Autoimmune Disease and Occupation March 6, 2020 Gabriela Schmajuk MD - - PDF document

▶
autoimmune disease and occupation
SMART_READER_LITE
LIVE PREVIEW

Autoimmune Disease and Occupation March 6, 2020 Gabriela Schmajuk MD - - PDF document

Nov 10, 2022 309 likes •553 views

Autoimmune Disease and Occupation March 6, 2020 Gabriela Schmajuk MD MS Associate Professor of Medicine Division of Rheumatology UCSF and the San Francisco VA I have nothing to disclose Outline Rheumatoid arthritis Systemic sclerosis

slide-1
SLIDE 1

Autoimmune Disease and Occupation

March 6, 2020 Gabriela Schmajuk MD MS Associate Professor of Medicine Division of Rheumatology UCSF and the San Francisco VA

I have nothing to disclose

Outline

  • Rheumatoid arthritis
  • Systemic sclerosis
  • Systemic lupus erythematosus
  • Other autoimmune conditions
slide-2
SLIDE 2

Case 1

  • 68 M underground coal miner with

longstanding shortness of breath, new hand pain and swelling x 3 months

  • 4 hours of morning stiffness
  • Exam: synovitis across MCPs, PIPs, and

wrists

  • RF+ and CCP+; quantiferon negative
  • CXR: multiple nodules

Rheumatoid Arthritis

Rheumatoid arthritis / Caplan Syndrome

  • In 1953, Caplan described the
  • ccurrence of multiple

peripheral lung nodules in chest X‐rays of Welsh coal miners with RA.

  • Caplan's syndrome =

rheumatoid pneumoconiosis

  • Clinical RA + pulmonary nodules

(rheumatoid) + inorganic dust exposure

slide-3
SLIDE 3

Rheumatoid Arthritis

  • Inflammatory arthritis
  • 1% of adults in the U.S.
  • Women > Men
  • Symmetric swelling/synovitis,

typically in the small joints of the hands/wrists

  • Stiffness > 1 hour, pain, bony

erosions, and deformities

  • Extra‐articular manifestations: lung

disease, skin nodules, vasculitis

  • Comorbid conditions: early CVD and
  • steoporosis

RF and anti‐CCP antibodies

Rheumatoid Factor

  • Sensitivity 70‐80%
  • Specificity 80%
  • Associated with poor

prognosis/erosions

  • Can also occur in Hepatitis C,
  • ther chronic infections

Anti cyclic citrullinated peptide

  • Sensitivity 60‐70%
  • Specificity >90%
  • Associated with poor

prognosis/erosions

  • Has been seen in TB infection

Arginine Citrulline

New focus on early diagnosis and treatment of RA

  • Disease activity + Inflammation  Bony erosions 

Disability

  • Erosions and disability can occur within 2 years of

disease onset

slide-4
SLIDE 4

Treatment approach

  • Goal is to minimize area under the curve
  • 1. Measure disease activity using a

composite measure at least every 3 months

  • 2. Adjust disease modifying agents with goal
  • f LOW disease activity or REMISSION
  • Early diagnosis and treatment:
  • Aim to treat within 3‐6 months of symptom
  • nset
  • Early use of DMARDs is associated with more

rapid and sustained response

Roberts LJ, et al. Early combination disease modifying antirheumatic drug treatment f

  • r rheumatoid arthritis. MJA 2006;184:122–5.

A Brief History of therapies for RA

  • 500 BC: Willow bark

(contained salicin, similar to salicylic acid)

  • 1899: Bayer trademarks

“aspirin”

  • 1959: Solumedrol
  • 1968: Azathioprine
  • 1988: Methotrexate
  • 1998: Infliximab, Etanercept

Choice of therapy in RA based on…

  • Level of disease activity

(mild/moderate/severe)

  • Poor prognostic signs (erosions, +

serologies)

  • Presence of comorbid conditions /

contraindications

  • Patient preferences (route and

frequency of drug administration, monitoring requirements, personal cost)

