a substantial subset of patients, a finding confirmed by others [15]. Multivariate analyses have confirmed that vasculitis in SjS patients is associated not only with lymphoma development but also with mortality. A subgroup of SjS patients who have systemic vasculitis coupled with peripheral neuropathy or glomerulonephritis is at increased risk of lymphomagenesis. These patients possess distinct serological characteristics (e.g., low C4 complement levels, the presence of cryoglobulins) that correlate independently with the development of lymphoproliferative disease and increased mortality [16].

12.11Treatment

Skin vasculitis characterized by mild, intermittent purpura may respond to local measures such as the avoidance of dependency (spending less time on one’s feet) during periods of active disease and support stockings. Hydroxychloroquine (200 mg twice daily) has not been studied formally in the setting of SjS-related vasculitis but appears to be a reasonable intervention for patients with recurrent mild disease. More severe cases typically respond initially at least to modest doses of glucocorticoids.

For patients whose disease cannot be controlled during prednisone tapers or for those whose disease is refractory to glucocorticoids alone, rituximab (anti-CD20) (1 g times two, separated by 15 days) is increasingly the agent to which clinicians turn. Palpable purpura and cryoglobulins disappear while complement levels return to normal after anti-CD20 therapy [17–19]. This approach has never been subjected to a randomized clinical trial in SjS, but data extrapolated from such trials in other patients support this approach [20].

If rituximab is not available, is ineffective, or is not tolerated well by the patient, then a variety of conventional immunomodulating therapies can be employed. These include azathioprine (up to 2 mg/kg/day) and methotrexate (up to 25 mg/week) [21, 22]. Cyclophosphamide, a potentially life-saving therapy if employed in a timely and prudent way, should be reserved for patients in whom rituximab is not an option and have vital organor life-threatening disease. The avoidance of cyclophosphamide whenever possible is particularly important because the use of this medication might contribute further to the potential for lymphomagenesis in SjS. Plasma exchange is seldom required but does appear to be effective in cases of overwhelming immune complex-mediated disease.

References

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2.Brito-Zeron P, Ramos-Casals M, Bove A, Sentis J, Font J. Predicting adverse outcomes in primary Sjögren’s syndrome: identification of prognostic factors. Rheumatology (Oxford). 2007;46(8): 1359–62.

3. Ramos-Casals M, Anaya JM, Garcia-Carrasco M, Rosas J, Bove A, Claver G, et al. Cutaneous vasculitis in primary Sjögren syndrome: classification and clinical significance of 52 patients. Medicine (Baltimore). 2004;83(2):96–106.

4. Tsokos M, Lazarou SA, Moutsopoulos HM. Vasculitis in primary Sjögren’s syndrome. Histologic classification and clinical presentation. Am J Clin Pathol. 1987;88(1):26–31.

5. Alexander E, Provost TT. Sjögren’s syndrome. Association of cutaneous vasculitis with central nervous system disease. Arch Dermatol. 1987;123(6):801–10.

6. Ferri C, Mascia MT. Cryoglobulinemic vasculitis. Curr Opin Rheumatol. 2006;18(1):54–63. 7. Stone JH, Nousari HC. “Essential” cutaneous vasculitis: what every rheumatologist should

know about vasculitis of the skin. Curr Opin Rheumatol. 2001;13:23–34.

8. Markusse HM, Schoonbrood M, Oudkerk M, Henzen-Logmans SC. Leucocytoclastic vasculitis as presenting feature of primary Sjögren’s syndrome. Clin Rheumatol. 1994;13(2):269–72.

9. Terrier B, Lacroix C, Guillevin L, Hatron PY, Dhote R, Maillot F, et al. Diagnostic and prognostic relevance of neuromuscular biopsy in primary Sjögren’s syndrome-related neuropathy. Arthritis Rheum. 2007;57(8):1520–9.

10. Collins MP, Mendell JR, Periquet MI, Sahenk Z, Amato AA, Gronseth GS, et al. Superficial peroneal nerve/peroneus brevis muscle biopsy in vasculitic neuropathy. Neurology. 2000;55(5): 636–43.

11. Ramos-Casals M, Solans R, Rosas J, Camps MT, Gil A, Del Pino-Montes J, et al. Primary Sjögren syndrome in Spain: clinical and immunologic expression in 1010 patients. Medicine (Baltimore). 2008;87(4):210–9.

12. Ioannidis JP, Moutsopoulos HM. Sjögren’s syndrome: too many associations, too limited evidence. The enigmatic example of CNS involvement. Semin Arthritis Rheum. 1999;29(1): 1–3.

13. Moutsopoulos HM, Balow JE, Lawley TJ, Stahl NI, Antonovych TT, Chused TM. Immune complex glomerulonephritis in sicca syndrome. Am J Med. 1978;64(6):955–60.

14. Ioannidis JP, Vassiliou VA, Moutsopoulos HM. Long-term risk of mortality and lymphoproliferative disease and predictive classification of primary Sjögren’s syndrome. Arthritis Rheum. 2002;46(3):741–7.

