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INTRODUCTION

 — Sjögren's syndrome (SS) is a chronic inflammatory disorder characterized by diminished lacrimal (tear) and salivary (spit) gland function and associated with lymphocytic infiltration of exocrine glands, especially the lacrimal and salivary glands.

So, the main problem with Sjogren’s syndrome is invasion of glands that secrete tears and saliva into eyes and mouth by white blood cells that eventually can destroy these glands.

 In addition to causing dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia), SS can affect extraglandular organ systems including

• skin
• lung
• heart
• kidney 
• neural 
• hematopoietic systems.

Definition

Sjögren syndrome (SS) is a chronic autoimmune disorder that targets exocrine glands. It is characterized by lymphocytic and plasma cell infiltration and destruction of salivary, lacrimal, and parotid glands, resulting predominantly in dry eyes and dry mouth, but it can affect other organ systems as well.[2]

Primary and secondary forms

Primary 

Dry mouth (xerostomia) and dry eyes (xerophthalmia) develop as isolated entities. Is immunogenetically associated with HLA-DRB1∗0301 and DRB1∗1501 and serologically associated with antibodies to Ro/SS-A and La/SS-B.

Secondary: Associated with other autoimmune connective tissue diseases. The immunogenetic and serologic findings are usually those of the accompanying disease (e.g., HLA-DR4 if associated with RA).

Secondary

Secondary SS is also common and can affect:

• up to 19% of patients with systemic lupus erythematosus (SLE)
• 26% to 31% of rheumatoid arthritis (RA) and scleroderma patients

SCIENCE

The salivary glands of patients with primary Sjogren’s syndrome (pSS) are infiltrated by a range of immune cells, mainly CD4 and CD8 T-cells, B-cells, and to a lesser extent dendritic cells (DCs), monocytes/macrophages and NK-cells. A complex interplay between these cells and their effector molecules results in chronic inflammation with B cell hyperactivity, auto-antibody production and ultimately formation of ectopic germinal centers.[4]

Incidence

4 per 100,000; of these cases, 70% had primary SS.

PREVALENCE

Prevalence is 0.2% to 2.7% of population.[5] However, some studies which screen for symptoms of SjS and confirm with biopsy, reveal a much higher prevalence.

Predominant Sex

Female:male ratio is approximately 10:1.[6]

EXTRAGLANDULAR MANIFESTATIONS

Overview/spectrum

Many organs other than the exocrine glands may be affected in patients with Sjögren's syndrome (SS); these include

• skin
• Joints
• Lungs
• Heart
• gastrointestinal tract
• pancreas
• Liver
• nephrology/Urogenital
• Kidneys
• Bladder
• gynecologic system
• Nervous
• peripheral nervous system (PNS)
• central nervous system (CNS)
• hematologic abnormalities
• lymphoproliferative disorders
• . Vascular disease
• cutaneous vasculitis
• Raynaud phenomenon
• Some extraglandular manifestations result from SS itself, while others result from comorbid rheumatic or other autoimmune disease. Examples of the latter include
  • autoimmune thyroid disorders
  • neuromyelitis optica
  • celiac disease

The relatively common overlap of SS with other autoimmune diseases may confound the interpretation of its extraglandular manifestations, since some organ involvement may not be unique to SS but instead reflects overlap with another autoimmune disorder that may be fully or only partially expressed. In addition, the presence of an associated rheumatic disease may increase the risk of lymphoma development in SS. In some cases (eg, interstitial cystitis, psychiatric symptoms), it is unclear whether abnormalities are related to the SS itself or an associated but separate condition. However, the presence of relatively disease-specific autoantibodies in patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), myositis, and systemic sclerosis (SSc, scleroderma) may help in making these distinctions, particularly when these antibodies are found in SS patients with overlap features of another systemic rheumatic disease.[7]

Question: Do Sjogren's extraglandular manifestations occur in patients with negative serology?

Pulmonary

Respiratory complications of SS include

• airway mucosal dryness (also known as xerotrachea)
• interstitial lung diseases (ILDs)
• non-Hodgkin lymphoma
• pleural thickening or effusion
• thromboembolic disease or pulmonary hypertension (rare)

Evidence of small airway dysfunction is often found in asymptomatic patients with normal radiologic studies. In symptomatic patients, NSIP appears to be the predominant type of lung involvement. The diagnosis can often be made on the basis of clinical presentation, pulmonary function tests (PFTs), and abnormal chest CT findings. PFTs in patients with NSIP show a restrictive pattern with reduced diffusion capacity of lung carbon monoxide (DLCO). Chest CT scans reveal ground-glass opacities and a reticular nodular pattern. Bronchoalveolar lavage (BAL), which is not usually required for diagnosis, shows evidence of alveolar inflammation, with elevated neutrophil or lymphocyte counts, or both.