  • METHOTREXATE is first line therapy
slide-5
SLIDE 5

Biologic and novel small molecule* therapies for RA

Generic (Brand) Target Year FDA approved Etanercept (Enbrel) TNFα 1998 Infliximab (Remicade) TNFα 1998 Adalimumab (Humira) TNFα 2002 Abatacept (Orencia) T‐cell costimulation 2005 Rituximab (Rituxan) CD‐20+ B cells 2006 Certolizumab (Cimzia) TNFα 2008 Golimumab (Simponi) TNFα 2009 Tocilizumab (Actemra) IL‐6 2010 Tocafitinib (Xeljanz)* Janus kinase (JAK) 2012 Infliximab biosimilars TNFα 2016

Pulmonary manifestations of RA

Parenchyma:

  • Interstitial disease
  • Usual interstitial pneumonitis
  • Organizing pneumonia
  • Non‐specific interstitial pneumonitis
  • Lymphoid interstitial pneumonitis
  • Desquamative interstitial

pneumonitis

  • Mixed morphology
  • Rheumatoid nodules
  • Rheumatoid pneumoconiosis
  • Apical fibrobullous disease

Airways: Large or small airway

  • bstruction

Pleura: Rheumatoid pleural disease Vasculature: Vasculitis or pulmonary hypertension

  • Drug‐related lung disease

secondary to drugs used to treat rheumatoid disease

  • Comorbid medical conditions (eg,

thoracic cage immobility, venous thromboembolism, lung cancer)

Caplan syndrome

  • Rheumatoid arthritis
  • Most patients have mild

pneumoconiosis at diagnosis

  • Hallmark is nodulosis (>0.5 ‐ 5 cm):
  • Sudden onset, appear in crops
  • “Uniform necrosis”
  • Similar to rheumatoid nodules but with

dust

  • Central necrotic area surrounded by

alternating layers of dust and necrosis

  • Outside the dust ring is a zone of cellular

infiltration with PMNs, macrophages, and occasional giant cells

  • Nodules can cavitate or calcify
slide-6
SLIDE 6

Lung disease in RA: cause or consequence?

The lung in rheumatoid arthritis, cause or consequence? Chatzidionisyou, Aikaterini; Catrina, Anca. Current Opinion in Rheumatology. 28(1):76‐82, January 2016. DOI: 10.1097/BOR.0000000000000238

Holers et al, Nat Review Immunology 2019.

A short history of Caplan syndrome…1

  • 1953 (March) Caplan summarizes

51 cases of concomitant RA + pneumoconiosis/ 14,000 disability benefits applicants in south Wales (4 per 1000).

  • 1953 (March) Colinet publishes

second case, 34 y. o. ♀ from age 15 in same silica flour facility (clinical findings of RA and scleroderma)

slide-7
SLIDE 7

A short history of Caplan syndrome…2

  • 1953 (December): Caplan and co‐authors from the Pneumoconiosis Research Unit

publish nested case‐control investigation.

  • Methods. 20 of the Caplan’s syndrome patients from the first series ‐ matched to 60 referents from the

pneumoconiosis cohort with progressive massive fibrosis (PMF). Subjects visited at home by study investigator blinded to their dx. Physical examination; involved joints x‐rayed. RA confirmed by 2/3 criteria +: examination consistent with RA; radiographic findings consistent with RA; serologic test for RF +.

  • Results. Of 20 presumptive cases, 9 met criteria for RA, as did 2/60 “controls” Sub‐analysis of “stone

dust exposure” [marker of silica jobs]. Of 9/20 presumptive cases with stone dust exposure, 7 true positive RA; all 5 with ≥3 years of such exposure in stone dust group (p<0.05).

  • 1958: Caplan ‐ “rheumatoid pneumoconiosis” in foundry sandblaster, cites 5 studies from
  • thers on RA in coal miners
  • 1962: Caplan publishes paper reversing himself on silica: “We have been unable to find any …
  • r evidence that the prevalence of rheumatoid arthritis is increased in this disease [silicosis].”

