Incidence of Skin Cancer in Rheumatoid Arthritis

1
Incidence of Skin Cancer in Rheumatoid Arthritis
Eliza F. Chakravarty1, Kaleb Michaud2, Frederick
Wolfe2, 1Stanford University, Palo Alto, CA
2National Data Bank for Rheumatic Diseases,
Wichita, KS
Purpose To determine the rates of reported
non-melanoma skin cancer (NMSC) in a large cohort
of patients with rheumatoid arthritis (RA) in
comparison to patients with osteoarthritis (OA).
To determine risk factors for the development of
NMSC in patients with RA. Methods
Self-reported information from 15,789 patients
with RA and 3,639 patients with OA were collected
through semi-annual questionnaires since 1999.
Survival analyses were used to determine
incidence rates for NMSC among RA and OA
patients. Multivariate Cox proportional hazard
models were used to estimate hazard ratios for
the development of NMSC. Separate analyses were
performed for RA patients to explore associations
between use of immunosuppressive medications and
development of NMSC.
Introduction
Baseline Demographics of RA and OA Patients
Multivariate Cox Regression Analysis for RA
Patients
Many studies have confirmed that, although rates
of overall cancers are not increased
substantially from the general population,
certain types of cancers may be seen with higher
frequency in patients with rheumatoid arthritis
(RA). It is unclear whether this increased risk
is due to aberrancies in the immune system from
higher inflammatory activity in RA, from certain
immunosuppressive agents used to treat RA, or a
combination of the two. Several studies of
European populations have suggested a slightly
increased risk for the development of
non-melanoma skin cancers (NMSC), such as basal
cell carcinoma (BCC) and squamous cell carcinoma
(SCC) in patients with RA when compared to rates
in the general population. Similar studies have
generally not been performed on US populations as
incidence rates of NMSC are not kept in national
cancer registries. The recent advent and
widespread use of tumor necrosis factor (TNF)
inhibitors to treat RA has raised additional
concerns about the risk of NMSC as well as other
malignancies with the use of these agents.

Results

The crude incidence rate for reported NMSC among
RA patients is 18.1 per 1000 person-years
compared to a rate of 20.4 per 1000 person-years
observed among OA patients (p0.13). Age, male
sex, Caucasian race, and history of NMSC prior to
entry into the database were associated with an
increased risk of NMSC in multivariate Cox
proportional hazard models. A diagnosis of RA
was associated with a slightly increased risk of
NMSC in multivariate survival analysis (HR 1.19,
p0.042). Among RA patients, the development
of NMSC was associated with use of prednisone (HR
1.31, p0.003) and TNF inhibitors alone or with
concomitant methotrexate (HR 1.20, p0.74 and HR
1.88, p.001, respectively) in addition to
established risk factors. No association was
found between use of methotrexate or leflunomide
and development of NMSC (HR 1.12, p0.471, HR
0.83, p0.173 respectively).

• Results
• Approximately 94 of NMSC reported during the
  most recent questionnaire were found to be valid
• 738 subjects with RA reported new cases of NMSC
  during follow-up, with a crude incidence rate of
  18.1 per 1000 person-years (95 CI 16.8-19.4)
• 204 subjects with OA reported new cases of NMSC
  during follow-up, with a crude incidence rate of
  20.4 per 1000 person-years (95CI 17.8-23.4)
• Crude incidence rates were reduced to 15.2 and
  15.8 per 1000 person-years for RA and OA
  respectively when subjects with prior history of
  NMSC were excluded

• Methods

• Study subjects are participants of the National
  Data Bank for Rheumatic Diseases who had
  completed at least 2 semi-annual
  self-administered questionnaires from January
  1999 through January 2003.
• 15,789 subjects with RA were identified (40,125
  person-years of follow-up)
• 3,639 subjects with OA were identified (9,988
  person-years) were identified to serve as a
  control group
• Demographic information, comorbid conditions,
  malignancies, and medication use was recorded
• Incidence rates for development of NMSC during
  the period of follow up were calculated
• Univariate and Multivariate Cox proportional
  hazard models were used to estimate hazard ratios
  for the development of NMSC
• Multivariate Cox proportional hazard models were
  used in an analysis performed only on subjects
  with RA to estimate hazard ratios to explore the
  relationship between use of immunosuppressive
  medications and the development of NMSC
• All analyses were repeated using only subjects
  without a reported history of NMSC prior to
  enrollment in the NDB (15, 191 RA and 3,428
  OA patients).

• Conclusions
• As expected, caucasian race and history of NMSC
  were the strongest risk factors for the
  development of NMSC
• There is a slightly increased hazard of
  developing NMSC in RA patients compared to OA
  patients (HR 1.19)
• No association was found between smoking status
  and incidence of NMSC. This may be because
  smoking has been associated with SCC only in the
  past, and we were unable to analyze SCC and BCC
  separately
• HAQ-DI scores were not found to be associated
  with an increased risk of NMSC
• Among RA patients, use of prednisone and use of
  combination TNF-inhibitor and methotrexate were
  associated with an increased hazard for the
  development of NMSC. Use of TNF inhibitor
  without con-committant methotrate showed a
  non-significant trend toward increased hazard of
  NMSC
• It is unclear whether the association between
  NMSC and prednisone and TNF inhibitors is a
  function of specific imunosuppressive agents,
  degree of immunosuppression, increased
  inflammatory activity of underlying disease, or a
  combination of all factors.

Univariate and Multivariate Cox Proportional
Hazard Model
Conclusions In this large, national cohort, RA
was associated with an increased risk for the
development of NMSC. Among patients with RA, use
of TNF inhibitors and prednisone were associated
with an increased risk of NMSC. 
Incidence Rates of NMSC per 1000 person-years
(95 CI) by Age and Gender
Total Income 1.00
0.842 Diabetes 0.92
0.451
Covariates not included in final multivariate
model
This study was supported by a grant from
Bristol-Meyers-Squibb. Dr. Chakravarty was a
recipient of the Centocor CHORD fellowship