1. Managing Rheumatoid Arthritis Post Malignancy: A Case-Based Discussion
Maria E. Suarez-Almazor, MD, PhD
Barnts Family Distinguished Professor
Section of Rheumatology and Clinical Immunology
University of Texas M. D. Anderson Cancer Center Houston, Texas
Supported by an independent educational grant from AbbVie.

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3. Faculty
Maria E. Suarez-Almazor, MD, PhD Barnts Family Distinguished Professor Section of Rheumatology and Clinical Immunology University of Texas M. D. Anderson Cancer Center Houston, Texas
Maria E. Suarez-Almazor, MD, PhD, has disclosed that she has received funds for research support from Pfizer.
This slide lists the faculty who was involved in the production of these slides.

4. Standardized Incidence Ratio
Cancer Risk in RA Pts
Meta-analysis of observational studies reporting risk of malignancy in RA pts vs general population[1,2]
Possible increase in melanoma and nonmelanoma skin cancer[5,6]
Overall Cancer
Lung Cancer
Non-Hodgkin’s Lymphoma
Hodgkin’s Lymphoma
Lymphoma
RA, rheumatoid arthritis.
Breast Cancer
Colorectal Cancer 1 2 3 4 5
Standardized Incidence Ratio
1. Cush JJ, et al. DSQ. 2012;4: Smitten AL, et al. Arthritis Res Ther. 2008;10:R45.
5. Raaschou P, et al. BMJ. 2013;346:f Askling J, et al. Ann Rheum Dis. 2005;64:

5. RA Treatment and the Risk of Lymphoma
Analysis of 18,572 RA pts enrolled in the US National Data Bank for Rheumatic Diseases[7]
Treatment Group
Pts at Risk, n
Lymphomas, n
SIR (95% CI)*
All pts
18,572 29
1.9 ( )
No MTX/biologics
3504 5
1.3 ( )
All biologics
8614 14
2.9 ( )
MTX only
6396 10
1.5 ( )
INF ± ETN
6465 9
2.6 ( )
ETN ± INF
3381 8
3.8 ( )
ETN, etanercept; INF, infliximab; MTX, methotrexate; NCI, National Cancer Institute; RA, rheumatoid arthritis; SEER, Surveillance, Epidemiology, and End Result; SIR, standardized incidence ratio; tx, treatment.
*SIRs calculated based on age- and sex-matched data from the NCI SEER resource.
Other studies, including a large meta-analysis, have not found a significant association between biologic RA tx and lymphoma risk[8,9]
7. Wolfe F, et al. Arthritis Rheum. 2004;50: Lopez-Olivo M, et al. JAMA. 2012;308:
9. Askling J, et al. Ann Rheum Dis. 2009;68:

6. RA Treatment and the Risk of Solid Tumors
Analysis of RA pts without prior cancer in the British Society for Rheumatology Biologics
Assessed risk of solid tumors in pts who received TNFis (n = 11,767) vs patients nbDMARDs (n = 3249)
No difference in relative risk of cancer for specific TNFis
nbDMARD
TNFi
Pts, n
3249
11,767
Total follow-up, PY
11,672
52,549
Solid cancers, n
136
427
Unadjusted HR (95% CI)
0.70 ( )
Adjusted HR* (95% CI)
0.83 ( )
nbDMARD, nonbiologic disease-modifying antirheumatic drug; PY, patient-years; RA, rheumatoid arthritis; TNFi, tumor necrosis factor inhibitor.
*Adjustment using propensity score stratified into deciles.
10. Mercer LK, et al. Ann Rheum Dis. 2015;74:

7. RA Treatment and the Risk of Melanoma
Analysis of data from Swedish ARTIS register
Assessed melanoma incidence in RA pts treated with TNFis (n = 10,878) or not treated with TNFis (n = 42,198) and in general population (n = 162,743)
Cancer Type
No Biologic Treatment
TNFi Treatment
Adjusted HR (95% CI)
Invasive malignant melanoma, events/PY
113/203,345
38/57,223
1.5 ( )
Invasive all site cancer,* events/PY
2788/196,826
558/55,947
1.0 ( )
Second primary melanoma, events/pts†
10/295
3/54
3.2 ( )
NS, not significant; PY, person years; RA, rheumatoid arthritis; TNFi, tumor necrosis factor inhibitor.
*All sites except basal cell skin cancer. †Pts with a history of melanoma at the start of RA treatment.
5. Raaschou P, et al. BMJ. 2013;346:f1939.

