204 |
C.P. Mavragani et al. |
involvement consisted mainly of ground-glass appearance or fine nodular pattern distributed in a predominantly peribronchial pattern. Both honeycombing and peripheral and lower lobe findings typical of fibrosing alveolitis were absent [13].
Parenchymal bullae and cysts are often seen in pSS patients. They are most likely related to a check-valve mechanism due to peribronchiolar mononuclear cell infiltration or amyloid deposition [50, 51]. In pSS patients with abnormal HRCT findings, the presence of bullae or cysts ranged from 20% to 30% [16, 19]. In some early reports, lung cysts coexisted with amyloidosis [41, 52, 53]. In a recent study, lung cysts were associated with anti-SSB/La seropositivity and occurrence of lymphoproliferative disease [9].
14.3.10Pulmonary Function Tests in pSS-Associated ILD
In pSS-associated ILD, a restrictive pattern with impairment of diffusing capacity for carbon monoxide (DLCO) is usually found [2, 6, 31, 35, 54]. Evidence of small airway dysfunction is also typically present [4–6]. Ito et al. reported that the vital capacity was lower in patients with an ILD pattern on HRCT than in patients with a different pattern (i.e., bronchiolar). In contrast, the FEV1/FVC ratio was lower in patients with a bronchiolar pattern [35]. HRCT and pulmonary function testing appear to be sensitive for detecting early lung involvement in asymptomatic patients with pSS, but abnormalities detected by HRCT do not necessarily connote significant functional impairment [19].
Although pulmonary function in most patients with pSS remains stable [20, 55], this is not always true for the subset of patients with ILD. In the largest study on pSSassociated ILD, Ito et al. reported that a low PaO2 at baseline and the presence of microscopic honeycombing on HRCT were associated with reduced survival [35].
14.4Pleuritis
Isolated pleuritis in pSS is very rare and is mainly linked to the underlying causes. Thus, patients with SS and pleuritis should be carefully investigated for the presence of a concomitant autoimmune disease, such as systemic lupus erythematosus or rheumatoid arthritis [10].
14.5Diagnosis and Management
The diagnostic approach to a pSS patient with respiratory complaints is, in general, similar to that used for patients with other connective tissue diseases and same symptoms. Following a detailed history and physical examination, pulmonary
14 Pulmonary Involvement |
205 |
function studies and HRCT testing are required in most patients. If HRCT features are compatible with NSIP or UIP, lung biopsy is not usually necessary, given the high correlation between HRCT and pathological findings for these two forms of ILD. In contrast, in the setting of non-specific CT patterns or suspicion for malignancy, open lung biopsy should be performed.
Because lung involvement can precede the onset of respiratory symptoms, we recommend complete pulmonary function tests and/or HRCT scanning at baseline. These studies may require repeating at various intervals depending upon the functional status and clinical manifestations of the individual patient.
Therapy of pSS-related pulmonary involvement is mainly empirical. Sinusitis in the context of upper respiratory involvement should be treated with antibiotics and, when indicated, surgical drainage. Dry cough related to “xerotrachea” can be alleviated in some cases with normal saline nebulizers and high doses of bromhexine. b-agonists and corticosteroids are of little benefit for patients with lower airway disease. For ILD, a rational approach is to establish therapies primarily upon evidence derived from the idiopathic interstitial pneumonitis literature. The standard treatment for patients with pSS and ILD (e.g., NSIP, COP) is prednisone at a dose of 1 mg/kg per day with subsequent tapering [56]. Only limited evidence supports the addition of a second immunosuppressive agent, but this is often suggested in severe cases. In a nonrandomized study of 20 patients, treatment with azathioprine led to substantial improvement in the FVC at 6 months compared to untreated patients [37]. Cyclophosphamide and cyclosporine have been also employed in small numbers of reported patients [57, 58]. B-cell depletion therapies appear to be a promising option, but definitive data from well controlled studies are needed.
