 30 mg extended release daily. The duration of the trials ranged from 2 to 10 weeks. Overall there were statistically significant results compared to placebo in the reduction of attacks per week, severity of attacks and improvement in ischemic attacks. The analysis showed an average reduction of six attacks per week. In five trials a reduction on severity of attacks of 1.8 on a 0–10 cm VAS was demonstrated. There was also an improvement in ischemic attacks of 1 on a 5-point scale in 6 of the RCTs. More adverse events (AEs) where found when higher doses are used [8, 9]. For example, in a crossover trial of 22 patients, AEs were found in 27 % on placebo, 45 % who used nifedipine 10 mg daily and 72 % who used nifedipine at 20 mg a day. Side effects of CCBs include lower extremity edema, flushing, tachycardia, palpitations, and headaches.
There were five trials that compared the frequency of attacks of nifedipine to placebo and two for the severity of attacks in SSc associated RP [6]. There were ten less attacks over 2 weeks in the nifedipine treated patients versus placebo treated and the severity was reduced in a clinically relevant and statistically significant way; thus nifedipine had a more positive effect than in the overall calcium channel blocker group.
Nicardipine
Nicardipine was studied in some RCTs, but full data was missing and a carryover effect that may occur in crossover trials was not reported. Although nicardipine may be used to treat primary RP the reported trials included mostly secondary RP. A trial by Feri et al. in 21 subjects with primary RP used slow-releasing nicardipine at 20 mg twice a day was effective in reducing the number of attacks over 2 weeks compared to placebo [10]. A larger trial of 69 people with primary Raynaud’s was of crossover design. Nicardipine significantly decreased the frequency of attacks over 8 weeks compared with placebo (attacks/week: 4.9 with nicardipine vs. 5.8 with placebo; mean difference 0.9; P = 0.02) and reduced overall disability (measured on a 10 cm visual analog scale; mean 2.6 with nicardipine vs. 3.3 with placebo; P = 0.018), but found no significant difference in the severity of attacks [11].
There was a trial of 27 patients with RP (12 with primary RP and 15 with secondary RP including systemic lupus erythematosus [2], SSc [4] and rheumatoid arthritis [12]) who participated in a 4 week per treatment arm, double-blind, crossover study of nicardipine versus placebo [13]. Nicardipine significantly improved pain, decreased the number of RP attacks, and was preferred over placebo in primary RP. In secondary RP it only showed a significant effect on a reduction in the number of attacks. Twenty patients with RP were treated in random order in a crossover study with 2 weeks of nicardipine 20 mg three times daily and 2 weeks of placebo [14]. Nicardipine significantly improved the frequency and severity of RP.
Not all studies find a consistent benefit for nicardipine in RP. There are two published negative trials of nicardipine versus placebo in RP treatment. A RCT with a crossover design studied 25 people, 16 with primary RP and nine with secondary RP, found no significant difference in the frequency, severity, or duration of attacks at 6 weeks between nicardipine 30 mg three times a day and placebo [15]. In the sub-analysis of the 16 people with primary Raynaud’s; the mean frequency of attacks/day was 4.4 for both nicardipine and placebo; the mean severity of attacks on a 10-point scale was 3.5 with nicardipine versus 3.7 with placebo; and the mean duration of attacks 13 min with nicardipine versus 11 min with placebo. Another negative trial reported no differences between nicardipine and placebo for the frequency and severity of RP attacks in a double-blind crossover study [16]. AEs caused more dropouts with nicardipine than placebo due to flushing, headache, and palpitations.
Amlodipine
There is one randomized crossover trial of amlodipine in the treatment of RP that is published [17]. There were 24 patients included of whom 15 had primary RP. The authors found that amlodipine significantly reduced the number of acute attacks per week from baseline at 7 weeks (from 11.8 attacks/week at baseline to 8.6 attacks/week after treatment; P < 0.001) and reduced the severity of attacks from baseline (from a discomfort score of 7.8 at baseline to 5.1 after treatment). However, the RCT did not assess the between-groups difference in frequency and severity of attacks. It found that amlodipine was associated with ankle edema (55 % of people taking amlodipine and none in placebo), flushing, and headaches compared with placebo (10–20 % with amlodipine and none with placebo).
