SSc and Raynaud’s phenomenon

Raynaud’s phenomenon (RP) is the most frequent and earliest manifestation of SSc. It is caused by digital vasospasms usually triggered by exposure to cold or stress, which lead to the three phases of the classical colour change from white to blue (cyanosis) and then red (erythema), and is frequently associated with pain and sometimes with paresthesia, numbness and impaired hand function. It can be effectively treated by various classes of drugs, whose benefits include a reduction in the frequency and severity of attacks, and the prevention and/or healing of digital ulcers. The first-line non-pharmacological treatment of Raynaud’s phenomenon involves avoiding or minimising exposure to cold, the use of warm gloves, and avoiding aggravating factors such as smoking and certain drugs, although these measures are more effective in the case of primary rather than secondary Raynaud’s phenomenon. Pharmacological measures usually start with calcium channel blockers but, if these are ineffective, other options include topical nitroglycerin, and alpha adrenergic or angiotensin receptor antagonists. Intravenous prostacyclin analogues are warranted in severe cases, particularly if there is a threat of digital ischaemia, but they are expensive and, as they burdened by substantial risks (including the induction of severe hypotension), close monitoring is required during their administration. Novel approaches include the use of endothelin receptor antagonists, phosphodiesterase inhibitors and statins, although their place in the therapeutic armamentarium remains to be established, and it may also be possible to combine drugs acting on different target mechanisms, although this may be limited by questions of cost.

Finally, surgical approaches (particularly thoracic sympathectomy) have fallen out of favour, probably because of improvements in pharmacological treatments .

SSc and digital ulcers

Often persistent and recurrent digital ulcers are one of the most frequent and burdensome clinical manifestations, and occur in more than 50% of patients. They may simultaneously affect more than one finger, and lead to severe pain and function limitations . The lack of validated guidelines has prompted a number of researchers to seek the best treatment, and a very recent study published by Giuggioli et al. tested the initial use of local lidocaine and prilocaine (25 mg of both per gram of 5% EMLA cream), followed by local and oral morphine depending on the severity of the pain as measured by means of a 10 cm visual analogue scale (VAS), and found that the deep wound debridement crucial for healing was better tolerated .

SSc and synovitis

Between 40% and 80% of SSc patients complain of musculoskeletal pain, which is more problematic in patients with early diffuse SSc. The pain may not be sufficiently localised to attribute it to a particular anatomical location, but a number of pain syndromes have been identified.

• 1.
  

  Tendinitis : Tendon friction rubs mainly affect patients with early diffuse SSc. They have a frequency of 23–65%, but this tends to decline over time . They are considered to be associated with more active disease and worse outcomes.

  
  
• 2.
  

  Polyarthritis : Between 36% and 80% of patients complain of polyarthralgias, which may be more frequent in those with early SSc, although some studies have found their occurrence more equally distributed between limited and diffuse SSc . The wide range of articular and non-articular changes observed in radiographs of SSc patients go from juxta-articular osteoporosis and joint space narrowing to frank erosions in the metacarpophalangeal (MCP), proximal interphalangeal (PIP), and distal interphalangeal (DIP) joints, and wrist. It has been said that bony erosions (mainly in the hands) affect 4–57% of patients who have had SSc for seven years, and joint space narrowing affects 16–92% ; however, concern has been raised that some of the joint space narrowing may be related to concomitant osteoarthritis and not just SSc.

  
  
• 3.
  

  Rheumatoid arthritis (RA) : The recent availability of anti-cyclicitrullinated peptide (CCP) assays has led to the finding that 1–15% of SSc patients have overlapping anti-CCP antibody-positive RA. However, it should be noted that anti-CCP antibodies alone do not define RA, and it is not known how many SSc patients without RA are anti-CCP positive.

  
  
• 4.
  

  Fibromyalgia (FM) : Studies reported that 48% of patients had 11 or more tender points (TPs), whereas the mean TP count was 7 (of 18) in the Malcarne study . Clinical experience suggests that FM is not uncommon in patients with SSc or other CTDs, and dedicated work is needed in this field, including studies using the 2010 fibromyalgia criteria.