CT findings of NSIP[8]

Ground glass opacities

Reticular nodular pattern

CT findings of LIP

Thin walled cysts

Interlobular septal thickening

Bronchovascular bundle thickening

CT findings of UIP

lower lobe fibrosis

honeycombing

traction bronchiectasis

LIP, a subset of NSIP, is also associated with a restrictive pattern on PFTs. Chest CT findings are ground-glass opacities and thin-walled cysts, with centrilobular nodules, interlobular septal thickening, and bronchovascular bundle thickening. Microscopically, the lung biopsy from patients with LIP shows a diffuse interstitial infiltrate composed of lymphocytes, plasma cells, and histiocytes that expand the interlobular and alveolar spaces.

ble long-lasting features related to damage and renal involvement not related to the disease. If biopsy has been performed, please rate activity based on histologic features first.

toms and objective measures of dryness and corneal epithelial findings three months following discontinuation of therapy; a small series of 21 patients showing statistically nonsignificant benefit in dry eye findings but significant benefit for dry mouth; and a randomized two-year crossover trial involving only 19 patients that failed to demonstrate benefit in ocular symptoms or findings, despite some improvement in signs of inflammation including acute phase reactants and hyperglobulinemia. In a randomized trial of HCQ in 120 patients, patient-reported dryness symptoms (assessed by a visual analog scale) and Schirmer test results did not show improvement from baseline when compared with placebo after only 24 weeks of treatment.[15]

Respiratory complications of SS include

• airway mucosal dryness (also known as xerotrachea)
• interstitial lung diseases (ILDs)
• non-Hodgkin lymphoma
• pleural thickening or effusion
• thromboembolic disease or pulmonary hypertension (rare)

Evidence of small airway dysfunction is often found in asymptomatic patients with normal radiologic studies. In symptomatic patients, NSIP appears to be the predominant type of lung involvement. The diagnosis can often be made on the basis of clinical presentation, pulmonary function tests (PFTs), and abnormal chest CT findings. PFTs in patients with NSIP show a restrictive pattern with reduced diffusion capacity of lung carbon monoxide (DLCO). Chest CT scans reveal ground-glass opacities and a reticular nodular pattern. Bronchoalveolar lavage (BAL), which is not usually required for diagnosis, shows evidence of alveolar inflammation, with elevated neutrophil or lymphocyte counts, or both.

CT findings of NSIP[8]

• Ground glass opacities
• Reticular nodular pattern

CT findings of LIP

• Thin walled cysts
• Interlobular septal thickening
• Bronchovascular bundle thickening

CT findings of UIP

• lower lobe fibrosis
• honeycombing
• traction bronchiectasis

LIP, a subset of NSIP, is also associated with a restrictive pattern on PFTs. Chest CT findings are ground-glass opacities and thin-walled cysts, with centrilobular nodules, interlobular septal thickening, and bronchovascular bundle thickening. Microscopically, the lung biopsy from patients with LIP shows a diffuse interstitial infiltrate composed of lymphocytes, plasma cells, and histiocytes that expand the interlobular and alveolar spaces.

Management strategies for Sjögren-associated lung diseases are empiric, since no controlled studies have been performed, and should be made on a case-by-case basis. (De Carvalho. Interstitial lung disease associated with Sjögren's disease: Management and prognosis. Uptodate. ) 

Treatment of NSIP

• some patients with NSIP can improve or stabilize without therapy
• For symptomatic patients with SjD-associated NSIP who have worsening symptoms, PFTs, and radiographic abnormalities, we typically initiate treatment with oral glucocorticoids, although clinical trial data are lacking. Prednisone is usually started at a dose of 0.5 to 1 mg/kg ideal body weight up to a maximum of 60 mg per day [3,5]. This treatment is similar to that used for idiopathic NSIP and is supported by the results of reported case series, in which the specific type of ILD was not specified but was most likely NSIP. In a series of five patients with a confirmed diagnosis of NSIP, four improved with prednisone at this dose
• For patients who do not improve with systemic glucocorticoids or who improve, but develop side effects of therapy, or for those who need long-term use, immunosuppressive therapy is required. The following immunosuppressants may be used at this phase:
  • Azathioprine – Azathioprine has been used with limited success in SjD-associated NSIP. As an example, a nonrandomized study found that 11 patients treated with azathioprine showed a significant improvement in forced vital capacity at six months when compared to untreated patients (p <0.05). We typically follow the treatment approach outlined for using azathioprine in NSIP. 
  • Mycophenolate mofetil – Small case series suggest that mycophenolate mofetil (MMF) may be effective in connective tissue disease-associated ILD, although few data exist regarding SjD-ILD. In a series of 125 patients with connective tissue disease of which five had SjD, MMF was well-tolerated and had a glucocorticoid-sparing effect.
  • Refractory disease – Rituximab and other agents may be used in refractory SjD-ILD, in cases without response to glucocorticoids and to the above immunosuppressants.
    • Rituximab – The optimal role of rituximab in SjD-associated ILD is not completely known. A few case reports and case series have described improvement in SjD-ILD with rituximab treatment, but as the patients did not undergo lung biopsy, the exact histopathology is not known. In one report, a patient with refractory pulmonary opacities, pleural effusion, and other systemic manifestations of primary Sjögren's disease (pSjD) responded to rituximab treatment with clearing of the lung manifestations. In a review of the efficacy of rituximab in pSjD from a French Registry, among 78 pSjD patients, 9 had pSjD-related pulmonary involvement: one bronchiolar and eight ILD. Six of the eight ILD patients responded to the first cycle of rituximab, as did the patient with bronchial involvement. Larger clinical trials are needed before rituximab is considered for routine use in SjD-associated ILD.
    • Other agents
      • Cyclophosphamide and cyclosporine have been employed in limited numbers of patients with SjD-ILD that is resistant to glucocorticoids. These agents carry potential toxicity. 
      •  Nintedanib, an antifibrotic agent, may be reasonable for patients with progressive fibrotic phenotype.

LIP

UIP