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Systematic review

Vol. 147 No. 3940 (2017)

Outcomes, rates and predictors of transition of isolated Raynaud’s phenomenon: a systematic review and meta-analysis

Cite this as:
Swiss Med Wkly. 2017;147:w14506



Published studies lack clear indicators of risk and predictors of transition from Raynaud’s phenomenon (Rp) to connective tissue diseases (CTDs). Therefore, we aimed to study the outcomes, rates and predictors of transition to CTDs in patients with Rp.


A sensitive search was developed in Medline and Embase. Observational studies reporting incidence and risk factors of transition from Rp to a CTD were analysed by two independent reviewers. The main outcome was the rate of transition to a CTD; the secondary outcome was the evaluation of predictors.


Of 856 articles captured, 7 selected studies met the inclusion criteria. A total of 4051 patients with primary Rp (pRp) and 1220 transitions to overt CTDs were recorded. The mean incidence rate of transition from pRp to a CTD was 2.65/100 person-years (standard error [SE] 1.2, 95% confidence interval [CI] 0.44–5.73). A total of 657 patients with suspected secondary Rp (ssRp) had antinuclear antibodies (ANAs) and/or capillary abnormalities; 188 transitions to CTDs were recorded, the mean incidence rate of transition from ssRp to CTD was 11.01/100 person-years (SE 4.0, 95% CI 0.11–22.12), and 135 transitions to systemic sclerosis (SSc), giving a mean incidence rate of transition from ssRp to SSc of 5.7/100 person-years (SE 2.19, 95% CI 1.02–13.19). With respect to patients with pRp, having ANAs without capillary abnormalities was associated with a risk for developing a CTD (pooled relative risks [RR] 7.63, 95% CI 2.87–20.29), whereas capillary abnormalities without ANAs resulted in a weaker risk of CTD transition (RR 5.53, 95% CI 1.45–21.06). The coexistence of ANAs and abnormal capillaroscopy significantly increased the risk of transition to CTD (RR 16.96, 95% CI 6.61–43.55).


A low incidence rate of transition from pRp to overt CTD was found. In spite of a possible study selection bias, ssRp appears to have a strong risk of transition to a CTD when there is concomitant presence of ANAs and abnormal capillaroscopy.