8. Biologic Therapy and Risk of Malignancy: Meta-Analysis
Meta-analysis of 63 RCTs comparing biologic therapy with nbDMARD therapy or placebo for treating RA (N = 29,423)
211 pts (0.72%) developed malignancy during RCT
No consistent significant differences in risk of any malignancy
TNFis vs placebo or nbDMARD
TNFis + nbDMARD vs nbDMARD
No specific TNFi was associated with increased risk of malignancy (assessed ADA, CTZ, ETN, GLM, INF)
No significant increases in risk of NMSC, melanoma, solid tumors, or lymphoma for RA pts treated with TNFi
Risk for lymphoma: OR 2.14 (NS)
ADA, adalimumab; CTZ, certolizumab; ETN, etanercept; GLM, golimumab; INF, infliximab; nbDMARD, nonbiologic disease-modifying antirheumatic drug; NMSC, nonmelanoma skin cancer; NS, not significant; OR, odds ratio; RA, rheumatoid arthritis; RCT, randomized controlled trial; TNFi, tumor necrosis factor inhibitor.
8. Lopez-Olivo M, et al. JAMA. 2012;308:

9. Cancer Prognosis and Recurrence After TNFi Treatment: Swedish Registries
Analysis of primary cancers and postcancer survival[12]
302 cancers in 8562 RA pts treated with biologics* (from ARTIS registry); cancers from matched controls RA pts not treated with biologics
Adjusted HR for death (biologic vs non-biologic tx) = 1.1 (95% CI: )
No significant differences in survival for specific cancers: breast, colorectal, prostate, lung, or malignant melanoma
Analysis of breast cancer recurrence[13]
TNFi-treated RA pts with history of breast cancer prior to TNFi tx (n = 120) compared with matched controls not treated with TNFis (n = 120)
Breast cancer recurrences not increased with TNFi: adjusted HR 1.1 (95% CI: ); median time to TNFi treatment after primary cancer: 9.4 yrs
NMSC, nonmelanoma skin cancer; RA, rheumatoid arthritis; TNFi, tumor necrosis factor inhibitor; tx, treatment.
*300 of 302 patients were treated with TNFis; 2 patients were treated exclusively with biologic agents other than TNFis.
12. Raaschou P, et al. Arthritis Rheum. 2011;63: Raaschou P, et al. Ann Rheum Dis. 2015;74: 9 9

10. TNF Inhibitors for RA Pts With Prior Malignancy
Analysis of RA pts in a British registry (BSRBR) study with a history of malignancy prior to treatment with TNFis or without TNFis
TNFi Treatment
nbDMARD Treatment
Pts with prior malignancy, n
177
117
Malignancy recurrence, n (%)
11 (6.2)
9 (7.7)
Recurrence rate per 1000 PY (95% CI)
25.3 ( )
38.3 ( )
Pts with prior melanoma, n 17 10
Melanoma recurrence, n (%)
3 (17.6)
0 (0)
BSRBR, British Society for Rheumatology Biologics Register; PY, patient-years; RA, rheumatoid arthritis; TNF, tumor necrosis factor; TNFi, tumor necrosis factor inhibitor.
14. Dixon WG, et al. Arthritis Care Res. 2010;62:

11. Cancer Recurrence Risk by Treatment Regimen
Analysis of cancer recurrence in RA patients in a German registry (RABBIT) with a history of malignancy prior to treatment with TNFis, rituximab, or nbDMARDs
nbDMARDs
Rituximab
TNFi*
Pts, n
3399
770
5231
Pts with prior solid malignancies, n (%)
112 (3.3)
77 (10)
109 (2.1)
Median yrs between malignancy and treatment start
5.9
3.3
6.8
Recurrence rate per 100 PY (95% CI)
3.6 ( )
3.9 ( )
5.7 ( )
nbDMARD, nonbiologic disease-modifying antirheumatic drug; PY, patient years; TNFi, tumor necrosis factor inhibitor.
*Adalimumab, certolizumab pegol, etanercept, golimumab, infliximab.
15. Strangfeld A, et al. ACR Abstract 806.

