CHAPTER TWO: Research part [620255]

CHAPTER TWO: Research part

Introduction

Usually, biological therapies are used for “systemic autoimmune processes ”. There can be
extrapolated a future therapeutic target: the potential effect of biological agents into reducing the
severe complications of chronic inflammation, including r enal i mpairment .
Former researches are associating r heumatoid arthritis was associated with a large suite of
kidney disorders , but most of them are attributable to drug use or chronic inflammation .
“Reported prevalence for kidney disease in patients with rheumatoid arthritis ranges from 5% to
50%” [1-2].
Classical treatments used for rheumatoid arthritis like gold salts or d-penicillamine were
likely to be involved in generating proteinuria and kidney disease ” [3].
Long -term administered non -steroidal anti -inflammatory treatment was generally
considered a cause of altered kidney function ”.[4]
A present effective battery of treatments with biologic agents like tumor necrosis factor α
inhibitors or “B cell depleting inductors ’ are widely used and may “elicit effects on renal
function ”.
An increase in mortality and morbidity is given by t he presence of kidney disease ,
considering the implications in the development of cardiovascular impairment . The association
of RA with renal amyloidosis “determines a higher mortality rate relative t o rest of population ”
[5]. Generally, the risk of death is correlated with the occurrence of proteinuria or CKD in
patients with RA ”[6], this involvement being identified also as independent risk factor for
cardiovascular events in such category [7] .

Motivation

Considering the pathological mechanisms involved in the occurrence of ch ronic renal
disease in patients with rheumatoid arthritis, a positive outcome can be obtained by using
biological therapies .

Aim of the study

57 patients diagnosed with rheumatoid arthritis and treated with different kinds of
biological therapies were evaluated retrospectively focusing on renal function. For compare were
also evaluated 62 RA patients treated conservatively with DMARDs .”

Material, methods

The patients were evaluated in the R heumatology Department of Clinical Emergency
hospital “Sf. Apostol Andre i” in Constanta. After taking the legal agreement of collecting
medical data, the information was analy zed from the medical files and the data base of hospital
laboratory . It was important to f ollow strictly the e xclusion criteria that “included pre -existent
renal disease, associated diabetes mellitus with re nal complications or long -term essential arterial
hypertension. “
The indicators used were , beside the demographic data, the lab tests that included the
evaluation of biological syndrome of inflammation ( evidentiated by ESR, CRP) , immunological
parameter s (RF, anti -CCP antibodies) ”and renal fu nction tests (serum creatinine, BUN, 24 -hrs
proteinuria). “Chronic kidney disease (CKD) was stratified according to the CKD -EPI formula
that is calculating estimated glomerular filtration rate (e -GFR) [8 ].”There were necessary 2
consecutive “estimated GFRs (eGFRs) < 6 0 mL/min/1.73 m2 at least 90 days apart using the
CKD -EPI (CKD Epidemiology Collaboration) creatinine equation ” [8].
Data that were collected, were introduced into a database using SPSS 20 for windows
version (SPSS Inc., Chicago, USA), calculating “nominal data SD, w ith Mann -Withney
equation compare for independent variables and t -test for means. ” A value of p ≤ 0,05 was
considered statistically significant.

Results
The groups were presenting a difference of almost a decade in mean age, due to the time
of initiati on for biological therapy – earlier is considered to be preferable in order to avoid the
development of complications.

Figure 14.”Mean age distribution in patients with RA ”

Table n o. I. Clinic and d emographic feature s of RA subgroups
RA treated with DMARDS
(No. = 63) RA treated with biologic
therapy (No. = 58)
Age± SD 65.45 ± 12.13 56.59 ± 13.01
AntiCCP± SD (UI/mL) “85.13 ± 100.78 ” “203.69 ± 214.01 ”
RF”± SD (UI/mL) “90.85 ± 169.5 ” “168.83 ± 251.76 ”
ESR”± SD (mm/h) “42.92 ± 25.17 ” “38.87 ± 25.40 “
CRP ”± SD (mg/L) “2.99 ± 5.42 ” “1.90 ± 3.44
Creatinine ± SD (mg/dL) “1.18 ± 1.01 ” ‘’0.69 ± 0.17 ”
eGFR ± SD ( mL/mi n/1.73
m2) “63.49 ± 21.60 ” “100.36 ± 16.76 ”
Corticotherapy (%, no.) “39.68% (25) ” “13.79% (8) ”
AINS (%, no.) ‘46.03% (29) ” “68.96 % (40) ”