References
1.Bucher U, Hadorn W. Chronic bronchitis: the significance of sputum examination for diagnosis and therapy. Med Klin. 1960;55:688–92.
2.Fairfax AJ, Haslam PL, Pavia D, Sheahan NF, Bateman JR, Agnew JE, et al. Pulmonary disorders associated with Sjögren’s syndrome. Q J Med. 1981;50:279–95.
3.Constantopoulos SH, Papadimitriou CS, Moutsopoulos HM. Respiratory manifestations in primary Sjögren’s syndrome. A clinical, functional, and histologic study. Chest. 1985;88:226–9.
4.Strimlan CV, Rosenow 3rd EC, Divertie MB, Harrison Jr EG. Pulmonary manifestations of Sjögren’s syndrome. Chest. 1976;70:354–61.
5.Oxholm P. Primary Sjögren’s syndrome–clinical and laboratory markers of disease activity. Semin Arthritis Rheum. 1992;22:114–26.
6.Vitali C, Tavoni A, Viegi G, Begliomini E, Agnesi A, Bombardieri S. Lung involvement in Sjögren’s syndrome: a comparison between patients with primary and with secondary syndrome. Ann Rheum Dis. 1985;44:455–61.
7.Segal I, Fink G, Machtey I, Gura V, Spitzer SA. Pulmonary function abnormalities in Sjögren’s syndrome and the sicca complex. Thorax. 1981;36:286–9.
8.Newball HH, Brahim SA. Chronic obstructive airway disease in patients with Sjögren’s syndrome. Am Rev Respir Dis. 1977;115:295–304.
9.Watanabe M, Naniwa T, Hara M, Arakawa T. Maeda T. Pulmonary manifestations in Sjögren’s syndrome: correlation analysis between chest computed tomographic findings and clinical subsets with poor prognosis in 80 patients. J Rheumatol. 2010;37:365–73.
206 |
C.P. Mavragani et al. |
10. Papiris SA, Tsonis IA, Moutsopoulos HM. Sjögren’s syndrome. Semin Respir Crit Care Med. 2007;28:459–71.
11. Vitali C, Viegi G, Tassoni S, Tavoni A, Paoletti P, Bibolotti E, et al. Lung function abnormalities in different connective tissue diseases. Clin Rheumatol. 1986;5:181–8.
12. Bloch KJ, Buchanan WW, Wohl MJ, Bunim JJ. Sjoegren’s syndrome. A clinical, pathological, and serological study of sixty-two cases. Medicine (Baltimore). 1965;44:187–231.
13. Papiris SA, Maniati M, Constantopoulos SH, Roussos C, Moutsopoulos HM, Skopouli FN. Lung involvement in primary Sjögren’s syndrome is mainly related to the small airway disease. Ann Rheum Dis. 1999;58:61–4.
14.Bariffi F, Pesci A, Bertorelli G, Manganelli P, Ambanelli U. Pulmonary involvement in Sjögren’s syndrome. Respiration. 1984;46:82–7.
15. Gardiner P, Ward C, Allison A, Ashcroft T, Simpson W, Walters H, et al. Pleuropulmonary abnormalities in primary Sjögren’s syndrome. J Rheumatol. 1993;20:831–7.
16. Koyama M, Johkoh T, Honda O, Mihara N, Kozuka T, Tomiyama N, et al. Pulmonary involvement in primary Sjögren’s syndrome: spectrum of pulmonary abnormalities and computed tomography findings in 60 patients. J Thorac Imaging. 2001;16:290–6.
17. Robinson DA, Meyer CF. Primary Sjögren’s syndrome associated with recurrent sinopulmonary infections and bronchiectasis. J Allergy Clin Immunol. 1994;94:263–4.
18. Franquet T, Gimenez A, Monill JM, Diaz C, Geli C. Primary Sjögren’s syndrome and associated lung disease: CT findings in 50 patients. AJR Am J Roentgenol. 1997;169:655–8.