12. Summary RA pts have an increased risk of specific malignancies
Lymphoma, lung cancer, melanoma, NMSC
Treatment of RA pts with biologic therapy does not increase the risk of malignancies vs pts not treated with biologics
Most observational studies suggest that biologic therapy does not increase the risk of recurrence for RA pts with a history of treated cancer diagnosed several yrs before biologic therapy
Risk for melanoma recurrence might be increased, but the data are not robust
NMSC, nonmelanoma skin cancer; RA, rheumatoid arthritis.

13. 2015 ACR Guidelines: Biologic Use in RA Pts With History of Malignancy
Recommendation
Previously treated/untreated melanoma or NMSC
Use DMARDs over biologics
Use DMARDs over tofacitinib
Previously treated lymphoproliferative disorder
Use rituximab over TNFi*
Use combination DMARD OR abatacept OR tocilizumab over TNFi
Previously treated solid organ malignancy
Same recommendations as in pts without condition
ACR, American College of Rheumatology; DMARD, disease-modifying antirheumatic drug; HCQ, hydroxychloroquine; LEF, leflunomide; MTX, methotrexate; NMSC, non-melanoma skin cancer; RA, rheumatoid arthritis; SSZ, sulfasalazine; TNFi, tumor necrosis factor inhibitor.
DMARD = HCQ, LEF, MTX, or SSZ. *Strongly recommended.
16. Singh JA, et al. Arthritis Care Res. 2015;[Epub ahead of print].

14. Management of RA Pts With Current or Recent Malignancy
Goals of management in RA pts with current malignancy
Improve/maintain quality of life
Maximize survival
Considerations for informed shared decision-making RA
Cancer
Disease activity
Type and stage
Prognostic features
Duration from diagnosis
Quality of life
Recurrences
Previous response to therapy
Probability of survival
Comorbidities
Median survival
Concurrent treatments
Treatment (curative vs palliative)
Patient preferences
RA, rheumatoid arthritis.

15. Case 1: History of Breast Cancer
50-yr-old woman
Diagnosed with stage II breast cancer 7 yrs ago
Underwent mastectomy and radiation therapy; received chemotherapy and tamoxifen for 5 yrs
No recurrences
Developed symmetric polyarthritis involving wrists and MCP, PIP, knee joints 1 yr ago
Positive RF and anti-CCP tests; diagnosed with RA
Initiated treatment with MTX (escalated to 20 mg PO QW) and prednisone 10 mg/day PO 10 mos ago
SSZ and HCQ added 4 mos ago
CCP, cyclic citrullinated peptide; HCQ, hydroxychloroquine; MCP, metacarpophalangeal; MTX, methotrexate; PIP, proximal interphalangeal; PO, by mouth; QW, weekly; RA, rheumatoid arthritis; RF, rheumatoid factor; SSZ, sulfasalazine.

16. Case 1: Current Status At current visit, pt presents with:
VAS pain: 7/10
Morning stiffness: 2 hrs
Joint tenderness and swelling in wrists/MCP, PIP, knee joints
DAS28: 5.2; ESR: 32
Hand radiographs: 2 MCP erosions
DAS28, disease activity score in 28 joints; ESR, erythrocyte sedimentation rate; MCP, metacarpophalangeal; PIP, proximal interphalangeal; VAS, visual analogue scale.