Modern data support the association of RA with dust exposure Swedish case‐control data

  • Swedish case control study (2005) of 276

cases: RA more prevalent among subjects with silica exposure (rock drilling/stone crushing)

  • OR 2.2 < 50 yo; OR 2.7 > 50 yo
  • + Dose response based on degree of exposure
  • Silica and smoking were synergistic
  • Swedish case control study (2010) of 577

cases: anti‐CCP+ RA more prevalent among subjects with silica exposure

  • OR for rock drilling 2.3; OR for silica exposure +

smoking 7.3

  • Silica and smoking were synergistic

Stolt et al, ARD 2005. Stolt et al, ARD 2010.

slide-8
SLIDE 8

Swedish (population‐based) case‐control data

  • Male Swedish construction industry employees, exposure defined by job‐

exposure matrix

  • Out of 240K men, 713 cases of RA
  • 12,582 cases / 129,335 controls, exposure determined by job exposure

matrix

  • Animal dust – OR 1.4 for seropositive RA
  • Textile dust – OR 1.2 for seropositive RA
  • No signal with wood, paper, or flour dusts

Blanc PD, Am J of Med, 2015. Ilar et al, RMD Open, 2019.

U.S. case‐control data

Design: Random‐digit‐dial telephone survey Setting: Selected counties in Appalachia with elevated coal workers’ pneumoconiosis mortality Participants: Males, age ≥50, any employment history Exposure: Coal mining employment and work‐related dust and ergonomic factors Outcomes: Self‐reported physician diagnosis of any arthritis and of RA with glucocorticoid treatment

Schmajuk et al, AC&R 2019.

Risk of arthritis and rheumatoid arthritis (RA) associated with coal and silica exposure adjusted for smoking, ergonomic factors, and age

All arthritis Model n=973 RA Model n=566* Non‐RA Arthritis Model n=861** Risk Factor OR (95% CI) OR (95% CI) OR (95% CI) Coal and Silica exposure Coal mining work 2.2 (1.6, 3.1) 3.5 (2.0, 6.0) 2.0 (1.3, 2.8) Silica, no coal exposure 1.7 (1.2, 2.4) 1.9 (1.01, 3.6) 1.6 (1.1, 2.4) Smoking Current 1.2 (0.8, 1.9) 2.0 (1.0, 3.8) 1.1 (0.7, 1.7) Former 1.1 (0.8, 1.4) 1.2 (0.7, 1.9) 1.1 (0.7, .5) Ergonomic exposure 11‐13 factors 1.5 (1.1, 2.0) 1.8 (1.1, 3.0) 1.4 (0.99, 2.0) Age (per year) 1.03 (1.01, 1.04) 1.04 (1.01, 1.05) 1.03 (1.01, 1.04)

For coal and silica, referent category=neither exposure; for smoking, referent=never smoker; for ergonomic exposure, referent category= 0 to 10 factors. *Excludes 407 reporting non‐RA arthritis or selected autoimmune diseases without concomitant RA. **Excludes 112 participants reporting RA and glucocorticoid treatment

slide-9
SLIDE 9

All Arthritis and RA Population Attributable Fraction Associated with Coal and Silica Exposure

All Arthritis RA PAF (95% CI) PAF (95% CI) Coal and Silica exposure Either exposure 0.28 (0.19, 0.36) 0.42 (0.29, 0.53) Coal mining work 0.19 (0.14, 0.24) 0.33 (0.26, 0.40) Other occupational silica exposure 0.09 (0.04, 0.13) 0.09 (0.02, 0.16)

RA = Rheumatoid Arthritis; PAF = Population Attributable Risk For coal or silica exposure, for all arthritis OR = 2.0 (95% CI1.5 to 2.7); for RA, OR =2.8 (95% CI 1.7 to 4.6) All estimates from multivariate models including age, smoking, and ergonomic exposures.

Environmental and occupational exposures and risk of RA

Holers et al, Nat Review Immunology 2019.

Case 2

  • 55 yo stone mason x 20 years
  • Developed Raynaud’s 6 years ago
  • Now with finger pain and muscle pain in

thighs/shoulders, worsening shortness

  • f breath
  • Exam: skin tightening at hands and

mouth, + synovitis

  • ANA, Scl‐70 +, + CK
  • CXR: ground glass at the bases
slide-10
SLIDE 10

Systemic sclerosis

Systemic Sclerosis (Scleroderma)

Systemic autoimmune disease affecting the skin and internal organs

  • Incidence: 20 per million per year
  • Prevalence: 200‐300 per million
  • Gender: 3 female to 1 male
  • Age of onset: Mean 40‐50 years
  • Race: All
  • Duration: Chronic
  • Treatment: Supportive