19. Uffmann M, Kiener HP, Bankier AA, Baldt MM, Zontsich T, Herold CJ. Lung manifestation in asymptomatic patients with primary Sjögren syndrome: assessment with high resolution CT and pulmonary function tests. J Thorac Imaging. 2001;16:282–9.
20.Salaffi F, Manganelli P, Carotti M, Baldelli S, Blasetti P, Subiaco S, et al. A longitudinal study of pulmonary involvement in primary Sjögren’s syndrome: relationship between alveolitis and subsequent lung changes on high-resolution computed tomography. Br J Rheumatol. 1998;37:263–9.
21. Papiris SA, Saetta M, Turato G, La Corte R, Trevisani L, Mapp CE, et al. CD4-positive T-lymphocytes infiltrate the bronchial mucosa of patients with Sjögren’s syndrome. Am J Respir Crit Care Med. 1997;156:637–41.
22. Andoh Y, Shimura S, Sawai T, Sasaki H, Takishima T, Shirato K. Morphometric analysis of airways in Sjögren’s syndrome. Am Rev Respir Dis. 1993;148:1358–62.
23. Taouli B, Brauner MW, Mourey I, Lemouchi D, Grenier PA. Thin-section chest CT findings of primary Sjögren’s syndrome: correlation with pulmonary function. Eur Radiol. 2002;12:1504–11.
24. Franquet T, Diaz C, Domingo P, Gimenez A, Geli C. Air trapping in primary Sjögren syndrome: correlation of expiratory CT with pulmonary function tests. J Comput Assist Tomogr. 1999;23:169–73.
25. Gudbjornsson B, Hedenstrom H, Stalenheim G, Hallgren R. Bronchial hyperresponsiveness to methacholine in patients with primary Sjögren’s syndrome. Ann Rheum Dis. 1991;50:36–40.
26. Ludviksdottir D, Janson C, Hogman M, Gudbjornsson B, Bjornsson E, Valtysdottir S, et al. Increased nitric oxide in expired air in patients with Sjögren’s syndrome. BHR study group. Bronchial hyperresponsiveness. Eur Respir J. 1999;13:739–43.
27. Stalenheim G, Gudbjornsson B. Anti-inflammatory drugs do not alleviate bronchial hyperreactivity in Sjögren’s syndrome. Allergy. 1997;52:423–7.
28. Tzelepis GE, Toya SP, Moutsopoulos HM. Occult connective tissue diseases mimicking idiopathic interstitial pneumonias. Eur Respir J. 2008;31:11–20.
29. Strange C, Highland KB. Interstitial lung disease in the patient who has connective tissue disease. Clin Chest Med. 2004;25:549–59, vii.
30. Fischer A, Swigris JJ, du Bois RM, Groshong SD, Cool CD, Sahin H, et al. Minor salivary gland biopsy to detect primary Sjögren syndrome in patients with interstitial lung disease. Chest. 2009;136:1072–8.
31. Papathanasiou MP, Constantopoulos SH, Tsampoulas C, Drosos AA, Moutsopoulos HM. Reappraisal of respiratory abnormalities in primary and secondary Sjögren’s syndrome. A controlled study. Chest. 1986;90:370–4.
14 Pulmonary Involvement |
207 |
32. Yazisiz V, Arslan G, Ozbudak IH, Turker S, Erbasan F, Avci AB, et al. Lung involvement in patients with primary Sjögren’s syndrome: what are the predictors? Rheumatol Int. 2010;30: 1317–24.
33. Dalavanga YA, Constantopoulos SH, Galanopoulou V, Zerva L, Moutsopoulos HM. Alveolitis correlates with clinical pulmonary involvement in primary Sjögren’s syndrome. Chest. 1991;99:1394–7.
34. Shi JH, Liu HR, Xu WB, Feng RE, Zhang ZH, Tian XL, et al. Pulmonary manifestations of Sjögren’s syndrome. Respiration. 2009;78:377–86.