Felodipine
One trial compared two doses of felodipine (10 mg a day and 10 mg twice a day) with nifedipine in 16 patients with a double-blind crossover design [18]. There were no significant between-groups differences. Although the study was underpowered to detect differences, it gives some evidence supporting the use of felodipine in the treatment of RP.
Nisoldipine
A RCT using Nisoldipine in 36 patients with primary RP in a dose of up to 10 mg/day did not find benefit [19].
Diltiazem
Sometimes a non-hydropyridine CCB drugs such as diltiazem are used for RP treatment when there is intolerability to dihydropyridine CCBs or if there is another indication for its use such as angina or hypertension. Although diltiazem is somewhat cardioselective, it has been studied in RP in two RCTs [20, 21]. The trial by Rhedda et al. was a crossover design with 30 subjects of whom 19 were classified as primary RP [20]. Diltiazem significantly reduced the number and duration of attacks over 8 weeks compared with placebo (mean reduction in attacks from baseline: 22.9/month with diltiazem versus 4.6/month with placebo; P = 0.01; mean reduction in duration from baseline: 444 min/month with diltiazem versus 160 min/month with placebo; P < 0.01). The results were reported as comparisons from baseline, removing the benefits of randomization. In addition, this analysis was not by intention-to-treat (8/30 [27 %] people withdrew from the trial). Two people using diltiazem withdrew from the trial because of adverse effects (rash or headache). In the Kahan et al. trial, there were 16 patients of whom six were primary RP and ten were secondary to CTD (7 had SSc) [21]. Diltiazem was dosed 120 mg three times a day for 2 weeks and compared to placebo in a crossover design. RP severity was assessed by a 10 cm visual analog scale (VAS). Diltiazem significantly decreased the frequency and severity of Raynaud’s phenomenon as compared with placebo in primary RP, but these outcomes were not statistically significant different in secondary RP.
Verapamil
Verapamil is another cardioselective non-hydropyridine CCB and should not have much effect on the peripheral circulation. There is one trial of verapamil in RP, comparing it to nifedipine and diltiazem. Verapamil was not effective [22]. It is not recommended for RP treatment.
Summary of CCBs
The evidence from clinical trials supports the use of dihydropyridine CCBs as first line therapy in both primary and secondary RP. The author prefers nifedipine but amlodipine, felodipine, and nicardipine are other options. The non-dihydropyridine CBB diltiazem can be used, but verapamil is not recommended. When using a CCB, an extended release preparation is preferred and before using combination therapy, the dose should be increased to clinically effective outcome within dosing tolerance.
Phosphodiesterase 5 (PDE5) Inhibitors
PDE5 inhibitors are used in erectile dysfunction and also the treatment of pulmonary arterial hypertension. PDE5 degrades cyclic GMP, which is a major mechanism for nitric oxide (NO) to cause vasodilation, so PDE5 inhibitors can potentially amplify or mimic NO. The potency and selectivity of a PDE5 inhibitor will be dependent on the expression and activity of the enzyme. They have been studied in clinical trials in the treatment of severe RP with most but not all trials having positive results. A meta-analysis of PDE5 inhibitors RCTs in the treatment of RP found statistically significant decreases in the Raynaud’s Condition Score (RCS) by −0.46 (−0.74 to −0.17), the daily frequency of RP attacks by −0.49 (−0.71 to −0.28), and the daily duration of RP attacks by −14.62 (−20.25 to −9.00) min [23]. The analysis included six trials (two with sildenafil, three with tadalafil, and one with vardenafil).
Sildenafil
There are two trials of sildenafil used in severe RP, particularly associated with scleroderma. One trial published in 2005, was a crossover study in 16 patients with symptomatic secondary RP failing other vasodilator therapy. Patients were treated with 50 mg sildenafil or placebo twice daily for 4 weeks. Compared to placebo, sildenafil decreased the frequency of RP attacks (35 ± 14 versus 52 ± 18, P = 0.0064), the cumulative attack duration (581 ± 133 versus 1,046 ± 245 min, P = 0.0038), and the Raynaud’s Condition Score (2.2 ± 0.4 versus 3.0 ± 0.5, P = 0.0386) [24]. Two patients discontinued the study due to AEs.
