Sjogren Syndrome

Resources

Sjogren's quarterly Fall 2022
Sjogren's fact sheet

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.

Glands are organs that make substances

^[1]

Endocrine versus exocrine

Endocrine glands make hormones. They release substances directly into the bloodstream.
Exocrine glands release substances into a duct or opening to the inside or outside of the body.

Endo = within

Exo = outside

Exodus was the second book of the Bible and about the leaving of the Israelites from Egypt.

So, in summary, 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 the skin, lung, heart, kidney, neural, and 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 have been described:

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 conne^[3]ctive tissue diseases. The immunogenetic and serologic findings are usually those of the accompanying disease (e.g., HLA-DR4 if associated with RA).

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.

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

Predominant Sex

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

DIAGNOSIS

Criteria for classification were devised in 2012 by ACR and 2016 by EULAR and are useful paradigms for diagnosis of pSS.

ACR (2012) proposed classification criteria for Sjögren’s syndrome.

The classification of Sjögren’s syndrome, which applies to individuals with signs/symptoms that may be suggestive of SS, will be met in patients who have at least two of the following three objective features:

Positive serum anti-SSA (Ro) and/or anti-SSB (La) or [positive rheumatoid factor and ANA ≥ 1:320]
Labial salivary gland biopsy exhibiting focal lymphocytic sialadenitis2 with a focus score ≥ 1 focus / 4 mm2
Keratoconjunctivitis sicca with ocular staining score ≥ 3 (assuming that individual is not currently using daily eye drops for glaucoma, and has not had corneal surgery or cosmetic eyelid surgery in the last 5 years)

Exclusions

Prior diagnosis of any of the following conditions would exclude participation in Sjögren’s syndrome studies or therapeutic trials because of overlapping clinical features or interference with criteria tests:

History of head and neck radiation treatment
Hepatitis C infection
Acquired Immunodeficiency Syndrome
Sarcoidosis
Amyloidosis
Graft versus host disease
IgG4-related disease

Ocular staining score

Ocular staining score (OSS) is the sum of a 0–6 score for fluorescein staining of the cornea and a 0–3 score for lissamine green staining of both nasal and temporal bulbar conjunctivae, yielding a total score ranging from 0 to 12. Alternative established tests for dryness used in prior criteria are tear break-up time (TBUT) and unanesthetized Schirmer test.

Summary of diagnostic evaluation

These are tests used to diagnose Sjogren’s:

Schirmer tear test
Saxon saliva test
Labial salivary gland biopsy
Ocular staining score

Fluorescein staining of the cornea
Lissamine green staining of conjunctivae

Tear break up time
SSA
SSB
ANA (<=1 to 320)
RF
Exclude other causes of dry eyes and dry mouth

Diagnosis can be confidently made in patients with Sicca symptoms and diagnostic criteria.

From Top Tips: Sicca Syndrome by Aisling MacComac Guidelines in Practice UK

Sicca syndrome = problematic symptoms of dry eyes and dry mouth (xerostomia). Symptoms are reported by up to 20% of the general population, increasing to 50% in older people as a result of rising polypharmacy and co-morbidity. In 2019, 480,000 prescriptions were issued in England for dry mouth and 4.4 million for dry eyes, at a cost to the NHS of £3.4 million and £22 million, respectively.

Classification criteria include:

ACR (2012)

At least two of the following three objective features:

Positive serology

serum anti-SSA (Ro) and/or anti-SSB (La) or
positive rheumatoid factor and ANA ≥ 1:320

Labial salivary gland biopsy exhibiting focal lymphocytic sialadenitis
Ocular staining score ≥ 3

Eular (2016)

Sum of five items ≥4 meet the criteria for primary SS

anti-SSA/Ro antibody positivity (3 points)
focal lymphocytic sialadenitis with a focus score of ≥1 foci/4 mm2 (3 points);
an abnormal Ocular Staining Score of ≥5 (or van Bijsterveld score of ≥4) (1 point)
a Schirmer's test result of ≤5 mm/5 min (1 point)
an unstimulated salivary flow rate of ≤0.1 mL/min (1 point)

So, in your office you could make a diagnosis of SjS with sicca + SSA + Schirmer or Saxon test.Without SSA, you would have to refer to an ophthalmologist for ocular staining but this would only afford one point so still fall short of diagnosis without SSA or a salivary gland biopsy. If SSA is negative, you could move to ACR criteria and substitute high ANA and positive RF for SSA, then refer to eye doctor for staining.

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.

Disease activity index

Two disease activity indices for use as SS endpoints are ESSPRI and ESSDAI.