35. Ito I, Nagai S, Kitaichi M, Nicholson AG, Johkoh T, Noma S, et al. Pulmonary manifestations of primary Sjögren’s syndrome: a clinical, radiologic, and pathologic study. Am J Respir Crit Care Med. 2005;171:632–8.
36. Parambil JG, Myers JL, Lindell RM, Matteson EL, Ryu JH. Interstitial lung disease in primary Sjögren syndrome. Chest. 2006;130:1489–95.
37. Deheinzelin D, Capelozzi VL, Kairalla RA, Barbas Filho JV, Saldiva PH, de Carvalho CR. Interstitial lung disease in primary Sjögren’s syndrome. Clinical-pathological evaluation and response to treatment. Am J Respir Crit Care Med. 1996;154:794–9.
38. American Thoracic Society; European Respiratory Society International. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors and by the ERS Executive Committee, June 2001. Am J Respir Crit Care Med. 2001;165:277–304.
39. Travis WD, Hunninghake G, King Jr TE, Lynch DA, Colby TV, Galvin JR, et al. Idiopathic nonspecific interstitial pneumonia: report of an American Thoracic Society project. Am J Respir Crit Care Med. 2008;177:1338–47.
40. Yamadori I, Fujita J, Bandoh S, Tokuda M, Tanimoto Y, Kataoka M, et al. Nonspecific interstitial pneumonia as pulmonary involvement of primary Sjögren’s syndrome. Rheumatol Int. 2002;22:89–92.
41. Kobayashi H, Matsuoka R, Kitamura S, Tsunoda N, Saito K. Sjögren’s syndrome with multiple bullae and pulmonary nodular amyloidosis. Chest. 1988;94:438–40.
42. Yousem SA, Colby TV, Carrington CB. Follicular bronchitis/bronchiolitis. Hum Pathol. 1985;16:700–6.
43.Liebow AA, Carrington CB. Diffuse pulmonary lymphoreticular infiltrations associated with dysproteinemia. Med Clin North Am. 1973;57:809–43.
44. Parke AL. Pulmonary manifestations of primary Sjögren’s syndrome. Rheum Dis Clin North Am. 2008;34:907–20, viii.
45. Ioannou S, Toya SP, Tomos P, Tzelepis GE. Cryptogenic organizing pneumonia associated with primary Sjögren’s syndrome. Rheumatol Int. 2008;28:1053–5.
46. Cordier JF. Update on cryptogenic organising pneumonia (idiopathic bronchiolitis obliterans organising pneumonia). Swiss Med Wkly. 2002;132:588–91.
47.Myers JL, Colby TV. Pathologic manifestations of bronchiolitis, constrictive bronchiolitis, cryptogenic organizing pneumonia, and diffuse panbronchiolitis. Clin Chest Med. 1993;14:611–22.
48. Lynch DA. Lung disease related to collagen vascular disease. J Thorac Imaging. 2009;24: 299–309.
49. Matsuyama N, Ashizawa K, Okimoto T, Kadota J, Amano H, Hayashi K. Pulmonary lesions associated with Sjögren’s syndrome: radiographic and CT findings. Br J Radiol. 2003;76:880–4.
50. Sakamoto O, Saita N, Ando M, Kohrogi H, Suga M, Ando M. Two cases of Sjögren’s syndrome with multiple bullae. Intern Med. 2002;41:124–8.
51. Hubscher O, Re R, Iotti R. Cystic lung disease in Sjögren’s syndrome. J Rheumatol. 2002;29:2235–6.
52. Schlegel J, Kienast K, Storkel S, Ferlinz R. Primary pulmonary nodular amyloidosis and multiple emphysematous bullae in Sjögren syndrome. Pneumologie. 1992;46:634–7.
53. Bonner Jr H, Ennis RS, Geelhoed GW, Tarpley Jr TM. Lymphoid infiltration and amyloidosis of lung in Sjögren’s syndrome. Arch Pathol. 1973;95:42–4.