SSc and gastrointestinal disorders

The gastrointestinal (GI) is the second most frequently involved organ system in SSc patients , who often experience complications such as gastro-esophageal symptoms, abdominal pain and distension, weight loss and nutritional deficiencies, diarrhea, incontinence, and constipation.

The esophagus is the most frequently affected part of the GI tract, and up to 90% of patients describe symptoms of heartburn, regurgitation and dysphagia. These dysfunctions are probably due to smooth muscle atrophy (particularly the inner circular layer of the muscularis propria ) and fibrosis affecting the distal two-thirds of the esophagus but sparing the proximal part that causes the loss of normal neural function. Lifestyle modifications and the avoidance of exacerbating food groups are often suggested first, but patients often need intensive treatment with proton pump inhibitors to control their symptoms.

Up to 50% of SSc patients report early satiety, nausea, bloating, and abdominal discomfort. The pathophysiology is not clear but it is possible that lymphocyte activation plays an important role in causing smooth muscle atrophy and collagen deposition, leading to severe ultrastructural alterations in smooth muscle cells and nerve fibres. It is thought that gut dysfunction relates to a neuropathic process in SSc patients .

The clinical management of gastric motility disorders can be difficult because of their poor correlations with symptoms. Dietary modifications with the addition of a prokinetic agent is often the mainstay of treatment, and probiotics may be useful in some patients. The use of metoclopramide can improve gastric motility and motor activity, and somatostatin analogues such as octreotide have also been used to induce contractile activity throughout the bowel. It has been reported that up to 18% of patients with SSc are at high risk of malnutrition due to perioral sclerosis, esophageal dysmotility and abdominal discomfort; the management of weight loss and malnutrition requires a multidisciplinary team approach in which dieticians, nutrition specialists and ward nursing staff play a crucial role.

Diarrhea can affect up to 50% of patients, who need to be fully assessed because the cause is multifactorial. Once the contributory causes of malabsorption have been investigated, symptomatic approaches such as dietary measures to increase stool consistency and use of loperamide to inhibit peristalsis and secretion can be tried; however, caution is required in order to avoid pseudo-obstruction. Cholestyramine or other bile salt acid sequestrants may be helpful .

The colon and anorectum are the second most frequently affected parts of the GI tract, and it has been suggested that the anorectal dysfunction reported by 50–70% of SSc patients is due to neuronal dysfunction, smooth muscle atrophy and fibrosis affecting the internal anal sphincter. Fecal urgency can arise because of reduced rectal compliance and capacity due to collagen deposition, and fecal incontinence has a significantly negative impact on the patient’s quality of life. Practical specialist management such as biofeedback and bowel and pelvic floor muscle training can be offered although the evidence is limited. Surgical repair of the anal sphincter has been attempted but the long-term outcomes suggest worsening of continence and so this approach is not generally advocated .

It has been reported that colonic involvement occurs in 20–50% of patients, who often lack the post-prandial gastrocolic response mediated by the cholinergic pathway, thus reducing colonic motility, prolonging colonic transit and leading to constipation. Unfortunately, laxatives frequently offer little benefit: stimulant laxatives rely on contact with the bowel mucosa, which is unpredictable, and osmotic laxatives can aggravate bloating and discomfort. It has been shown that the 5HT4 receptor agonist prucalopride accelerates colonic transit but, although the results have been promising, they have only been published in case reports. Opioid antagonists such as methylnaltrexone do not seem to be very beneficial in patients with SSc because of the nature of their bowel dysmotility. Biofeedback training is useful in the case of idiopathic constipation, but it has not been studied in SSc. There are no published data corning the effect of sacral nerve stimulation (SNS) on constipation in SSc patients, although it is useful in idiopathic constipation; however, the drawbacks of SNS are that it is an expensive invasive procedure associated with the risks of infection, lead migration and pain.

Intestinal pseudo-obstruction is a rare GI manifestation of SSc. The treatment algorithms mention professional patient counselling, and depressive symptoms have been reported to be associated with GI involvement in SSc patients. Treating gastroenterologists should take an overall holistic approach and their patients’ quality of life, functional status and depressive symptoms, whereas treatment interventions for SSc are limited .