Slide courtesy of Dr. Francesco Boin, UCSF

I mmune activation Fibrosis Vascular injury

  • Skin
  • Lung fibrosis (ILD)
  • Upper/lower GI dysmotility
  • Kidneys (chronic nephropathy)
  • Heart (myocardial scarring)
  • Raynaud’s disease
  • Digital ischemia
  • Pulmonary Hypertension
  • Kidneys (renal crisis)
  • CVD, stroke

Scleroderma Pathologic Hallmarks

  • Autoantibodies
  • Inflammation (skin, lungs)

Slide courtesy of Dr. Francesco Boin, UCSF

slide-11
SLIDE 11

Haustein UF., Lietzberg B. (2018) Occupational Connective Tissue Disorders. In: John S., Johansen J., Rustemeyer T., Elsner P., Maibach H. (eds) Kanerva’s Occupational Dermatology. Springer, Cham

SSc fibrosis of the skin

Scleroderma Onset After 6 years

SSc fibrosis of the lung

slide-12
SLIDE 12

UPPER GI Swallowing difficulties Acid reflux Delayed gastric emptying Dyspepsia Gastro Intestinal Disease Fibrosis involving muscle layers Hypo‐motility

Calcinosis Raynaud’s phenomenon

Esophageal dysmotility

Sclerodactily Telangiectasias

SSc fibrosis of the GI tract

Double‐contrast barium enema showing sacculation of the terminal ileum and bunching of folds (open arrows) due to fibrosis in the muscular layers.

LOWER GI Dysmotility Constipation/Diarrhea Bacterial Overgrowth Malabsorption Malnutrition

SSc fibrosis of the GI tract

Scleroderma Vascular Disease

Progressive impairment of MICROVASCULAR bed leading to decreased blood supply, ultimately to tissue and organ chronic ischemia Microvascular

Capillaries Arterioles

Macrovascular

Medium and large size arteries

Slide courtesy of Dr. Francesco Boin, UCSF

slide-13
SLIDE 13

Vasoreactivity

Scleroderma is a Vascular Disease

Capillary/ Vessel Loss Microvascular Occlusion Macrovascular Occlusion Defective vascular repair

Raynaud’s phenomenon

  • First symptom in SSc
  • Raynaud’s can be induced by

vibrations from pneumatic tools (chainsaws, jackhammers)

  • This form of Raynaud’s has not been

associated with SSc

Pulmonary Hypertension Renal Disease

Scleroderma is a Vascular Disease

Cardiac

slide-14
SLIDE 14

Skin ILD Gastrointestinal (GAVE, dysmotility)

Scleroderma is a Vascular Disease

Slide courtesy of Dr. Francesco Boin, UCSF

Systemic sclerosis / Erasmus syndrome

  • The association of silica exposure and

subsequent development of SSc.

  • Indistinguishable from idiopathic SSc.
  • 1957 ‐ Erasmus observed 17 cases of SSc

among 8000 underground miners in South Africa, 6 of them with silicosis.

  • In the following years (from 1960 until 1969),

29 additional cases of SSc were registered in miners who had been working in the South African gold mines.

  • Incidence of 7.7 cases per 100,000 miners per

year in contrast with an incidence of 0.33 in 100,000 in a control group consisting of railway and harbor workers.

slide-15
SLIDE 15

Scleroderma‐like diseases

  • Organic solvents such as (chlorinated)

aliphatic and aromatic hydrocarbons can trigger scleroderma‐like diseases (SLDs)

  • Localized skin thickening
  • Toxicity to liver, kidney, nervous system
  • Absence of autoantibodies
  • Can be reversible

Haustein UF., Lietzberg B. (2018) Occupational Connective Tissue Disorders. In: John S., Johansen J., Rustemeyer T., Elsner P., Maibach H. (eds) Kanerva’s Occupational Dermatology. Springer, Cham

U.S. case control data

  • U.S. data: Rodnan (1967) analyzed occupation of 60 male cases of SSc – 26

were coal miners and 10 were foundry works exposed to quartz

  • German data: Zschunke (1981) 77% of all males with SSc (n=137) in

Germany had workplace silica exposure; 50% with silicosis

  • OR for SSc with silica exposure is around 12.
  • Average time of exposure was 13 years
  • Delay in disease from beginning of exposure was 24 years
  • Gold et al (2007) found cause of death and “usual occupation” as reported
  • n the death certificate
  • SSc associated with industrial machine repairers (OR 2.3), typesetters