208 |
C.P. Mavragani et al. |
54.Kelly C, Gardiner P, Pal B, Griffiths I. Lung function in primary Sjögren’s syndrome: a cross sectional and longitudinal study. Thorax. 1991;46:180–3.
55.Davidson BK, Kelly CA, Griffiths ID. Ten year follow up of pulmonary function in patients
with primary Sjögren’s syndrome. Ann Rheum Dis. 2000;59:709–12.
56. Mavragani CP, Moutsopoulos NM, Moutsopoulos HM. The management of Sjögren’s syndrome. Nat Clin Pract Rheumatol. 2006;2:252–61.
57. Ogasawara H, Sekiya M, Murashima A, Hishikawa T, Tokano Y, Sekigawa I, et al. Very lowdose cyclosporin treatment of steroid-resistant interstitial pneumonitis associated with Sjögren’s syndrome. Clin Rheumatol. 1998;17:160–2.
58. Schnabel A, Reuter M, Gross WL. Intravenous pulse cyclophosphamide in the treatment of interstitial lung disease due to collagen vascular diseases. Arthritis Rheum. 1998;41: 1215–20.
59. Lohrmann C, Uhl M, Warnatz K, Ghanem N, Kotter E, Schaefer O, et al. High-resolution CT imaging of the lung for patients with primary Sjögren’s syndrome. Eur J Radiol. 2004;52: 137–43.
Chapter 15
Raynaud’s Phenomenon and Sjögren’s
Syndrome
Fredrick M. Wigley
Contents
15.1 |
Evaluation of the Sjögren’s Syndrome and Raynaud’s Phenomenon.................... |
214 |
|
15.2 |
Management of Raynaud’s Phenomenon ................................................................. |
215 |
|
|
15.2.1 |
Vasodilator Therapy ........................................................................................ |
216 |
|
15.2.2 |
Calcium Channel Blockers.............................................................................. |
216 |
|
15.2.3 |
Adrenergic Blockers........................................................................................ |
216 |
|
15.2.4 |
Nitrates ............................................................................................................ |
217 |
|
15.2.5 |
Phosphodiesterase Inhibitors........................................................................... |
217 |
|
15.2.6 |
Prostacyclins ................................................................................................... |
217 |
|
15.2.7 |
Other Agents ................................................................................................... |
218 |
15.3 |
Surgical Options.......................................................................................................... |
219 |
|
|
15.3.1 |
Sympathectomies ............................................................................................ |
219 |
|
15.3.2 Management of Critical Digital Ischemia....................................................... |
219 |
|
References.............................................................................................................................. |
. |
221 |
|
In 1862, Maurice Raynaud published his medical school thesis in which he argued that some people have transient digital ischemia when exposed to cold temperatures. It is now recognized that skin blood flow in humans provides an important mechanism for normal thermoregulation. In fact, a normal response to cold exposure is vasoconstriction of the cutaneous blood vessels, leading to a decrease in heat loss from the body and protection against hypothermia [1]. Human cutaneous vessels are innervated by the sympathetic adrenergic vasoconstrictor nerves that initiate thermoregulatory responses to cold [2]. This accounts, in part, for the clinical connection between emotional stress and vasoconstriction in the skin.