  1. Herrick AL. The pathogenesis, diagnosis and treatment of Raynaud phenomenon. Nat Rev Rheumatol. 2012;8(8):469–79. doi:.
  2. Maricq HR, Carpentier PH, Weinrich MC, Keil JE, Franco A, Drouet P, et al. Geographic variation in the prevalence of Raynaud’s phenomenon: Charleston, SC, USA, vs Tarentaise, Savoie, France. J Rheumatol. 1993;20(1):70–6.
  3. Carpentier PH, Satger B, Poensin D, Maricq HR. Incidence and natural history of Raynaud phenomenon: A long-term follow-up (14 years) of a random sample from the general population. J Vasc Surg. 2006;44(5):1023–8. doi:.
  4. Suter LG, Murabito JM, Felson DT, Fraenkel L. The incidence and natural history of Raynaud’s phenomenon in the community. Arthritis Rheum. 2005;52(4):1259–63. doi:.
  5. Hirschl M, Hirschl K, Lenz M, Katzenschlager R, Hutter HP, Kundi M. Transition from primary Raynaud’s phenomenon to secondary Raynaud’s phenomenon identified by diagnosis of an associated disease: results of ten years of prospective surveillance. Arthritis Rheum. 2006;54(6):1974–81. doi:.
  6. De Angelis R, Salaffi F, Grassi W. Raynaud’s phenomenon: prevalence in an Italian population sample. Clin Rheumatol. 2006;25(4):506–10. doi:.
  7. Silman A, Holligan S, Brennan P, Maddison P. Prevalence of symptoms of Raynaud’s phenomenon in general practice. BMJ. 1990;301(6752):590–2. doi:.
  8. Garner R, Kumari R, Lanyon P, Doherty M, Zhang W. Prevalence, risk factors and associations of primary Raynaud’s phenomenon: systematic review and meta-analysis of observational studies. BMJ Open. 2015;5(3):e006389. doi:.
  9. Spencer-Green G. Outcomes in primary Raynaud phenomenon: a meta-analysis of the frequency, rates, and predictors of transition to secondary diseases. Arch Intern Med. 1998;158(6):595–600. doi:.
  10. Wigley FM, Flavahan NA. Raynaud’s Phenomenon. N Engl J Med. 2016;375(6):556–65. doi:.
  11. De Angelis R, Del Medico P, Blasetti P, Cervini C. Raynaud’s phenomenon: clinical spectrum of 118 patients. Clin Rheumatol. 2003;22(4-5):279–84. doi:.
  12. Ingegnoli F, Boracchi P, Gualtierotti R, Biganzoli EM, Zeni S, Lubatti C, et al. Improving outcome prediction of systemic sclerosis from isolated Raynaud’s phenomenon: role of autoantibodies and nail-fold capillaroscopy. Rheumatology (Oxford). 2010;49(4):797–805. doi:.
  13. Valentini G, Marcoccia A, Cuomo G, Vettori S, Iudici M, Bondanini F, et al. Early systemic sclerosis: analysis of the disease course in patients with marker autoantibody and/or capillaroscopic positivity. Arthritis Care Res (Hoboken). 2014;66(10):1520–7. doi:.
  14. Koenig M, Joyal F, Fritzler MJ, Roussin A, Abrahamowicz M, Boire G, et al. Autoantibodies and microvascular damage are independent predictive factors for the progression of Raynaud’s phenomenon to systemic sclerosis: a twenty-year prospective study of 586 patients, with validation of proposed criteria for early systemic sclerosis. Arthritis Rheum. 2008;58(12):3902–12. doi:.
  15. Pavlov-Dolijanovic S, Damjanov NS, Stojanovic RM, Vujasinovic Stupar NZ, Stanisavljevic DM. Scleroderma pattern of nailfold capillary changes as predictive value for the development of a connective tissue disease: a follow-up study of 3,029 patients with primary Raynaud’s phenomenon. Rheumatol Int. 2012;32(10):3039–45. doi:.
  16. Bernero E, Sulli A, Ferrari G, Ravera F, Pizzorni C, Ruaro B, et al. Prospective capillaroscopy-based study on transition from primary to secondary Raynaud’s phenomenon: preliminary results. Reumatismo. 2013;65(4):186–91. doi:.
  17. Minier T, Guiducci S, Bellando-Randone S, Bruni C, Lepri G, Czirják L, et al.; EUSTAR co-workers; EUSTAR co-workers. Preliminary analysis of the very early diagnosis of systemic sclerosis (VEDOSS) EUSTAR multicentre study: evidence for puffy fingers as a pivotal sign for suspicion of systemic sclerosis. Ann Rheum Dis. 2014;73(12):2087–93. doi:.
  18. Shiboski SC, Shiboski CH, Criswell L, Baer A, Challacombe S, Lanfranchi H, et al.; Sjögren’s International Collaborative Clinical Alliance (SICCA) Research Groups. American College of Rheumatology classification criteria for Sjögren’s syndrome: a data-driven, expert consensus approach in the Sjögren’s International Collaborative Clinical Alliance cohort. Arthritis Care Res (Hoboken). 2012;64(4):475–87. doi:.
  19. Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA. 2000;283(15):2008–12. doi:.
  20. Wells G, Shea B, O’Connell J, Robertson J, Peterson V, Welch V, et al. (2013) The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analysis.
  21. Higgins JPT, Green SE. (2011) Cochrane handbook for systematic reviews of interventions version 5.1.0 [updated March 2011]. The Cochrane Collaboration.
  22. LeRoy EC, Medsger TA, Jr. Raynaud’s phenomenon: a proposal for classification. Clin Exp Rheumatol. 1992;10(5):485–8.
  23. Maricq HR, Harper FE, Khan MM, Tan EM, LeRoy EC. Microvascular abnormalities as possible predictors of disease subsets in Raynaud phenomenon and early connective tissue disease. Clin Exp Rheumatol. 1983;1(3):195–205.
  24. Cutolo M, Sulli A, Pizzorni C, Accardo S. Nailfold videocapillaroscopy assessment of microvascular damage in systemic sclerosis. J Rheumatol. 2000;27(1):155–60.
  25. Mosca M, Tani C, Vagnani S, Carli L, Bombardieri S. The diagnosis and classification of undifferentiated connective tissue diseases. J Autoimmun. 2014;48-49:50–2. doi:.
  26. Petri M, Orbai AM, Alarcón GS, Gordon C, Merrill JT, Fortin PR, et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum. 2012;64(8):2677–86. doi:.
  27. Pavlov-Dolijanovic S, Damjanov NS, Stojanovic RM, Vujasinovic Stupar NZ, Stanisavljevic DM. Scleroderma pattern of nailfold capillary changes as predictive value for the development of a connective tissue disease: a follow-up study of 3,029 patients with primary Raynaud’s phenomenon. Rheumatol Int. 2012;32(10):3039–45. doi:.
  28. LeRoy EC, Medsger TA, Jr. Criteria for the classification of early systemic sclerosis. J Rheumatol. 2001;28(7):1573–6.
  29. Valentini G, Cuomo G, Abignano G, Petrillo A, Vettori S, Capasso A, et al. Early systemic sclerosis: assessment of clinical and pre-clinical organ involvement in patients with different disease features. Rheumatology (Oxford). 2011;50(2):317–23. doi:.
  30. Ingegnoli F, Gualtierotti R. A systematic overview on the use and relevance of capillaroscopy in systemic sclerosis. Expert Rev Clin Immunol. 2013;9(11):1091–7. doi:.
  31. Bissell LA, Abignano G, Emery P, Del Galdo F, Buch MH. Absence of Scleroderma pattern at nail fold capillaroscopy valuable in the exclusion of Scleroderma in unselected patients with Raynaud’s Phenomenon. BMC Musculoskelet Disord. 2016;17(1):342. doi:.