17. Case 1: Management Management considerations: RA
Pt has established RA with high disease activity despite treatment with steroids and triple DMARD therapy along with features of poor prognosis
Management considerations: cancer
History of breast cancer (diagnosed 7 yrs ago)
No recurrences after treatment
Treatment options
ACR guidelines: pts with prior solid organ malignancy can be treated as any other RA pt
Prednisone already at maximum dose; pt should initiate treatment with biologic agent
ACR, American College of Rheumatology; DMARD, disease-modifying antirheumatic drug; RA, rheumatoid arthritis.
16. Singh JA, et al. Arthritis Care Res. 2015;[Epub ahead of print].

18. Case 2: Recent History of NSCLC
58-yr-old man
Diagnosed with seropositive RA 5 yrs ago
Initial treatment: MTX followed by triple therapy (MTX + SSZ + HCQ); little response
Switched to MTX + ETN 3 yrs ago; excellent control of disease activity
Diagnosed with stage IB NSCLC 18 mos ago
Solitary 4-cm nodule in right lung
RA medications stopped
Underwent surgery; histology showed positive margins
Chemoradiation completed 8 mos ago
ETN, etanercept; HCQ, hydroxychloroquine; MTX, methotrexate; NSCLC, non-small-cell lung cancer; RA, rheumatoid arthritis; SSZ, sulfasalazine.

19. Case 2: Current Status
Developed synovitis of MCP, PIP, and knee joints 5 mos ago
DAS28 score: 5.6
Hand radiographs: several PIP erosions
Started on MTX (increasing to 25 mg PO QW) and prednisone 7.5 mg/day PO with no improvement
Completed cancer staging 1 mo ago; no recurrences
DAS28, disease activity score in 28 joints; MCP, metacarpophalangeal; MTX, methotrexate; PIP, proximal interphalangeal; PO, by mouth; QW, weekly.

20. Case 2: Management Management considerations: RA
Pt has high disease activity and poor prognostic factors despite MTX and prednisone
Poor prior response to triple therapy; excellent prior response to ETN
Management considerations: cancer
Recent history of NSCLC (stage IB, diagnosed 18 mos ago); biopsy showed poor margins; currently no recurrences
Treatment options
ACR guidelines: pts with prior treated solid organ malignancy can be treated as any other RA pt
However, due to cancer type and recent diagnosis/treatment, recurrence a possibility; as prednisone/MTX already at maximum doses, consider rituximab
ACR, American College of Rheumatology; ETN, etanercept; MTX, methotrexate; NSCLC, non-small-cell lung cancer; RA, rheumatoid arthritis.
16. Singh JA, et al. Arthritis Care Res. 2015;[Epub ahead of print].

21. Case 3: Current Metastatic Pancreatic Cancer
62-yr-old woman
Diagnosed with RA 17 yrs ago
Receiving MTX 15 mg PO QW and IV abatacept
Excellent response; no evidence of disease activity in past 1 yr
Developed severe back pain and epigastric discomfort 4 mos ago
Diagnosed with unresectable pancreatic cancer with liver metastases
MTX and abatacept discontinued
Pt started gemcitabine and oxycodone for pain control
IV, intravenous; MTX, methotrexate; PO, by mouth; QW, weekly; RA, rheumatoid arthritis.

22. Case 3: Current Status
Developed synovitis of her elbows, wrists, MCP and PIP joints 2 mos ago
Severe shoulder pain
Marked decrease in ability to perform usual daily activities
Initiated treatment with prednisone 10 mg/day PO with mild improvement
MCP, metacarpophalangeal; PIP, proximal interphalangeal; PO, by mouth.