SSc and Raynaud’s phenomenon

Raynaud’s phenomenon (RP) is the most frequent and earliest manifestation of SSc. It is caused by digital vasospasms usually triggered by exposure to cold or stress, which lead to the three phases of the classical colour change from white to blue (cyanosis) and then red (erythema), and is frequently associated with pain and sometimes with paresthesia, numbness and impaired hand function. It can be effectively treated by various classes of drugs, whose benefits include a reduction in the frequency and severity of attacks, and the prevention and/or healing of digital ulcers. The first-line non-pharmacological treatment of Raynaud’s phenomenon involves avoiding or minimising exposure to cold, the use of warm gloves, and avoiding aggravating factors such as smoking and certain drugs, although these measures are more effective in the case of primary rather than secondary Raynaud’s phenomenon. Pharmacological measures usually start with calcium channel blockers but, if these are ineffective, other options include topical nitroglycerin, and alpha adrenergic or angiotensin receptor antagonists. Intravenous prostacyclin analogues are warranted in severe cases, particularly if there is a threat of digital ischaemia, but they are expensive and, as they burdened by substantial risks (including the induction of severe hypotension), close monitoring is required during their administration. Novel approaches include the use of endothelin receptor antagonists, phosphodiesterase inhibitors and statins, although their place in the therapeutic armamentarium remains to be established, and it may also be possible to combine drugs acting on different target mechanisms, although this may be limited by questions of cost.

Finally, surgical approaches (particularly thoracic sympathectomy) have fallen out of favour, probably because of improvements in pharmacological treatments .

SSc and digital ulcers

Often persistent and recurrent digital ulcers are one of the most frequent and burdensome clinical manifestations, and occur in more than 50% of patients. They may simultaneously affect more than one finger, and lead to severe pain and function limitations . The lack of validated guidelines has prompted a number of researchers to seek the best treatment, and a very recent study published by Giuggioli et al. tested the initial use of local lidocaine and prilocaine (25 mg of both per gram of 5% EMLA cream), followed by local and oral morphine depending on the severity of the pain as measured by means of a 10 cm visual analogue scale (VAS), and found that the deep wound debridement crucial for healing was better tolerated .

SSc and synovitis

Between 40% and 80% of SSc patients complain of musculoskeletal pain, which is more problematic in patients with early diffuse SSc. The pain may not be sufficiently localised to attribute it to a particular anatomical location, but a number of pain syndromes have been identified.

• 1.
  

  Tendinitis : Tendon friction rubs mainly affect patients with early diffuse SSc. They have a frequency of 23–65%, but this tends to decline over time . They are considered to be associated with more active disease and worse outcomes.

  
  
• 2.
  

  Polyarthritis : Between 36% and 80% of patients complain of polyarthralgias, which may be more frequent in those with early SSc, although some studies have found their occurrence more equally distributed between limited and diffuse SSc . The wide range of articular and non-articular changes observed in radiographs of SSc patients go from juxta-articular osteoporosis and joint space narrowing to frank erosions in the metacarpophalangeal (MCP), proximal interphalangeal (PIP), and distal interphalangeal (DIP) joints, and wrist. It has been said that bony erosions (mainly in the hands) affect 4–57% of patients who have had SSc for seven years, and joint space narrowing affects 16–92% ; however, concern has been raised that some of the joint space narrowing may be related to concomitant osteoarthritis and not just SSc.

  
  
• 3.
  

  Rheumatoid arthritis (RA) : The recent availability of anti-cyclicitrullinated peptide (CCP) assays has led to the finding that 1–15% of SSc patients have overlapping anti-CCP antibody-positive RA. However, it should be noted that anti-CCP antibodies alone do not define RA, and it is not known how many SSc patients without RA are anti-CCP positive.

  
  
• 4.
  

  Fibromyalgia (FM) : Studies reported that 48% of patients had 11 or more tender points (TPs), whereas the mean TP count was 7 (of 18) in the Malcarne study . Clinical experience suggests that FM is not uncommon in patients with SSc or other CTDs, and dedicated work is needed in this field, including studies using the 2010 fibromyalgia criteria.