(OR 2.7), machine feeders (OR 2.2), hand painting/coating/decorating

  • Some data also exists for “solvents” – esp chlorinated and aromatic

hydrocarbons (petrochemical plants)

U.S. death certificate data

  • Gold et al found cause of death and “usual occupation” as reported
  • n the death certificate
  • SSc associated with industrial machine repairers (OR 2.3),

typesetters (OR 2.7), machine feeders (OR 2.2), hand painting/coating/decorating

  • Animal farmers associated with RA death (OR 1.3)
  • Mining machinery operators associated with RA (OR 1.2) and SLE (OR 1.8)
  • Textile machine operators associated with SLE (OR 1.5)

Gold et al, Epidemiology 2007.

slide-16
SLIDE 16

Swedish case‐control data

  • Male Swedish construction industry employees, exposure defined by

job‐exposure matrix

  • For 240K men, 128 cases of SLE, SSc, DM

Blanc PD, Am J of Med, 2015.

Case 3

  • 49 year old previously healthy man

presents with 3 day history of severe, progressive lower extremity swelling and low grade fevers.

  • Also reports nocturia, puffy eyes, joint

pain, and rashes of 1‐2 weeks duration.

  • Family history notable for maternal

aunt with rheumatoid arthritis.

  • Bilateral LE edema to shins
  • WBC 2.6, Cr1.7, + ANA, + dsDNA
  • Urinalysis: proteinuria, hematuria
  • Low C3 and C4

Systemic lupus erythematosus

slide-17
SLIDE 17

Overview of SLE

  • Prototypic systemic autoimmune disease.
  • Involvement of multiple organ systems with varying degrees of

severity.

  • Unpredictable, waxing and waning course.
  • Lupus nephritis- most common internal organ manifestation

and associated with high morbidity and mortality.

  • Characterized by the production of various autoantibodies,

particularly anti-nuclear antibodies.

  • Treatment with steroids and steroid-sparing agents

(cyclophosphamide, mycophenolate, hydroxychloroquine)

Epidemiology of SLE

  • Female predominance (female: male ratio in adults 10:1).
  • Peak disease incidence during reproductive years.
  • Increased incidence/prevalence in people of African, Asian,

Hispanic/Latino descent.

  • Prevalence from CA Lupus Surveillance Project.
  • African American females ~1:250.
  • Hispanic and Asian American females ~1:700.
  • Caucasian females ~1:1000.

Slide courtesy of Dr. Maria Dall’Era, UCSF

Major Clinical Manifestations of SLE

Manifestation Frequency Constitutional 90% Mucocutaneous 80-90% Musculoskeletal 80-90% Serositis 50-70% Lupus Nephritis 40-60% Neuropsychiatric 40-60% Cytopenias 20-30%

Slide courtesy of Dr. Maria Dall’Era, UCSF

slide-18
SLIDE 18

Two Major Forms of Joint Involvement in SLE

1) Symmetric, inflammatory, polyarthritis with predilection for wrists and small joints of the hands. 2) Jaccoud’s‐like arthropathy. Key distinguishing features from RA:

  • No joint erosions on x-ray.
  • Joint deformities reducible.

Slide courtesy of Dr. Maria Dall’Era, UCSF

The Many Faces of SLE

Slide courtesy of Dr. Maria Dall’Era, UCSF

Important Laboratory Clues in SLE

  • Positive anti-nuclear antibody (ANA).
  • High anti-dsDNA in active disease.
  • Low complement C3 and C4 in active disease.
  • Leukopenia, anemia, thrombocytopenia.
  • Elevated erythrocyte sedimentation rate (ESR).
  • Typically normal C Reactive Protein (CRP).
  • Abnormal urinalysis (proteinuria, hematuria) in lupus nephritis.

Slide courtesy of Dr. Maria Dall’Era, UCSF

slide-19
SLIDE 19

Suspect New Onset Lupus Nephritis

  • Renal involvement is common in SLE

(60%)

  • Usually occurs in first five years of
  • nset of SLE
  • Associated with significant morbidity

and mortality and end stage renal disease.

