ORADE Grant Recipient – Dr. Andreu Fernandez-Codina

Review of the European League Agains Rheumatism’s 8th Course on Capillaroscopy on Rheumatic Diseases

Author: Andreu Fernández-Codina1

1Connective tissue disease and vasculitis clinical fellow. Saint Joseph’s Health Care London, Western University, London, ON, Canada

Conflicts of interest: none.

I would like to express my gratitude to the Ontario Rheumatology association after being awarded an ORADE grant to attend the 8th Course on Capillaroscopy in Rheumatic Diseases, supported by the European League Against Rheumatism (EULAR). The course was held in Genoa, Italy, from September 12 to September 15, 2018.

This course is organized every 2 years in Genoa. Speakers were all European, mostly Italian. The coordinator of the course was Maurizio Cutolo (EULAR group on microcirculation in rheumatic diseases). The aims of the conference were to review the different microvascular abnormalities in autoimmune diseases, to know the different technologies used to assess microvasculature, to know its potential clinical usefulness and to provide the participants with a basic practical approach. Most of the investigations in microvasculature are focused in connective tissue disease (CTD), especially in systemic sclerosis (SSc) and primary Raynaud’s phenomenon (RP). The course consisted of standard lectures, some lectures supported by live examinations viewed in the projectors and the opportunity to test the participant’s abilities with a videocapillaroscope with live patients. In the following lines I will try to summarize the contents that I considered of a greater interest.

Dr. Eric Hachulla (France) described the microvascular involvement in CTD and its importance. In SSc, endothelial damage and myofibroblast activation prompt myofibrolast proliferation, collagen deposition and the growth of the adventitia layer. These processes end up in significant consequences as scleroderma renal crisis (SRC), pulmonary arterial hypertension (PAH) or digital ulcers (DU). The consequences of the microvascular damage are associated with a higher mortality. In CTD, there is also some macroangiopathy, with an increased incidence of coronary ischemia, stroke, finger arterial ischemia. It is not clear if there is an accelerated atherosclerosis like in Rheumatoid arthritis.

Treatment of micro and macrovascular complications in CTD has shown an impact on morbidity and mortality in SSc, according to Dr. Christopher Denton (UK). The use of angiotensin converting enzyme inhibitors dramatically improved survival in SSc patients with SRC (Ann Intern Med. 2000;133(8):600-3). Regarding PAH, three therapeutic pathways have positive data: endothelin receptor antagonists, nitric oxide pathways stimulants and prostacyclin analogues. Recently, their combination has shown to obtain better results in some randomized clinical trials (Ann Rheum Dis. 2017:76:1219-27). Finally, for DU, the same treatment pathways are used, in combination with other drugs less supported by evidence or surgery. Currently more innovative treatments like riociguat or nindentanib, and new pathways like VEGF and Fra-2 are under study to treat these complications.

Capillaroscopy has a significant role differentiating primary RP from secondary according to Dr. Smith (Belgium). Ten % of the general population has RP, and 90% of them will have primary RP. Among secondary RP, 90% will correspond to autoimmune diseases, and, among them, 90% corresponds to SSc. The rate of progression of primary RP to SSc after approximately 4 years of follow up is 12.6% (Arthritis Rheum. 2008;58(12):3902-12). None of the patients with normal nailfold capillaroscopy, absence of antinuclear autoantibodies and scleroderma specific antibodies (centromere, topoisomerase, RNA polymerase III), and absence of clinical manifestations (puffy hands, sclerodactyly, DU) developed SSc. As RP and potential CTD are the reason for frequent referrals to rheumatologists, the use of a simple capillaroscopic assessment, anamnesis, physical exploration and a single basic autoantibody profile, can rule out easily a severe disease as SSc in an early stage (Ann Rheum Dis. 2014;73(12):2087-93).

Arianne Herrick (UK), explained the multiple devices that can be used to assess microcirculation. All of them have different characteristics, uses and pricing.

  • Videocapillaroscopy is the gold standard for the observation of nailfold capillaries. Advantages: it allows to us to take picture, to make counts and measures and it has a great magnification power. Research and clinical uses. Disadvantages: cost around 10,000 CAD, narrow field of view, not always portable.
  • Similar to videocapillaroscopy, used in the first studies by Maricq. Advantages: variable magnification, image capture. Research and clinical uses. Disadvantages: fixed device, no measurements, cost (cheaper than videocapillaroscopy).
  • Advantages: portable, intermediate price (500 CAD), wide field of view. Focused towards the clinic. Disadvantages: low magnification, no measurements, no capture but a camera can be attached.
  • USB microscope. Advantages: portable, variable field of view, low cost (50 CAD), captures with an attached computer. Disadvantages: low magnification, no measurements.

Depending on the use we want to give to the device, we will need one or another. A British study (Rheumatology (Oxford). 2015;54(8):1435-42) comparing dermoscopy vs videocapillaroscopy showed a moderate agreement within the two techniques, but videocapillaroscopy scored more severe alterations. Another study (Rheumatology (Oxford). 2018;57(6):1115-16) showed that dermoscopy and videocapillaroscopy had a sensitivity of 60 and 82 %, and a specificity of 93 and 85%, respectively.

