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

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

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 occurrence 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

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 osteoporosis RF and anti ‐ CCP antibodies Rheumatoid Factor Anti cyclic citrullinated peptide • Sensitivity 70 ‐ 80% • Sensitivity 60 ‐ 70% • Specificity 80% • Specificity >90% • Associated with poor • Associated with poor prognosis/erosions prognosis/erosions • Can also occur in Hepatitis C, • Has been seen in TB infection other chronic infections 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

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 of LOW disease activity or REMISSION • Early diagnosis and treatment: • Aim to treat within 3 ‐ 6 months of symptom onset • Early use of DMARDs is associated with more rapid and sustained response Roberts LJ, et al. Early combination disease modifying antirheumatic drug treatment f or 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

Biologic and novel small molecule* therapies for RA Generic (Brand) Target Year FDA approved Etanercept (Enbrel) TNF α 1998 Infliximab (Remicade) TNF α 1998 Adalimumab (Humira) TNF α 2002 Abatacept (Orencia) T ‐ cell costimulation 2005 Rituximab (Rituxan) CD ‐ 20+ B cells 2006 Certolizumab (Cimzia) TNF α 2008 Golimumab (Simponi) TNF α 2009 Tocilizumab (Actemra) IL ‐ 6 2010 Tocafitinib (Xeljanz)* Janus kinase (JAK) 2012 Infliximab biosimilars TNF α 2016 Pulmonary manifestations of RA Airways : Large or small airway Parenchyma : obstruction • Interstitial disease Pleura : Rheumatoid pleural disease • Usual interstitial pneumonitis • Organizing pneumonia Vasculature: Vasculitis or pulmonary hypertension • Non ‐ specific interstitial pneumonitis • Lymphoid interstitial pneumonitis • Drug ‐ related lung disease • Desquamative interstitial secondary to drugs used to treat pneumonitis rheumatoid disease • Mixed morphology • Comorbid medical conditions (eg, • Rheumatoid nodules thoracic cage immobility, venous • Rheumatoid pneumoconiosis thromboembolism, lung cancer) • Apical fibrobullous disease 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

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)

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 others on RA in coal miners • 1962: Caplan publishes paper reversing himself on silica: “We have been unable to find any … or 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.

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 RA Non ‐ RA Arthritis Model n=973 Model n=566* 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