The shadow zone of capillaroscopy in the classification of the Raynaud’s phenomenon

Abstract

Raynaud's phenomenon (RP) is a frequent clinical finding in the general population that can be observed across multiple medical specialties and nailfold videocapillaroscopy is a first line imaging tool to early differenziate primitive and secondary forms of RP. According to the criteria of LeRoy and Medsger normal nailfold capillaries characterize a primary RP. The recognition of vascular alterations at capillaroscopy is the key to a correct framing of the phenomenon. Capillaroscopy is of significant practical value as it allows a reliable predictive assessment of the developmental risk of the disorder. However, to date, the variety of nomenclature for subjects affected by RP generates uncertainty in patient management and in the possibility of comparing studies. The capillaroscopic findings have a very broad range of normality and a significant presence of non specific microvascular abnormalities are reported also in patients with primary RP. The presence of these non specific vascular changes can make it difficult to differenziate primary and secondary RP. Here we highlight some critical points in the capillaroscopic distinction of primary and secondary RP and relaunch the debate on the classification of the RP because it is likely that what we identify today as the primary RP (pRP) collects different clinical entities with different prognostic significance and different therapeutic needs.

Keywords:

• Capillaroscopy
• NVC
• Raynaud’s phenomenon
• connective tissue disease
• microvascular abnormalities
• microcirculation

RP is a frequent clinical finding with a prevalence of 5–10% in the general population that can be observed across multiple medical specialties. Two groups are identified, the first with a favourable prognosis, a benign type occurring as the only manifestation without associated diseases defined as primary RP (pRP) and distinguished from the second, the secondary RP (sRP), occurring with variable progression and prognosis in several conditions including connective tissue diseases (CTDs)¹. Some authors have identified an additional category by naming it as suspected secondary RP^2,3.

pRP identifies a thermoregulatory defect with an exaggerated response to temperature. Instead, the altered vascular reactivity of the sRP is caused by an underlying pathology. The onset of RP therefore represents an opportunity for the clinician for the early diagnosis of a connective tissue disease and capillaroscopy the easiest tool to use⁴.

The evaluation of RP requires careful clinical and laboratory assessment⁵. A significant number of signs and symptoms define RP in practice and help in the differential diagnosis. Strong and symmetrical peripheral pulses, attacks of acral pallor or cyanosis which are entirely reversible, normal nailfold capillaries, no evidence of digital pitting, ulceration or gangrene, a normal erythrocyte sedimentation rate and a negative antinuclear antibody (ANA) (titre < 1/100) are established criteria for pRP^6,7. Nailfold videocapillaroscopy is the gold standard method for distinguishing between primary and secondary Raynaud phenomenon, through the identification of a “scleroderma” pattern, and for quantifying differences in microvascular morphology⁸.

With the increasing use of nailfold capillaroscopy internationally, it is important to have consensus concerning methods of acquiring and analysing nailfold capillaries, as well as having clarity concerning what the terminology “abnormal” means. In order to be classified as having primary RP, a patient needs to fulfil the criterion of having a normal capillaroscopy, conversely to patients with secondary RP due to SSc who usually have a “scleroderma pattern” on capillaroscopy. Besides the “scleroderma patterns,” a variety of “non-scleroderma patterns” exists (i.e. stereotype “normal” or “non-specific abnormalities”), which can occur in healthy individuals or in CTDs other than SSc⁵.

The role of nailfold videocapillaroscopy

Detect microvascular damage in rheumatic diseases is essential⁸. Nailfold videocapillaroscopy (NVC) among a variety of imaging tools, is recognized as a first-line investigation for the early distinction of the primitive and secondary forms of Raynaud’s phenomenon (RP)^9,10. NVC allows to recognize the “scleroderma pattern” and to quantify the differences in microcirculatory morphology. Capillaroscopic studies have a predictive value on the evolution to a definite connective tissue disease (CTD) of subjects affected by RP¹¹. RP is the most common clinical feature of subjects with Interstitial Pneumonia with Autoimmune Features (IPAF) and recently was suggested that NVC can be useful in predicting a possible evolution of IPAF patients into a definite form of scleroderma spectrum disorders or antisynthetase syndrome¹². The recognition of vascular alterations at capillaroscopy is the key to a correct framing of the phenomenon. Vasculopathy can precede the other manifestations of systemic sclerosis by years, hence the importance of the early study of the microcirculation. RP can occurr twenty years before a systemic disease and this explains the importance of the follow-up of patients with this manifestation and the need to identify valid predictive factors. We still do not have clear risk indicators and predictors of transition of RP in a connective tissue disease⁴ and perhaps this also depends on a classification system that should be updated and which should probably be able to identify different subgroups corresponding to different clinical entities.