EULAR Sjögren's syndrome disease activity index (ESSDAI)^[9]

Domain	Exclusion(s) and notes	Activity level	Description
Constitutional	Exclusion of fever of infectious origin and voluntary weight loss	No = 0	Absence of the following symptoms
		Low = 3	Mild or intermittent fever (37.5 to 38.5°C)/night sweats and/or involuntary weight loss of 5 to 10% of body weight
		Moderate = 6	Fever (>38.5°C)/night sweats and/or involuntary weight loss of >10% of body weight
Lymphadenopathy and lymphoma	Exclusion of infection	No = 0	Absence of the following features
		Low = 4	Lymphadenopathy ≥1 cm in any nodal region or ≥2 cm in inguinal region
		Moderate = 8	Lymphadenopathy ≥2 cm in any nodal region or ≥3 cm in inguinal region, and/ or splenomegaly (clinically palpable or assessed by imaging)
		High = 12	Current malignant B-cell proliferative disorder
Glandular	Exclusion of stone or infection	No = 0
		Low = 2
		Moderate = 4
Articular	Exclusion of osteoarthritis	No = 0
		Low = 2
		Moderate = 4	1 to 5 (of 28 total count) synovitis
		High = 6
Cutaneous	Rate as "no activity" stable long-lasting features related to damage	No = 0
		Low = 3
		Moderate = 6
		High = 9
Pulmonary	Rate as "no activity" stable long-lasting features related to damage or respiratory involvement not related to the disease (tobacco use, etc)	No = 0	Absence of currently active pulmonary involvement
		Low = 5	Persistent cough due to bronchial involvement with no radiographic abnormalities on radiography or Radiologic or HRCT evidence of interstitial lung disease with no breathlessness and normal lung function test
		Moderate = 10	Moderately active pulmonary involvement, such as interstitial lung disease shown by HRCT with shortness of breath on exercise (NYHA II) or abnormal lung function tests restricted to DLCO <70% and ≥40% or FVC <80% and ≥60%
		High = 15	Highly active pulmonary involvement, such as interstitial lung disease shown by HRCT with shortness of breath at rest (NYHA III, IV) or with abnormal lung function tests: DLCO<40% or FVC <60%
Renal	Rate as "no activity" stable 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.	No = 0
		Low = 5
		Moderate = 10
		High = 15
Muscular	Exclusion of weakness due to glucocorticoids	No = 0	Absence of currently active muscular involvement
		Low = 6	Mild active myositis shown by abnormal EMG, MRI, or biopsy with no weakness and creatine kinase (CK ≥ULN and ≤2x ULN)
		Moderate = 12
		High = 18
PNS	Rate as "no activity" stable long-lasting features related to damage or PNS involvement not related to the disease	No = 0
		Low = 5
		Moderate = 10
		High = 15



CNS	Rate as "no activity" stable long-lasting features related to damage or CNS involvement not related to the disease	No = 0
		Moderate= 10
		High = 15
Hematologic	For anemia, neutropenia, and thrombocytopenia, only autoimmune cytopenia must be considered Exclusion of vitamin or iron deficiency, drug-induced cytopenia	No = 0
		Low = 2
		Moderate = 4
		High = 6	Cytopenia of autoimmune origin with neutropenia (ANC <500/mm3) and/or anemia (hemoglobin <8 g/dL) and/or thrombocytopenia (platelets <50,000/mm3)
Biologic		No = 0	Absence of any of the following biologic features
		Low = 1	Clonal component and/or hypocomplementemia (low C4 or C3 or CH50) and/or hypergammaglobulinemia or high IgG level between 16 and 20 g/L
		Moderate = 2	Presence of cryoglobulinemia and/or hypergammaglobulinemia or high IgG level >20 g/L, and/or recent-onset hypogammaglobulinemia or recent decrease of IgG level (<5 g/L)

Treatment of moderate to severe Sicca

No consensus guideline exists for the management of sicca syndrome in primary care. ^[10]

Systemic antiinflammatory and immunosuppressive therapy

— Generally, systemic antiinflammatory or immunosuppressive therapies for the treatment of sicca symptoms alone, such as dry eye and mouth, is not done. Several of these agents, alone or in combination, were efficacious in one small case series of four patients with severe keratitis in the context of active systemic rheumatic disease, including Sjögren's syndrome, rheumatoid arthritis, and systemic lupus erythematosus.^[11]^[12]

Hydroxychloroquine and Leflunomide

( from E VanDerHeijden. Additive immunosuppressive effect of leflunomide and hydroxychloroquine supports rationale for combination therapy for Sjögren’s syndrome)

Peripheral blood mononuclear cells (PBMCs) of six healthy individuals and nine pSS patients were stimulated with superantigen and TLR9 agonist to mimic the hallmark features. LEF, HCQ and their combinations were tested at clinically observed concentrations and proliferation, cytokine and immunoglobulin production were measured.