A double-blind, placebo-controlled randomized trial of 57 patients with RP associated with SSc who were nonsmokers received either placebo or sildenafil as a modified-release 100 mg tablet once daily for 3 days followed by modified-release sildenafil 200 mg once daily for 25 days [25]. The mean number of attacks per week improved in the placebo group from 25 at baseline to 19 and from 31 to 19 after sildenafil; the difference in attacks per week between the drug and placebo was not statistically significant. However, the percentage reduction in the number of attacks was significant. Raynaud’s Condition Score (RCS) and pain were not significantly different. The frequent adverse events were headache and dyspepsia.
Tadalafil
There are three randomized trials with tadalafil in RP. One trial included patients with SSc and mixed connective tissue disease (MCTD) having at least four RP attacks per week despite being on vasodilators [26]. They were randomized to receive either placebo or tadalafil (20 mg) on alternate days as add-on therapy to their current vasodilators for 6 weeks. After a 7-day washout, patients were crossed over to the alternative treatment. Twenty-five patients were enrolled. All the patients were receiving calcium channel blockers and in addition 18 were receiving other vasodilators. During tadalafil treatment, there were significant improvements in frequency and duration of RP and the mean daily Raynaud Condition Score. All the 24 digital lesions healed during tadalafil therapy as compared with 3/13 during the placebo treatment (P < 0.0001). There were no serious AEs. One patient dropped out of the study.
A short trial compared tadalafil in 20 subjects with RP on two separate study days, when subjects received either placebo or tadalafil (10 mg) [27]. The study duration was too short to draw any conclusions on the efficacy of tadalafil in RP. Another trial was negative where sexual dysfunction and RP were studied in 39 women with RP secondary to SSc over 4 weeks using tadalafil 20 mg daily [28].
Vardenafil
A RCT of Vardenafil in RP was published [29]. Patients with primary and secondary RP were recruited in a double-blind, randomized, placebo controlled, crossover design study for 6 weeks to assess the efficacy and safety of vardenafil (10 mg twice daily). Treatment was switched from vardenafil to placebo or vice versa after a 1-week washout phase. Vardenafil significantly reduced the RCS by −0.45 compared with placebo (P = 0.03) and decreased the number (−0.51 versus. placebo; P = 0.005) and cumulative duration of daily RP attacks (−11.43 min versus. placebo; P = 0.003). The drug was overall well tolerated, but AEs included flushing, headache, dyspepsia, and dizziness.
Udenafil
Udenafil, a relatively new PDE5 inhibitor, was compared to amlodipine (10 mg/day) at a dose of udenafil of 100 mg/day. The RCT was a crossover design with a double blind with 4 weeks treatment prior to washout. Included in the trial were 29 patients with secondary RP associated with connective tissue diseases (most of the patients had diffuse SSc) [30]. There were no between groups differences in decreasing the frequency of RP attacks (P = 0.99). Udenafil treatment significantly decreased pain compared to baseline, whereas amlodipine did not; but there were not significant between group differences. This implies that udenafil and amlodipine are seemingly equally effective in RP. In addition, adverse events were similar.
Summary of PDE5 Inhibitors
These clinical trials support the use of PDE5 inhibitors either alone or in conjunction with a CCB. There is no evidence to define one PDE5 agent over another and specific dosing is not fully studied. Sildenafil is preferred and a dose of 20 mg three times or 50 mg twice daily is suggested.
Other Phosphodiesterase Inhibitors
Some drugs used in peripheral vascular disease (PAD) have been tried in RP treatment. These drugs are, however, not routinely used in RP. The PAD drugs include: cilostazol and pentoxifylline: these are the preferred treatments due to effectiveness and cost for the treatment of claudication [31, 32]. Pentoxifylline is a nonselective phosphodiesterase inhibitor with hemorrheologic vasoactive properties that improves blood flow and is used for the treatment of peripheral vascular disease. There is one negative trial in RP comparing pentoxifylline to ketanserin. Pentoxifylline was slightly more effective, but neither drug was very effective in RP treatment [33]. In fact, in systematic reviews of claudication pentoxifylline is even thought to be relatively ineffective [31, 32]. Therefore, it is not recommended for treatment of RP. Cilostazol is a quinolinone that inhibits cellular phosphodiesterase III which suppresses the degradation of cAMP leading to inhibition of platelet aggregation and vasodilation. In a small study it was found to increase brachial artery diameter in primary and secondary RP patients [34]. However no clinically relevant RP outcomes were studied.