Slide courtesy of Dr. Maria Dall’Era, UCSF

Pathogenesis‐ Importance of Autoantibodies

  • Autoantibodies to self antigens are key to disease onset and

tissue damage

  • Can develop many years before clinical manifestations
  • Target antigens:
  • Nuclear antigens (dsDNA, RNP

, Sm)

  • Cytoplasmic antigens (ribosomal proteins)
  • Cell surface antigens (blood cells)
  • Immune complexes deposit in tissue activate complement

acute inflammation with influx of inflammatory cells permanent tissue damage and end organ failure.

Slide courtesy of Dr. Maria Dall’Era, UCSF

Pathogenesis‐ Development of SLE Occurs in Steps

slide-20
SLIDE 20

Antinuclear Antibody Subtypes in SLE

Antibody Prevalence Clinical Significance

ANA 99% High sensitivity, low specificity Anti‐dsDNA 60% Highly associated with nephritis, high specificity, fluctuates with disease activity Anti‐Smith 20‐30% High specificity Anti‐RNP 20‐30% Associated with mixed connective tissue disease Anti‐SSA 30% Associated with Sjogren’s Syndrome, SCLE, and neonatal lupus Anti‐SSB 30% Associated with Sjogren’s Syndrome, SCLE, and neonatal lupus Anti‐Histone 70% Associated with drug‐induced lupus

Slide courtesy of Dr. Maria Dall’Era, UCSF

Case reports and case‐control data

  • Mehlhorn and Gerlach (1990): 37 cases of SLE among ore (esp

uranium) miners and foundry worker

  • Ziegler (1991): 30 cases of SLE, 5 with silicosis among silica‐exposed

workers

  • Parks (2002): Risk of SLE after silica exposure was OR 2.4 for medium

exposure and 4.6 for high exposure (n=19 of 265 SLE patients)

Other autoimmune conditions

slide-21
SLIDE 21

Other Auto‐Immune Diseases and Silica

Published Associations:

  • “Overlap Syndrome”
  • Sjogren’s syndrome
  • ANCA+ vasculitis
  • Polymyositis/dermatomyositis
  • Bullous pemphigoid
  • Interstitial granulomatous dermatitis (Ackerman Syndrome)
  • Autoimmune renal disease
  • Primary biliary cholangitis, primary sclerosing cholangitis, autoimmune

hepatitis

Also ‐Spouses / close contacts ‐Launderers of clothes

Haustein UF., Lietzberg B. (2018) Occupational Connective Tissue Disorders. In: John S., Johansen J., Rustemeyer T., Elsner P., Maibach H. (eds) Kanerva’s Occupational Dermatology. Springer, Cham

Questions

slide-22
SLIDE 22

Question 1

Which of the following affect the risk of rheumatoid arthritis?

  • A. Coal dust exposure
  • B. Silica dust exposure
  • C. Tobacco smoke
  • D. Genetic susceptibility
  • E. All of the above

Question 2

Which of the following is true about systemic sclerosis?

  • A. Silica‐associated disease is less likely to be diffuse vs. limited
  • B. Silica‐associated disease is less likely to affect the lungs
  • C. Men with SSc are more likely to have been exposed to silica than

women

  • D. Systemic sclerosis can be reversible with cessation of exposure to

silica

Question 3

Which of the following occupations are NOT reported to be associated with silica exposure?

  • A. Foundry casters
  • B. Sandstone crushers
  • C. Dental technicians
  • D. Radiology technicians
  • E. Tire industry workers
slide-23
SLIDE 23

Relevant references

  • Schreiber J, Koschel D, Kekow J, Waldburg N, Goette A, Merget R.

Rheumatoid pneumoconiosis (Caplan's syndrome). Eur J Intern Med. 2010 Jun;21(3):168‐72. doi: 10.1016/j.ejim.2010.02.004. Epub 2010 Mar 2. Review. PubMed PMID: 20493416.

  • Haustein UF., Lietzberg B. (2018) Occupational Connective Tissue
  • Disorders. In: John S., Johansen J., Rustemeyer T., Elsner P., Maibach
  • H. (eds) Kanerva’s Occupational Dermatology. Springer, Cham