Dr. Cutolo and Dr. Sulli commented on the ways to examine the capillaries and the scleroderma patterns. Normal capillaries should appear a palisade of red hairpins. The basic items regarded in a capillariscopic exploration are the number of capillaries (7/mm is normal), the number/presence of megacapillaries (diameter >50 µm), the number/presence of enlarged capillaries (20-50 µm), the number/presence of hemorrhages, the presence/number of capillaries with ramifications or angiogenesis. The evaluation of the capillaries might be qualitative, quantitative or semiquantitative. Initially, Maricq established two patterns, active and late. Currently, Cuttolo’s patterns (J Rheumatol. 2000;27(1):155-60) are preferred.

  • Early: few enlarged/megacapillaries, few capillary hemorrhages, well preserved capillary distribution, no capillary loss
  • Active: frequent megacapillaries and hemorrhages, some capillary loss.
  • Late: severe capillary loss with avascular areas and capillary ramifications, disruption of the capillary distribution. Few megacapillaries or hemorrhages.
  • Patients without these alterations would have an unspecific pattern.

EULAR is developing a new simplified assessment tool dividing all explorations into 2 patterns (1 for the non-scleroderma or unspecific and 2 for the scleroderma patterns), which might make easier the fast interpretation of capillaroscopy. There is a Capillaroscopic Skin Ulcer Risk Index (CSURI), based on several quantitative measurements, that correlates with the risk of developing new DU (Arthritis Rheum. 2009;61(5):688-94). Explorations should be done at 200x, measuring couple of 1 mm captures per finger (2nd to 5th fingers bilaterally), 20-22 C room temperature, patient in the room for 15 minutes prior to the test.

Changes in the capillaroscopic patterns have been related to complications in scleroderma. Dr. Smith (Belgium) that a study in 2012 (Arthritis Rheum. 2012;64(3):821-5) showed that 50 % of patients with an initial early pattern, progressed during follow up to an active or late pattern. Those who progressed, significantly developed more complications as lung involvement, PAH or DU. Another study in 2017 (Semin Arthritis Rheum. 2017;47(1):86-94) showed that in a prospective cohort of patients with sequential yearly videocapillaroscopic assessments for 3 years, those who had a decrease in the number of capillaries had more DU (HR 5.33), PAH (HR 18.53), progression of skin fibrosis (HR 4.22) and worsening of the Medsger Severity Score (HR 5.26).

According to Dr. Müller-Ladner (Germany), the 2013 American College of Rheumatology/EULAR classification criteria for SSc (Ann Rheum Dis. 2013;72(11):1747-55) improved the sensitivity and specificity of the previous criteria (91 and 92% in the validation cohort, respectively). The presence of SSc capillaroscopic patterns was one of the new items of these criteria. Therefore, capillaroscpy has a relevant paper in the diagnosis of SSc. Moreover, in the absence of a SSc patter in nailfold capillaroscopy had a 90% negative predictive value for the diagnosis of SSc (BMC Musculoskelet Disord. 2016;17(1):342).

Dr. Cutolo (Italy) hypothesized that since the progression of the capillaroscopic pattern leads to more complications in SSc, there is a rationale to try to treat the disease earlier, to stop this progression. Treatment with vasodilators alone like iloprost (Rheumatology (Oxford). 2018;57(8):1408-1416) has shown to induce changes in the microvasculature, but this improvement in the blood flow does persist with time, having a worsening before the next infusion. The combination of bosentan and iloprost (Mod Rheumatol. 2017;27(1):110-114) showed to increase the number of capillaries and to stabilize CSURI, which worsened in patient treated only with iloprost. Overall, capillaroscopy could be an item to assess the response to treatment and monitor it along the follow up.

Finally, Dr. Sulli (Italy) gave a lecture on common mistakes on capillaroscopy. He reviewed the general recommendations to perform the test. Manicure could lead to artifacts, as well as the presence of nail polishers. Smoking or caffeine should be avoided in the 4 hours prior to the test. He stated that in his experience, with 5 non-consecutive hours of nailfold videocapillaroscopy, an untrained person could reach a good level of assessment. The EULAR microcirculation study group may facilitate stages at expert centers upon request.

There were some other lectures on capillaroscopy and other rheumatic diseases, capillaroscopy in pediatric patients and some other techniques used mostly in research for the study of the microvasculature.

CONCLUSION

In summary, after attending this interesting course, in my opinion:

  • Capillaroscopic explorations using patterns seem more feasible in the clinic setting due to time issues. Moreover, most of the relevant alterations have been described with Cutolo’s late pattern. Easier pattern recognition algorithms might make easier the performance and interpretation of nailfold capillaroscopy. Quantitative measures are more time-consuming, require more sophisticated hardware, thus, they could be used mainly in research.
  • There is a rationale to use videocapillaroscopy or dermoscopy in a general rheumatology practice for primary RP assessment as it is a non-invasive test that can be easily done in the office, to be interpreted along with autoantibodies and clinical findings, given its high negative predictive value for SSc when normal.
  • In order to help with an earlier diagnosis of SSc, capillaroscopy shall be performed in patients referred to rule out this disease, as it is included in the current classification criteria. Clinical judgment should prevail.
  • Prognosis and treatment. In patients with SSc, a baseline capillaroscopic assessment would predict a potential risk for future complications. It is another danger sign, but no randomized controlled trials have explored modifying the treatment just according to the capillaroscopic pattern.