The term “Raynaud’s phenomenon” (RP) is now used to describe an exaggerated response in the skin thermoregulatory vessels to exposure to cold and/or emotional
F.M. Wigley
Johns Hopkins University, Department of Medicine, Division of Rheumatology, Baltimore, MD, USA
M. Ramos-Casals et al. (eds.), Sjögren’s Syndrome, |
209 |
DOI 10.1007/978-0-85729-947-5_15, © Springer-Verlag London Limited 2012 |
|
210
Table 15.1 Primary Raynaud’s phenomenon (Raynaud’s disease)
F.M. Wigley
•Vasospastic attacks precipitated by cold or emotional stress
•Symmetric attacks in both hands
•Absence of tissue necrosis or gangrene
•No history or physical findings suggestive of secondary cause
•Normal nailfold capillaries
•Normal erythrocyte sedimentation rate (ESR)
•Negative serologic findings
Source: Modified with permission from LeRoy et al. [7]
stress. These episodic events sometimes involve the superficial thermoregulatory vessels alone and present as cold skin that has a cyanotic, mottled appearance. In contrast, in other cases, the vasoconstriction is more intense and extends to involve the digital arteries, precapillary arterioles, and cutaneous thermoregulatory arteriovenous shunts. These more intense episodes, which represent true ischemia, present clinically with pallor of the skin. The white appearance of the digital skin results from the absence of blood flow to the skin and deeper tissues.
Raynaud’s phenomenon is characterized by episodic tissue ischemia that most commonly involves the digits of the hands and feet and sometimes affects the ears, nose, face, tongue, or nipples. Either dual (white/pallor [no flow] and blue/cyanosis [reduced flow]) or tricolor skin color changes (pallor, cyanosis, and erythema) can occur. When erythema is present, this color phase represents the recovery and rebound of blood flow to the skin. Patients with RP often experience numbness and paresthesias during the ischemic phase that involves digital vessel vasospasm. True pain is a symptom of deprived tissue nutrition and constitutes a warning of potential tissue injury. Uncomplicated ischemic events are typically over about 15 min after relief from the cold exposure and the occurrence of rewarming.
The index and middle fingers tend to be more sensitive to cold exposure while the thumb is often spared [3]. However, severe RP can involve all fingers with demarcation of the ischemia, leading to pallor from the fingertip to the proximal digit. A history of typical cold sensitivity with blue or white color changes is adequate to make a diagnosis of Raynaud’s phenomenon. Provocative testing with cold exposure (e.g., immersion of the hand in ice water) are important research tools but are not needed to confirm the diagnosis made by a good clinical history.
RP can be simply the manifestation of a normal (but exaggerated) response of the cutaneous thermoregulatory vessels and digital arteries to cold, stress, or trauma (primary Raynaud’s phenomenon). However, RP can also be associated with a disease state such as Sjögren’s syndrome (SS), in which case the digital ischemia is termed secondary RP. Primary RP is characterized by the absence of an underlying systemic disorder and represents a common symptom in the general population; it is observed in approximately 3–5% of individuals in the USA [4–6]. Criteria for making a diagnosis of primary RP include considerations of clinical features, physical examination, and laboratory testing (see Table 15.1) [7]. A frequent cause of secondary RP is an underlying systemic rheumatic disease. The highest prevalence of RP among patients with a rheumatic disease is observed in systemic sclerosis
15 Raynaud’s Phenomenon and Sjögren’s Syndrome |
211 |
(scleroderma) or in mixed connective tissue disease (MCTD), approaching 90% or greater in most studies [8–11]. It is estimated that approximately 21–44% of patients who have SLE [12, 13], up to 17% of patients who have rheumatoid arthritis [14], and approximately 10% of patients who have polymyositis suffer from Raynaud’s phenomenon. Furthermore, patients who have undifferentiated connective tissue disease (UCTD) demonstrate a high prevalence (~50%) of RP [15, 16].
The reported prevalence of RP in primary SS varies from 13% to 33% of patients [17–20]. The true prevalence of RP in primary Sjögren’s is not well defined because studies have employed varying definitions of primary SS. In addition, most studies have been retrospective and therefore have contained substantial potential for errors in the detection of true RP. Investigations also suggest that the prevalence of RP varies depending on regional ambient temperature of the study population [21]. In addition, RP often (reportedly 40–50% of the time) precedes the onset of sicca symptoms and may be an early manifestation of SS [18, 20]. A longitudinal study in northern England involving 100 patients with primary SS found 81% of patients had RP that did not associate with systemic disease or the presence or absence of anti-Ro/SSA antibodies [22]. Although both RP and primary SS are both more common among women, one survey of 521 females and 28 males found no statistical difference in the presence of RP between men and women with primary SS [23].