The shadows in the classification

In patients with Raynaud’s phenomenon, capillaroscopy is of significant practical value as it allows a reliable predictive assessment of the developmental risk of the disorder. However, to date, the variety of nomenclature for subjects affected by RP generates uncertainty in patient management and in the possibility of comparing studies². The capillaroscopic findings have a very broad range of normality and a significant presence of non specific microvascular abnormalities are reported also in patients with primary RP⁶. The presence of these vascular changes can make it difficult to differenziate primary and secondary RP⁵.

The transition of pRP to a secondary form is described in 12–20% of patients² and the combination of capillaroscopic abnormalities with immunological data represent an effective tool to predict the evolution towards a CTD¹³. People with primary RP can show non specific abnormalities as may happen in healthy individuals and to diagnose primary RP may be present only non specific abnormalities in the morphology, density or dimension of capillaries⁸. There are still some gray areas in the capillaroscopic diagnostics of RP and it is also for this reason that the search for new methodologies for the study of digital vasculopathy is progressing and is giving interesting results¹⁴.

NVC is the most used technique to study microvessels in daily clinical practice and it is therefore a topic of great interest to many. Probably we term primary RP a complex of several clinical conditions¹⁵. To diagnose a primary RP with the LeRoy and Medsger criteria we need “normal nailfold capillaries” so that a recent study, but it is not the first nor the only one, introduced a third category of of RP: suspected secondary RP, the group of patients with capillaroscopic and or serological abnormalities but without any clinical finding of a CTD^6,11. There is a temporal inconsistency between the classification criteria of the RP, the latest standardization of NVC and the Delphi international consensus for data reporting¹¹ that distinguishes these capillaroscopic pictures: normal, scleroderma (early, active and late) and non-specific anomalies. The classification among the primitive forms remains quite equivocal when we detect non-specific capillaroscopic anomalies in a RP. In fact, as already mentioned, it is very common to find nonspecific capillaroscopic anomalies in the absence of immunological alterations and/or clinical manifestations of diseases, in patients who undergo capillaroscopy for RP. Regular follow-up of patients with RP is of utmost importance as RP may predate systemic illness up to two decades.¹ Considering that a proportion of pRP evolves into secondary, does the presence of non-specific capillaroscopic anomalies play a prognostic role? Patients with RP may show non-significant or minimal microvascular changes before development of scleroderma pattern and/or transition to secondary RP, but it should also be considered that some non specific capillary abnormalities may occur in healthy subjects¹⁶.

Sharing the experience of many colleagues in their daily activity, in our clinic we encounter a large group of patients who for the sole finding of nonspecific capillaroscopic anomalies doubtfully enter the group of primitive RP. In our experience, we found on the total number of NVC performed, about 2/3 of secondary RP, the remaining 1/3 about 60% primary RP and 40% with non specific abnormalities. Can we define these latter: primary RP with capillaroscopic anomalies? Often the different authors identify capillaroscopic pictures that do not rank exactly among these recognized. For example, the term scleroderma-like pattern has been used to indicate a mixture of alterations in the microcirculation that do not properly fall into the three categories of the scleroderma pattern¹¹.

Hirschl et al. identified a suspected secondary RP when findings in an ongoing screening process, suggest a probable underlying disease³.

Similarly, Ingegnoli et al. refer to suspected secondary RP in RP associated with abnormal capillaroscopy and/or ANA positivity with physical findings or symptoms suggestive of secondary causes but not fulfilling criteria for a specific connective tissue disease². In this context it is also important to underline that to study the structure and function of the finger microvasculature in patients with RP, different diagnostic imaging techniques are available. Among these, videocapillaroscopy, dermoscopy, stereomicroscopy, digital USB microscopy are four different nailfold capillaroscopy methods. Then, four laser Doppler methods are available: laser Doppler flowmetry, imaging, anemometry/velocimetry and laser speckle contrast analysis and still thermographic imaging and upper limb arterial Doppler ultrasound. However, techniques other than capillaroscopy are currently little used and confined to specialist centers¹⁷. Furthermore, emerging, new diagnostic techniques may help to reliably discriminate between primary and secondary Raynaud’s phenomenon¹⁸. However some shadows remain in the classification of RP and perhaps only two categories are not sufficient to define such a varied syndrome.

Conclusions and future directions

In everyday practice, we need to know the clinical relevance of the RP because on it depends the management. We want to relaunch the debate on the classification of the RP because it is likely that what we identify today as the pRP collects different clinical entities¹⁵. Prospective studies and a broad consensus are needed to redefine and possibly broaden the current classification of this disorder, to have greater diagnostic clarity and homogeneity and to be able to identify subgroups with different evolutionary characteristics. Longitudinal patient assessment is critical for understanding suspected secondary RP and the time frame for such assessment should be defined.

In conclusion, we believe that a better understanding of how to discriminate the different forms of RP and their possible evolution it is urgent and can no longer be postponed.

Transparency

Declaration of funding

This paper was not funded.

Declaration of financial/other relationships

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

All Authors contributed equally to the work

Acknowledgements

None reported.