Prostacyclins
Prostacyclin (prostacyclin I2, PGI2) is also called epoprostenol. There are several analogs on the market including iloprost and trepostinil. PGI2 is produced in endothelial cells from prostaglandin H2 (PGH2) through the enzyme prostacyclin synthase. Prostacyclin is a potent vasodilator working on the systemic and pulmonary vasculature and is now used worldwide in the treatment of severe pulmonary arterial hypertension. It has many biological effects including inhibiting smooth muscle proliferation, providing endothelial cell protection and inhibiting platelet aggregation. Prostacyclins can be delivered intravenously, orally or by inhalation. However, there is little data to support the benefit of oral or inhaled prostacyclins in the treatment of RP. Intravenous iloprost and other prostacyclins are mostly used in severe RP secondary to SSc. Cisaprost and beraprost are orally delivered synthetic analogs of prostacyclin. The side effects of prostacyclins are common and may limit the ability to complete the full course of a treatment protocol. They include headaches, flushing, hypotension, gastrointestinal upset, and jaw pain.
Epoprostenol
There is one RCT of intravenous epoprostenol in 14 patients that was showed benefit by reducing the frequency and severity of RP attacks. The response lasted from 6 to 10 weeks after the infusion [35]. Epoprostenol is available in the USA and other countries. Therefore, it is an option for those who cannot obtain intravenous iloprost. These are patients with severe RP requiring treatment after multidrug failure or with threatened digital loss from severe ischemia.
Iloprost
Intravenous iloprost can be effective for RP for several months after a peripheral intravenous delivery at 0.5–2.0 ng/kg/min continuously for 6 h daily for 5 consecutive days. Intravenous iloprost is now commonly used in severe SSc associated secondary RP in Europe. There are many completed positive clinical trials supporting its use. Seven randomized trials and 332 patients were included in a meta-analysis of RP from SSc [36]. Five trials compared intravenous iloprost, one oral iloprost and one oral cisaprost. The analysis showed that Iloprost decreases the frequency and severity of Raynaud’s attacks. Review of secondary or exploratory outcome found that intravenous iloprost could also heal and potentially prevent digital ulcers. Oral iloprost and other prostacyclins studied thus far do not appear as effective as intravenous iloprost, perhaps due to drug instability or poor absorption. Lower doses of intravenous iloprost may have similar efficacy to the current usual recommended dosage of iloprost [37].
Beraprost
Beraprost is an oral prostacyclin (a synthetic analog). In 125 patients with primary RP, beraprost was compared to placebo over 8 weeks [38]. There were no significant differences in the outcomes comparing beraprost to placebo. In another RCT, beraprost was found to have numerically but not statistically fewer ulcers in SSc patients. Although RP was not the primary outcome of this trial, in general the results favored beraprost but were not statistically significant [38]. Although available and used in Japan for RP, these data do not support the use of beraprost in the treatment of RP.
Treprostinil
Treprostinil may be effective for RP, but there are no RCTs. It used by subcutaneous, intravenous or inhalation delivery for the treatment of pulmonary hypertension. Nineteen scleroderma patients (84 % female, 53 % limited scleroderma) received treprostinil diethanolamine SR orally with dose titration up to 4 mg twice daily as tolerated [39]. Peak concentrations (mean maximum plasma concentration [Cmax] = 1,176 and 2,107 pg/mL) occurred approximately 3.6 h after dose administration, and overall exposure (under the plasma concentration-time curve from time 0–12 h post dose [AUC0-12] = 7,187 and 12,992 h pg/mL) was linear between the 2 and 4 mg doses. Perfusion and digital skin temperature were positively associated with log-transformed plasma concentration at the 4 mg dose (P = 0.015 and P = 0.013, respectively). This laboratory based study suggested that oral treprostinil may have benefit in patients with SSc related RP. However, treprostinil was used in a clinical trial as a stable oral preparation for the treatment of SSc digital ulcers with some early benefit but was not superior to placebo in the longer term [40].