23. Case 3: Management Management considerations: RA
Pt has high disease activity and poor quality of life
Excellent prior response to MTX + abatacept; MTX not good choice, as pt is on chemotherapy and has liver metastases
Management considerations: cancer
Current metastatic disease; no curative therapy (median expected survival from diagnosis ~ 6 mos to 1 yr)
Treatment options
ACR guidelines: no specific guidance for pts with current solid tumors/metastases
Pt preferences and shared decision-making; abatacept a possibility
ACR, American College of Rheumatology; MTX, methotrexate; RA, rheumatoid arthritis.
16. Singh JA, et al. Arthritis Care Res. 2015;[Epub ahead of print] Weinberg BA, et al. Oncology. 2015;29:pii:

24. Case 4: History of Recurrent Melanoma
42-yr-old woman
First diagnosed with melanoma 3 yrs ago
0.5-cm lesion in her arm with negative sentinel nodes
Underwent wide excision
Developed a new lesion 4 cm proximal to the primary tumor 2 yrs ago
Lesion was excised and pt underwent chemotherapy with no recurrences in the past 2 yrs
Developed polyarthritis and was diagnosed with RA 6 mos ago
Initiated treatment with MTX; minimal response after 4 mos
Positive RF, negative anti-CCP, normal hand radiographs, DAS28 score: 4.8
CCP, cyclic citrullinated peptide; DAS28, disease activity score in 28 joints; MTX, methotrexate; RA, rheumatoid arthritis; RF, rheumatoid factor.

25. Case 4: Management Management considerations: RA
Early onset RA; moderate disease; no radiographic evidence of structural damage
Poor response to MTX
Management considerations: cancer
Young pt with recurrent melanoma; no current evidence of disease
Treatment options
ACR guidelines: use DMARDs over biologics/tofacitinib
Triple combination DMARD therapy
ACR, American College of Rheumatology; DMARD, disease-modifying antirheumatic drug; MTX, methotrexate; RA, rheumatoid arthritis.
16. Singh JA, et al. Arthritis Care Res. 2015;[Epub ahead of print].

26. Case 5: No Prior Malignancy but Elevated Risk
36-yr-old woman
Diagnosed with RA 4 yrs ago
Well-controlled on SC adalimumab for past 2 yrs
No swollen joints, mild pain, morning stiffness: 10 mins
RF positive and anti-CCP negative
Hand radiographs show juxta-articular osteoporosis but no erosions
Does not want to receive MTX because of desire to get pregnant/have second child
CCP, cyclic citrullinated peptide; MTX, methotrexate; RA, rheumatoid arthritis; RF, rheumatoid factor; SC, subcutaneous.

27. Case 5: Current Status
Pt concerned about her genetic predisposition to cancer
Mother died from ovarian cancer 7 yrs ago
Older sister diagnosed with breast cancer 4 mos ago
Recently underwent genetic testing: BRCA1 mutation carrier
MTX, methotrexate

28. Case 5: Management Management considerations: RA
Patient is well-controlled with TNFi; has not tried MTX or other DMARDs
Prognostic factors are moderate: positive RF, negative anti-CCP, no hand erosions
Future pregnancy a possibility
Management considerations: cancer
Young patient with no current/prior cancer; increased risk for breast and ovarian cancer due to BRCA1 mutation
Treatment options
ACR guidelines: no specific guidance for at-risk pts with no history of malignancy
Discuss uncertainties with pt
If mastectomy/oophorectomy are desirable, no need to alter RA management
If mastectomy/oophorectomy are not desirable, consider switch to another DMARD/biologic in view of uncertainty
Pregnancy considerations with choice of therapy
ACR, American College of Rheumatology; CCP, cyclic citrullinated peptide; DMARD, disease-modifying antirheumatic drug; MTX, methotrexate; RA, rheumatoid arthritis; RF, rheumatoid factor; TNFi, tumor necrosis factor inhibitor.
16. Singh JA, et al. Arthritis Care Res. 2015;[Epub ahead of print].

29. Summary Prior malignancy Risk of malignancy Current malignancy
ACR guidelines offer recommendations for pts with history of solid tumors, lymphoma, and skin cancer
TNFis should be avoided in pts with lymphoma/skin cancers
Risk of malignancy
No clear evidence or guidelines; focus on shared decision making
Current malignancy
Personalized approach required for pt with RA and cancer
Goal is to maximize quality of life with no significant detriment to survival
Consider cancer features
Focus on shared decision making, both for known and unknown issues
ACR, American College of Rheumatology; RA, rheumatoid arthritis; TNFi, tumor necrosis factor inhibitor.

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