In the author’s experience, RP in SS varies in intensity. Most SS patients with RP have mild expressions of digital ischemia that are similar in severity to that of individuals with primary RP. In fact, given the common occurrence of both primary RP and SS, it is possible that some patients who have primary RP develop SS and that the two problems are independent of each other. Some investigators have reported that the clinical course of RP is generally benign and not associated with vascular sequelae such as digital ulcers or amputation [17, 20].
Although RP appeared to be a common manifestation (33%) in patients with primary SS in one study, the symptom of RP disappeared in 14% and decreased in severity in 30% over the course of follow-up [18]. Other studies indicate that vascular complications of RP in SS are unusual. In one series of 40 patients with primary SS and RP, there were no vascular complications and only 40% were treated with vasodilatory drugs [20]. These findings, confirmed by others [19], pose a striking contrast to patients with scleroderma, who tend to have severe RP and digital ulcers or vascular complications in approximately 30% of cases [24]. Thus, when one encounters a patient with SS and severe RP, especially with critical ischemia and painful attacks associated with tissue injury (ulcerations, gangrene, or amputation); a secondary disease process associated with SS must be considered (Table 15.2).
The significance of RP in a patient with SS is not fully defined but studies suggest that its presence may associate with unique clinical features and pathological risks. A large cohort study of 1,010 patients found that the subset of SS patients with antiRo/La antibodies had the highest frequency of RP, altered parotid scintigraphy, positive salivary gland biopsy, peripheral neuropathy, thrombocytopenia, and positive rheumatoid factor [25]. Although these single-center observations are interesting, they do not identify clinical associations that are consistent between published surveys. For example, a survey of 320 patients with primary SS reported that RP
212
Table 15.2 Secondary causes of Raynaud’s phenomenon
F.M. Wigley
•Immune: Autoimmune disease
•Trauma: Hand-arm vibration syndrome
•Mechanical: Thoracic outlet syndrome
•Proteins: Cryoglobulins; cryofibrinogens
•Neurogenic: Carpal tunnel syndrome
•Hormones: Hypothyroid
•Toxins/drugs/vasoconstrictors: smoking
•Vascular disease: Vasculitis, atherosclerosis
was present in 40 (13%) of patients [20]. Compared to patients without RP, those with RP showed a higher prevalence of articular involvement, cutaneous vasculitis, antinuclear antibodies, anti-Ro/SSA and anti-La/SSB patients. Kraus et al. suggested that patients with primary SS and RP are significantly more likely to have nonerosive arthritis, vasculitis, and pulmonary fibrosis compared to those without RP [19]. Skopouli suggested that patients with primary SS and RP develop glomerulonephritis, myositis, and peripheral neuropathy more often than patients without RP, but the differences did not achieve statistical significance [18]. Another study found that 36 of 108 patients with RP and primary SS were more likely to have leukopenia, thyroiditis, and low complement (C3) than primary SS patients without RP [26]. Foster et al. and Youinou et al. reported a higher frequency of arthritis among SS patients with RP and suggested that the symptom of RP was a marker for secondary SS [17, 27].