Other Prostanoids
PGE1 (Alprostadil) has been used for critical limb ischemia and can improve RP acutely but when the infusion is stopped, there is no long lasting benefit. It needs a central line for delivery and close monitoring. Compared to iloprost, intravenous PGE1 is not superior to placebo at 4 weeks, so it is not indicated in the long term treatment of SSc associated RP. However, intravenous alprostadil may have similar acute benefits as intravenous iloprost in a small study of CTD associated RP [41]. It is an option for an ischemic digital crisis, but its benefit is likely not sustained [42, 43].
In one RCT of RP used a topical placebo or prostaglandin E2 analog applied daily for 6 weeks. The active agent had fewer and shorter spasm attacks and better healing of ulcers [44].
Summary of Prostanoids
The evidence supports the use of prostacyclin delivered intravenously in cases of severe RP, especially when due to SSc. This does not exclude other clinical situations with critical ischemia or severe RP. Iloprost is the best studied, but epoprostenol is an option that is available in the USA. The dose recommended is low dose (0.5–2 ng/kg/min); infused intravenously via a peripheral vein daily for 3–5 days. It can be used once during an ischemic crisis coupled then with maintenance of an orally delivered CCB or other effective vasodilator (e.g., PDE5). Prostacyclins can also be delivered intermittently with intervals defined by clinical benefit, usually 10–12 weeks. Some decide to use it prior to severe weather or known periods of worsening symptoms. Oral prostanoids have not yet shown clinical benefit. Prostaglandin E1 is only recommended for short term therapy for acute ischemia if a prostacyclin is not available.
Other Vasoactive Drugs Used for RP
Other vasoactive treatments that may be effective include: topical or systemic nitrates; angiotensin II-converting-enzyme inhibitors; and selective serotonin reuptake inhibitors; long acting drugs are usually better tolerated than short acting preparations. Local Injection of botulinum is also being used in severe cases (see Chap. 22). These alternative agents are often used because calcium channel blockers may cause orthostatic hypotension, and are therefore poorly tolerated by many people with RP; particularly young patients with normal or low blood pressures.
Alpha-blockers, angiotensin-converting-enzyme inhibitors, and a variety of other vascular agents (see below) that have been used are disappointing and are not recommended due to significant side effects or lack of evidence of benefit. There is a meta-analysis of potential oral vasodilators in primary RP [45]. This article updated a previous meta-analysis of oral vasodilators [46]. There were 8 RCTs with less than 300 subjects studied. All compared a drug to placebo. Unfortunately, the quality of most of these trials was poor and most had a negative outcome. In fact, in an enalapril trial, it slightly increased the frequency of attacks per week. There was a significant reduction by buflomedil on the frequency of attacks per week (WMD −8.8), but no significant effect on the Raynaud’s severity score. In a trial of moxisylyte, four times more subjects reduced the number of RP attacks in the moxisylyte treatment group compared to placebo. However, there was no evidence of benefit on the frequency, severity or duration of attacks in primary RP in the trials of captopril, beraprost, dazoxiben, or ketanserin. Beraprost and moxisylyte gave significantly more adverse effects than placebo. In general, there is sparse data to support benefit of oral vasodilators beyond the use of CCBs for primary RP.
Nitrates
Exogenous nitrates generate NO, so they are somewhat analogous to using prostacyclins—providing an endothelium-derived protective agent that may be diminished in SSc. Also, there is the complicating issue that some nitrates (esp. nitroglycerin) require metabolism to release NO, and the distribution of the metabolizing enzyme is not completely defined. Oral nitrates are used rarely due to their side effects. In theory, there is an advantage of a far lower dose and less side effects if topical nitrates are used. However, like the oral preparations, transdermal or topical nitrates creams or ointments may also cause side effects such as headaches, which could limit their use. There are randomized controlled trials of topical nitrates that can vasodilate blood vessels and be potentially effective in the treatment of RP. They have been found to decrease the frequency and severity of attacks in primary and secondary RP and may improve digital ulcers.
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