Results: TCR/TLR9 activation of PBMCs induced strong proliferation of T and B-cells and production of CXCL13, IFN-α, IFN-γ, IgG and IgM. LEF dose-dependently inhibited all measured parameters, where HCQ potently and dose-dependently decreased B cell proliferation, CXCL13, IFN-α, IgG and IgM production. At different concentration combinations, HCQ and LEF inhibited several immune hallmark features more potently than each single compound.

Conclusion: A combination of LEF and HCQ at clinically applicable concentrations additively inhibits immune activation, supporting a potential implementation of this drug combination in pSS treatment.^[13]

In 2016, 21 patients with Sjs were randomized to Lef Hxc and 8 placebo.^[14]

Hydroxychloroquine

Hydroxychloroquine (HCQ) has shown mixed results. These include a study showing improvement in symptoms and objective measures of dryness and corneal surface findings in 50 to 60 percent of 40 patients who received HCQ (6 to 7 mg/kg/day) for 24 to 48 months; a study of 32 patients treated for at least 48 months with HCQ, who were found to have worsening in dry eye symptoms 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]

Hydroxychloroquine JOQUER Trial

(From Gottenberg JE et al. Effects of hydroxychloroquine on symptomatic improvement in primary Sjögren syndrome: the JOQUER randomized clinical trial.JAMA. 2014 Jul;312(3):249-58. )

Hydroxychloroquine is the most frequently prescribed immunosuppressant for Sjogren’s syndrome yet evidence regarding its efficacy is limited. OBJECTIVE of this trial was to evaluate the efficacy of hydroxychloroquine for the main symptoms of primary Sjögren syndrome: dryness, pain, and fatigue.

DESIGN, SETTING, AND PARTICIPANTS

From April 2008 to May 2011, 120 patients with primary Sjögren syndrome according to American-European Consensus Group Criteria from 15 university hospitals in France were randomized in a double-blind, parallel-group, placebo-controlled trial. Participants were assessed at baseline, week 12, week 24 (primary outcome),and week 48. The last follow-up date for the last patient was May 15, 2012.

INTERVENTIONS

Patients were randomized (1:1) to receive hydroxychloroquine (400 mg/d) or placebo until week 24. All patients were prescribed hydroxychloroquine between weeks 24 and 48.

MAIN OUTCOMES AND MEASURES

The primary end point was the proportion of patients with a 30% or greater reduction between weeks 0 and 24 in scores on 2 of 3 numeric analog scales (from 0 [best]to 10 [worst]) evaluating dryness, pain, and fatigue.

RESULTS

At 24 weeks, the proportion of patients meeting the primary end point was 17.9% (10/56) in the hydroxychloroquine group and 17.2% (11/64) in the placebo group (odds ratio, 1.01; 95% CI, 0.37-2.78; P = .98). Between weeks 0 and 24, the mean (SD) numeric analog scale score for dryness changed from 6.38 (2.14) to 5.85 (2.57) in the placebo group and 6.53 (1.97) to 6.22 (1.87) in the hydroxychloroquine group. The mean (SD) numeric analog scale score for pain changed from 4.92 (2.94) to 5.08 (2.48) in the placebo group and 5.09 (3.06) to 4.59 (2.90) in the hydroxychloroquine group. The mean (SD) numeric analog scale for fatigue changed from 6.26 (2.27) to 5.72 (2.38) in the placebo group and 6.00 (2.52) to 5.94 (2.40) in the hydroxychloroquine group. All but 1 patient in the hydroxychloroquine group had detectable blood levels of the drug. Hydroxychloroquine had no efficacy in patients with anti-SSA autoantibodies, high IgG levels, or systemic involvement. During the first 24 weeks, there were 2 serious adverse events in the hydroxychloroquine group and 3 in the placebo group; in the last 24 weeks, there were 3 serious adverse events in the hydroxychloroquine group and 4 in the placebo group.

CONCLUSIONS AND RELEVANCE

Among patients with primary Sjögren syndrome, the use of hydroxychloroquine compared with placebo did not improve symptoms during 24 weeks of treatment. Further studies are needed to evaluate longer-term outcomes.^[16]

Rituximab

Rituximab, which has shown limited evidence of benefit for dry eye (or dry mouth), despite evidence of benefit for systemic and extraglandular manifestations of SS. Some benefit was suggested in a randomized trial involving 30 patients in only one of three measures of lacrimal gland function (corneal staining with lissamine green, but not Schirmer's testing or tear breakup time) and improvement in subjective scoring of ocular dryness compared with baseline values. In another randomized trial involving 17 patients, there was no significant change in glandular function six months after administration of rituximab, and there was no improvement in Schirmer's test scores or in the unstimulated salivary flow rate at that time point. In a prospective, two-center follow-up study of 41 patients with early active SS, Schirmer test results were improved at 120 weeks in the 19 who received rituximab treatments every 24 weeks, relative to the 22 who received conventional disease-modifying antirheumatic drug (DMARD) therapy. These findings need to be reproduced in a randomized trial, but they suggest that prolonged therapy with rituximab in early active disease is needed to realize meaningful clinical benefit.