A survey of 402 patients with primary SS found that 20% had autoantibodies characteristic of another autoimmune disease (anti-DNA, anti-Sm, anti-RNP, antitopoisomerase, anticentromere, anti-Jo1, antineutrophil cytoplasmic antibodies, and anticardiolipin antibodies) [28]. RP was more frequent among the patients with one of these autoantibodies (28% vs 7%, p = 0.001), which are not typical for SS alone. A MEDLINE search for articles published between January 1966 and December 2005 that specifically analyzed the overlap between SS and other systemic autoimmune disease identified a list of diagnostic problems in patients with primary SS who had features considered typical of other diseases including arthritis, Raynaud’s phenomenon, cutaneous features, interstitial pulmonary disease, cytopenias, and autoantibodies [29]. It is important to recognize that RP and a variety of other clinical and immunological manifestations can be seen in patients who are considered to have a diagnosis of primary SS. These patients with clinical features that overlap with other rheumatic diseases make it challenging to associate some of these features as secondary to SS alone. For example, SS was identified in 26 of 283 systemic lupus erythematosus (SLE) patients who had a higher frequency of RP than those without SS; the SS syndrome preceded the diagnosis of SLE in 69%, again suggesting that the presence of RP in a patient with SS indicates an increased risk for another autoimmune disease [30]. Another example is the fact that antineutrophil cytoplasmic antibodies (ANCA) can be found in patients with primary SS and they associate with the presence of cutaneous vasculitis, peripheral neuropathy, and Raynaud’s phenomenon, features that can be seen in primary
15 Raynaud’s Phenomenon and Sjögren’s Syndrome |
213 |
vasculitis [31]. A recent survey to define the clinical characteristics of primary and secondary SS found that RP was more common in those with secondary SS (pSS 16% vs secondary SS 41%, p = 0.001) [32].
In the general population, the presence of anticentromere antibodies (ACA) in a patient presenting with RP is of value in predicting systemic disease or possible future development of distinct clinical manifestations, especially scleroderma [33, 34]. Gelber et al. compared 45 patients with primary SS with 33 patients with limited cutaneous scleroderma and found that 29% of the patients with primary SS had RP compared to 100% of the limited scleroderma patients [35]. An interesting finding pertained to the fact that 10 of 45 patients (22%) with primary SS and 18 of 33 (55%) with scleroderma had antibodies directed against centromere proteins. Although the CENP-positive patients with primary SS recognize predominantly CENP C alone, this pattern was very uncommon among CENP-positive patients with scleroderma. In contrast, dual recognition of CENP B and CENP C was a feature found exclusively in patients with limited scleroderma and was absent in those with primary SS [35].
Other surveys find a high frequency of RP among primary SS who have a positive test for ACA [25, 36–40]. This suggests that the presence RP associates with ACA in primary SS and identifies a unique subset of patients who are at risk for developing another rheumatic disease, especially scleroderma. In a study of patients with ACA, Miyawaki et al. found SS in 40 of 108 patients (37%) examined, including 10 with primary SS and 30 with secondary SS (27 with scleroderma and 3 with other diseases) [41]. Patients who have ACA and present with “primary” SS may develop scleroderma several years later [25, 39, 41]. Moreover, careful examination in prospective studies of SS patients with ACA often find subtle features of limited scleroderma [41], suggesting that retrospective surveys may overestimate the prevalence of primary SS in patients with ACA and RP and miss the presence of another disease process.
Other surveys support the idea that the presence of both ACA and RP identifies patients with primary SS who also have an associated overlap syndrome [36, 42]. For example, a recent survey of 212 patients with primary SS found 4.7% had ACA [36]. Patients with ACA and SS were found to have a greater frequency of RP, objective xerophthalmia, peripheral neuropathy, and evidence of another autoimmune disorder, such as biliary cirrhosis [36]. SS is known to complicate the course of patients with primary biliary cirrhosis and CREST syndrome [43, 44]. However, Caramaschi et al. found that while the ACA positive SS patients were more likely to have RP, they were less likely to have leucopenia, polyclonal hypergammaglobulinemia, rheumatoid factor, and antibodies to the SSA/Ro antigen [39]. The takehome message from these studies is that a SS patient who presents with RP should be examined carefully for clinical and serological evidence of another rheumatic disease. In addition, the presence of ACA should make one think of scleroderma and its associated features.
RP is associated with migraine headaches in the general population [45]. An association between migraine headaches and RP in patients with primary SS has been suggested but not confirmed [46, 47]. Pulmonary arterial hypertension (PAH), a