SSc and gastrointestinal disorders

The gastrointestinal (GI) is the second most frequently involved organ system in SSc patients , who often experience complications such as gastro-esophageal symptoms, abdominal pain and distension, weight loss and nutritional deficiencies, diarrhea, incontinence, and constipation.

The esophagus is the most frequently affected part of the GI tract, and up to 90% of patients describe symptoms of heartburn, regurgitation and dysphagia. These dysfunctions are probably due to smooth muscle atrophy (particularly the inner circular layer of the muscularis propria ) and fibrosis affecting the distal two-thirds of the esophagus but sparing the proximal part that causes the loss of normal neural function. Lifestyle modifications and the avoidance of exacerbating food groups are often suggested first, but patients often need intensive treatment with proton pump inhibitors to control their symptoms.

Up to 50% of SSc patients report early satiety, nausea, bloating, and abdominal discomfort. The pathophysiology is not clear but it is possible that lymphocyte activation plays an important role in causing smooth muscle atrophy and collagen deposition, leading to severe ultrastructural alterations in smooth muscle cells and nerve fibres. It is thought that gut dysfunction relates to a neuropathic process in SSc patients .

The clinical management of gastric motility disorders can be difficult because of their poor correlations with symptoms. Dietary modifications with the addition of a prokinetic agent is often the mainstay of treatment, and probiotics may be useful in some patients. The use of metoclopramide can improve gastric motility and motor activity, and somatostatin analogues such as octreotide have also been used to induce contractile activity throughout the bowel. It has been reported that up to 18% of patients with SSc are at high risk of malnutrition due to perioral sclerosis, esophageal dysmotility and abdominal discomfort; the management of weight loss and malnutrition requires a multidisciplinary team approach in which dieticians, nutrition specialists and ward nursing staff play a crucial role.

Diarrhea can affect up to 50% of patients, who need to be fully assessed because the cause is multifactorial. Once the contributory causes of malabsorption have been investigated, symptomatic approaches such as dietary measures to increase stool consistency and use of loperamide to inhibit peristalsis and secretion can be tried; however, caution is required in order to avoid pseudo-obstruction. Cholestyramine or other bile salt acid sequestrants may be helpful .

The colon and anorectum are the second most frequently affected parts of the GI tract, and it has been suggested that the anorectal dysfunction reported by 50–70% of SSc patients is due to neuronal dysfunction, smooth muscle atrophy and fibrosis affecting the internal anal sphincter. Fecal urgency can arise because of reduced rectal compliance and capacity due to collagen deposition, and fecal incontinence has a significantly negative impact on the patient’s quality of life. Practical specialist management such as biofeedback and bowel and pelvic floor muscle training can be offered although the evidence is limited. Surgical repair of the anal sphincter has been attempted but the long-term outcomes suggest worsening of continence and so this approach is not generally advocated .

It has been reported that colonic involvement occurs in 20–50% of patients, who often lack the post-prandial gastrocolic response mediated by the cholinergic pathway, thus reducing colonic motility, prolonging colonic transit and leading to constipation. Unfortunately, laxatives frequently offer little benefit: stimulant laxatives rely on contact with the bowel mucosa, which is unpredictable, and osmotic laxatives can aggravate bloating and discomfort. It has been shown that the 5HT4 receptor agonist prucalopride accelerates colonic transit but, although the results have been promising, they have only been published in case reports. Opioid antagonists such as methylnaltrexone do not seem to be very beneficial in patients with SSc because of the nature of their bowel dysmotility. Biofeedback training is useful in the case of idiopathic constipation, but it has not been studied in SSc. There are no published data corning the effect of sacral nerve stimulation (SNS) on constipation in SSc patients, although it is useful in idiopathic constipation; however, the drawbacks of SNS are that it is an expensive invasive procedure associated with the risks of infection, lead migration and pain.

Intestinal pseudo-obstruction is a rare GI manifestation of SSc. The treatment algorithms mention professional patient counselling, and depressive symptoms have been reported to be associated with GI involvement in SSc patients. Treating gastroenterologists should take an overall holistic approach and their patients’ quality of life, functional status and depressive symptoms, whereas treatment interventions for SSc are limited .