15. Theander E, Henriksson G, Ljungberg O, Mandl T, Manthorpe R, Jacobsson LT. Lymphoma and other malignancies in primary Sjögren’s syndrome: a cohort study on cancer incidence and lymphoma predictors. Ann Rheum Dis. 2006;65(6):796–803.

16. Voulgarelis M, Tzioufas AG. Pathogenetic mechanisms in the initiation and perpetuation of Sjögren’s syndrome. Nat Rev Rheumatol. 2010;6(9):529–37.

17. Quartuccio L, Fabris M, Salvin S, Maset M, De Marchi G, De Vita S. Controversies on rituximab therapy in Sjögren syndrome-associated lymphoproliferation. Int J Rheumatol. 2009; 2009:424935.

18. Gottenberg JE, Guillevin L, Lambotte O, Combe B, Allanore Y, Cantagrel A, et al. Tolerance and short term efficacy of rituximab in 43 patients with systemic autoimmune diseases. Ann Rheum Dis. 2005;64(6):913–20.

19. Voulgarelis M, Giannouli S, Anagnostou D, Tzioufas AG. Combined therapy with rituximab plus cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP) for Sjögren’s syndromeassociated B-cell aggressive non-Hodgkin’s lymphomas. Rheumatology (Oxford). 2004;43(8): 1050–3.

20. Stone JH, Merkel PA, Spiera R, et al. Rituximab compared with cyclophosphamide for remission induction in ANCA-associated vasculitis. N Engl J Med. 2010;363:221–32.

21. Jayne D, Rasmussen N, Andrassy K, Bacon P, Tervaert JW, Dadoniene J, et al. A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med. 2003;349(1):36–44.

22. Pagnoux C, Mahr A, Hamidou MA, Boffa JJ, Ruivard M, Ducroix JP, et al. Azathioprine or methotrexate maintenance for ANCA-associated vasculitis. N Engl J Med. 2008;359(26): 2790–803.

Chapter 13

Cardiovascular Involvement

George E. Tzelepis, Clio P. Mavragani, and Haralampos M. Moutsopoulos

13.1Introduction

Cardiac involvement occurs rarely in primary Sjögren’s syndrome (pSS), with the majority of descriptions coming primarily from single case reports or small patient series. In this respect, pSS differs from other systemic autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis, or systemic sclerosis, in which cardiac complications are quite common [1]. The rarity of clinically overt cardiac involvement in pSS should be kept in mind so that an exhaustive search for other autoimmune diseases, especially SLE with secondary Sjögren’s syndrome, or diseases of non-immune etiology, should be first considered in the differential diagnosis. The spectrum of cardiovascular complications described in pSS includes

G.E. Tzelepis (*) • C.P. Mavragani • H.M. Moutsopoulos

Department of Pathophysiology, University of Athens Medical School, Laiko University Hospital, Athens, Greece

complications in primary Sjögren’s syndrome

Myocarditis

Valvular abnormalities

Diastolic dysfunction

Atrioventricular block

Subclinical atheromatosis

Raynaud’s phenomenon

Pulmonary arterial hypertension

Autonomic cardiovascular dysfunction

pericarditis, myocarditis, valvular abnormalities, pulmonary arterial hypertension, left ventricular diastolic dysfunction, and autonomic dysfunction (Table 13.1).

13.2Pericarditis

Acute pericarditis in pSS has been described in few reports in the literature [2–4], with only one reporting an exudative effusion [3]. In the remaining reports, acute pericarditis with pericardial effusion was reported in patients with renal or other system involvement, or in patients with features of mixed connective tissue disease [5]. In nine patients with pSS and pulmonary hypertension reported by Launey et al. [6], pericardial effusion was found in three patients. In contrast, more frequent is the echocardiographic finding of small, silent pericardial effusions or evidence of previous pericardial inflammation [3, 7]. The frequency of these echocardiographic findings in several studies involving pSS patients with no cardiac manifestations ranges from 8% to 33% [3, 7–10]. In an echocardiographic study that included more than 100 patients with pSS [7], clinically silent pericardial effusions were found in 8% of patients and were associated with the presence of cryoglobulinemia and primary biliary cirrhosis. The etiology of pericardial inflammation is poorly understood when one considers that pSS does not cause serositis. Pericardial effusion due to cardiac lymphoma is extremely rare in pSS [11].

13.3Myocarditis

Autoimmune myocarditis is rare in pSS. Clinically, autoimmune myocarditis should be suspected in the setting of tachycardia out of proportion to fever, presence of a gallop rhythm, and suggestive ECG changes. In the English literature, there are few reports of pSS patients diagnosed with myocarditis. In all cases, patients presented with dyspnea, fever, increased inflammatory markers (erythrocyte sedimentation rate, C-reactive protein) and signs of dilated or restrictive cardiomyopathy [12–14]. In one patient, there was a unique uptake of gallium-67-labelled isotope by the myocardium [14]. In the absence of myocardial biopsies, the diagnosis of myocarditis was made by excluding other causes of cardiomyopathy, primarily of infectious etiology. Autoimmune myocarditis responded to augmented immunosuppression with glucocorticoids, cyclophosphamide, and azathioprine.