Raynaud’s phenomenon (RP) is a vasospastic disorder characterized by whitening and purplish extremities after cold or emotional triggers, followed by flushing and return to normal skin tone when exposed to heat. The former is a benign disease due to altered vascular and/or innervation function, while the latter is an organic disease that can be complicated by ulceration, scar formation or gangrene of the extremity. Refractory RP is mostly secondary RP, which is treated with conventional management including warmth, smoking ban, treatment of the primary disease and vasodilators (calcium channel blockers, α-adrenergic receptor blockers and angiotensin II receptor inhibitors, etc.) with poor results, and the disease may persist and progress to ulceration or gangrene of the extremity. Clinically, these patients are not uncommon and difficult to treat, and in recent years, there have been more studies related to them, which are reviewed as follows. The rheumatology and immunology department of the Third Hospital of Peking University, Liu Xiangyuan. 1. prostaglandins and their analogues Iloprost is a prostacyclin analogue, which has the effect of vasodilatation, inhibition of platelet aggregation and inhibition of vascular remodeling. According to several experimental studies, the efficacy of these drugs in the treatment of RP is controversial, but most scholars prefer that they can improve the clinical manifestations of refractory RP. Back in the 1990s, a review analysis by Cochrane et al. showed that intravenous iloprost was more effective than oral iloprost in treating RP, not only by significantly reducing the frequency of secondary RP episodes but also by promoting healing of finger-end ulcers. Another study showed that short-term intravenous iloprost treatment was better than oral nifedipine in reducing the frequency, time interval, and severity of RP episodes, while significantly improving skin scores and RP severity scores. Low doses (0.5 ng/kg/min) and standard doses (2 ng/kg/min) of intravenous iloprost also reduced the frequency, severity, and interval of RP episodes. Common adverse effects of iloprost include headache, flushing and nausea, most of which are reversible and may disappear after reducing the number of doses or discontinuing the drug, but some patients may experience severe hypotension and should be used with caution in patients with severe cardiovascular disease. Trepostinil is also a prostacyclin analogue and has been shown to improve existing fingertip ulcers and reduce the incidence of new ulcers. The common adverse effects are redness, swelling, and pain at the acupuncture site, which may resolve on their own after removal of the needle. Endothelin receptor antagonists include endothelin receptor A (ERA) and endothelin receptor B (ERB). Endothelin A receptor (ETA) is expressed in vascular smooth muscle cells and has the effect of promoting the proliferation of vasoconstrictor cells. Endothelin B receptor (ETB) is expressed in endothelial cells and dilates blood vessels through the vasodilating effect of nitric oxide. Bosentan is a non-selective endothelin receptor inhibitor that acts primarily on ETA to inhibit vasoconstriction. Although the efficacy of bosentan in RP is controversial, several studies evaluating bosentan in refractory RP have shown a variable (30%-48%) reduction in the incidence of new ulcers in the bosentan group compared to the placebo group, but poor efficacy in improving finger-end pain, Health Assessment Questionnaire disability index, and pre-existing finger-end ulcers. Adverse effects of bosentan mainly include liver injury and infant birth defects, so it is prohibited for pregnant women. Phosphodiesterase inhibitors Phosphodiesterase 5 receptor inhibitors (PDE5I) can be used for the treatment of refractory RP by inhibiting phosphodiesterase activity and thereby increasing cGMP concentrations. Fries R et al. showed that sildenafil significantly improved Raynaud’s phenomenon scores and capillary hemodynamics in patients with secondary RP who had poor outcomes with conventional vasodilators, while reducing the frequency and prolonging the interval between RP episodes. The main side effects of PDE5I include headache, facial flushing, nausea and back pain, but most patients can tolerate them. 4. Nitrates There are various types of nitrates, including oral, topical and intravenous drugs. Because of strong vasodilating effect, they can be used for the treatment of refractory RP, but their widespread use is limited by adverse effects such as headache and hypotension. In recent years, a new topical nitroglycerin formulation, MQX-503, consisting of 50% lecithin microemulsion organic component and 50% water nitroglycerin, has entered the clinical trial stage. Preliminary results showed that topical MQX-503 accelerated blood flow recovery and shortened limb blood flow recovery time, and significantly improved Raynaud’s Condition Score (RCS), but was not effective in the mean number of RP episodes and time interval between episodes. MQX-503 was well tolerated, with side effects including headache, dizziness and skin irritation, but there was no significant difference compared to the placebo group. All of the above drugs contribute to the relief of refractory Raynaud’s phenomenon, so is there an order of preference? Recently, during the 2013 annual meeting of the American College of Rheumatology, an expert consensus was published that the best choices are epoprostenol, bosentan, sildenafil and trepostinil. Invasive treatment 1. Botulinum toxin Botulinum toxin inhibits vasospasm mainly by blocking vasoconstriction due to cold stimulation and prevents the increase of a-adrenergic receptors in vascular smooth muscle under cold stimulation. It is used to treat RP. There are few studies on the treatment of refractory RP with botulinum toxin injections. A recent review summarizing the efficacy of botulinum toxin in RP showed that intra-finger-end injections of botulinum toxin were effective in treating RP, not only reducing the frequency of RP episodes but also promoting ulcer healing at the fingertip by accelerating local blood flow velocity. However, there is a lack of large-scale clinical trials to confirm its efficacy. 2. sympathectomy Sympathectomy has been used as a second-line treatment for refractory RP. Covelier et al. summarized the results of thoracic sympathectomy for primary and secondary RP, which showed that the efficiency of primary and secondary RP patients was 92% and 89%, respectively, while the long-term efficiency was 58% and 89%, respectively. In addition, 95% of patients with secondary RP had ulcer healing or improvement, suggesting that patients with RP with severe ischemia can be treated with the above treatment for pain relief. In recent years, thoracoscopic sympathectomy has replaced open surgery. However, there are some side effects of these procedures, including compensatory sweating (45%-98.6%), Horner syndrome (0-6.9%) and other operation-related side effects such as pneumothorax, hemothorax and phrenic nerve palsy. Epicardial sympathectomy can be performed to treat RP by stripping the epicardium of the affected finger artery, theoretically blocking sympathetically mediated nerve contraction permanently and removing arterial spasm episodes, with better long-term and near-term outcomes than previous surgical approaches. 3. Others Transcutaneous electrical nerve stimulation can also induce local vasodilation in patients with refractory RP. Case reports have shown that spinal cord stimulation is effective in the treatment of refractory RP. Spinal cord stimulation can reduce pain and promote ulcer healing in patients with refractory RP. In conclusion, patients with refractory RP can be treated with topical nitrates, PDE5I, endothelin receptor antagonists or prostaglandin analogs in addition to general therapy to enhance the efficacy of the original drugs. For severe ischemia or refractory finger-end ulcers, topical nitroglycerin preparations, intravenous iloprost, or PDE5I inhibitors may be added to calcium channel blockers. For multiple ulcers of the fingertip, bosentan may be given to reduce the incidence of new ulcers. Blood pressure should be monitored closely when the above drugs are administered, and attention should be paid to their associated side effects. If the above treatments are not effective, surgical intervention should be considered.