Other medications that have been evaluated in patients with SS without objective evidence of benefit include systemic glucocorticoids, methotrexate, leflunomide, azathioprine , infliximab, etanercept, abatacept, mycophenolate, and belimumab.

Other therapies

Contact lens use — Large-diameter gas-permeable scleral contact lenses (PROSE) may be used in selected patients with severe dry eye. These lenses are completely supported by the sclera and have a fluid reservoir in the space between the posterior surface of the lens and the anterior surface of the cornea. They protect the ocular surface and provide continuous hydration of the ocular surface. The main indications for their use are improvement in visual acuity and protection of the ocular surface from the shearing forces of the eyelid on blink; they require a complex fitting process, and they are costly, which limit their availability.

Bandage contact lens use may result in symptomatic improvement; however, the risk of corneal infection is considerable.

Autologous serum tears — Several randomized trials and other studies have shown that a dilution of patient's serum (termed "autologous tears") may be useful in patients with refractory dry eye. Artificial tears prepared from umbilical cord serum have also been used in severely dry patients.

Topical NSAID drops — Topical nonsteroidal antiinflammatory drug (NSAID) drops should never be used in patients with SS-related dry eye due to potential risks such as corneal-scleral melts, perforation, and severe keratopathy.

Tarsorrhaphy — Tarsorrhaphy is a surgical procedure in which a part or all of the upper and lower eyelids are sutured together to protect the cornea. This procedure is mostly applicable to dry eye patients with nonhealing corneal epithelial defects.

Tests for Sjogren’s syndrome

ANA (IFA, DLO code 249, screen with reflex titer and pattern)
RF
SSA, SSB (Sjogren’s antibodies)

Billing

Sjogren’s ICD Codes Table from Clinical Key (https://www.clinicalkey.com/#!/content/derived_clinical_overview/76-s2.0-B9780323755702008419)

ICD-10CM CODES
M35.00	Sicca syndrome, unspecified
M35.01	Sicca syndrome with keratoconjunctivitis
M35.02	Sicca syndrome with lung involvement
M35.03	Sicca syndrome with myopathy
M35.04	Sicca syndrome with tubulo-interstitial nephropathy
M35.09	Sicca syndrome with other organ involvement

[1] https://www.cancer.gov/publications/dictionaries/cancer-terms/def/gland

[2] Sjögren Syndrome. CLINICAL OVERVIEW. by Elsevier, Inc. Released January 1, 2022.

[3] Sjögren Syndrome. CLINICAL OVERVIEW. by Elsevier, Inc. Released January 1, 2022.

[4] E VanDerHeijden et al. Additive immunosuppressive effect of leflunomide and hydroxychloroquine

supports rationale for combination therapy for Sjögren’s syndrome. EXPERT REVIEW OF CLINICAL IMMUNOLOGY 2019

[5] Sjögren Syndrome. CLINICAL OVERVIEW. by Elsevier, Inc. Released January 1, 2022.

[6] Ibid

[7] A Baer. Clinical manifestations of Sjögren's syndrome: Extraglandular disease. Uptodate.

[8] Ibid

[9] Seror R, Bowman SJ, Brito-Zeron P, et al. EULAR Sjögren's syndrome disease activity index (ESSDAI): A user guide. RMD Open 2015; 1e000022.

[10]A MacCormac. Top tips: Sicca Syndrome. 22 Dec 2020 Guidelines in Practice UK

[11] A Baer. Treatment of severe dry eyes in Sjogren’s syndrome. Uptodate.

[12] Ocul Immunol Inflamm. 2007 Mar-Apr;15(2):99-104. Systemic immunomodulatory therapy in severe dry eyes secondary to inflammation.

[13] E VanDerHeijden. Additive immunosuppressive effect of leflunomide and hydroxychloroquine supports rationale for combination therapy for Sjögren’s syndrome

[14] E VanDer Heijden et al. Leflunomide-Hydroxychloroqiine comiantion therapy in patient siwht primary Sjoren’s DSysn (RepurpSS-I) a place controlled double blinded randomised clinical trial. Lancet Rheumatology. 2020

[15] Treatment of moderate to severe dry eyes in Sjogren’s syndrome. Uptodate

[16] Gottenberg JE et al. Effects of hydroxychloroquine on symptomatic improvement in primary Sjögren syndrome: the JOQUER randomized clinical trial.JAMA. 2014 Jul;312(3):249-58.