The patients included in the study were diagnosed with constituted rheumatoid arthritis.
The subgroup treated with classical disease modifying drugs (DMARDs) included :”monotherapy
with methotrexate (MTX – 38.09%), leflunomide ( LEF – 9.52%), salazopirine (SLZ – 11.11%)
or combined therapy (41.26%). “
The subgroup that received biologic therapy was represent ed by 10.34% patients treated
with infliximab ( INFLIXIMAB = chimeric half -murine monoclonal antibody against tumour
50 55 60 65 70
RA treated with DMARDS
RA treated with biologic
therapy 65.45 yrs
56.59 yrs Age

necrosis factor alpha – anti TNF – α), 25.86% with adalimumab ( ADALIMUMAB ”= “human
monoclonal antibody against tumour n ecrosis factor alpha – anti TNF – α), 17.24% with
etanercept ( ETANERCEPT ”= fusion protein for TNF receptor by recombinant DNA) and
46.55% with rituximab ( RITUXIMAB ”= chimeric monoclonal antibody against protein CD20
on B cells). Administration of b iologic therapy was made in combinat ion with DMARDs
(51.72% MTX, 32.75% LEF) in all patients .

Figure 15. Types of b iological therap ies used
Both subgroups were presenting use of non -steroidal anti -inflammatory treatment , with a
significant difference in between biologically treated subgroup and patients treated with
DMARDs (39.68% vs.13.79%) 10.34% 25.86%
17.24% 46.55%
0 5 10 15 20 25 30 35 40 45 50
infliximab adalimumab etanercept rituximab

Figure 16.”The use of non -steroidal anti -inflammatory drugs ”

Figure 17.”The use of corticotherapy ”
An interesting observation was made related to i mmunological test results : they were
different in the analyzed subgroups, ”with high values in patients tr eated with biological therapy
for rheumatoid factor (a mean value of 168.83 ± 251.76 UI/mL vs. 90.85 ± 169.5 UI/mL) and for
anti-citrullinated peptide antibodies (203.69 ± 214.01 UI/mL vs. 85.13 ± 100.78 UI/mL) ’. (Table
I) 29 40
0 5 10 15 20 25 30 35 40 45 RA treated with DMARDS RA treated with biologic therapy AINS
25 8
0 5 10 15 20 25 30 RA treated with DMARDS RA treated with biologic therapy Corticotherapy

Figure 18. Mean value of rheumato id factor

Figure 19. Mean value of anti -citrullinated peptide antibodies

“Biologic syndrome of inflammation showed mild difference in mean values of
indicators between the two subgroups, expressed by erythrocyte sedimentation rate (ESR – 42.92
± 25.17mm/1 h vs. 38.87 ± 25.40 mm/1h) and C reactive protein (CRP – 2.99 ± 5.42mg/L vs. 90.85 168.83
0 20 40 60 80 100 120 140 160 180
RA treated with DMARDS RA treated with biologic therapy RF
85.13 203.69
0 50 100 150 200 250
RA treated with DMARDS RA treated with biologic therapy AntiCCP

1.90 ± 3.44mg/L), showing a better control of inflammation in biological therapy group. (table
I)”

Figure 20. Mean value of erythrocyte sedimentation rate

Figure 21.Mean value of C – reactive protein
The two cohorts are presenting different r esults for renal function tests . Those treated
with biological therapies presented a lower mean value for serum creatinine ‘measured both at
baseline and after 6 months of treatment, statistical ly significant compared with the subgroup 42.92
38.87
36 37 38 39 40 41 42 43 44
RA treated with DMARDS RA treated with biologic therapy ESR
2.99
1.9
0 0.5 1 1.5 2 2.5 3 3.5
RA treated with DMARDS RA treated with biologic therapy CRP

treated with DMARDs (figure 21),”showing a mean value of 0.69 ± 0.17 mg/dL vs. 1.18 ± 1.01
mg/dL, p = 0.003. After correction with calculati on of estimated filtration rate, results confirmed
the trend: 100.36 ± 16.76 mL/mi n/1.73 m2 vs. 63.49 ± 21.60 mL/min/1.73 m2, p < 0.00001.

Figure 22.”Different mean values for kidney function parameters in RA patients treated with
biological therapy ’
“Even more, in the biologically treated cohort, patients receiving rituximab present ed a
decrease in the value of creatinine after 6 months of treatment, also minor decrease in case of
those receiving etanercept. The evolution was different when treated with other biological agents
(Figure 23). Still, variations for creatinine values acco rding with the type of biological therapy
were not statistically significant (rituximab vs.etanercept p = 0.09; rituximab vs.infliximab p =
0.11; rituximab vs. adalimumab p = 0.17). ”
1.183
0.694
0 0.2 0.4 0.6 0.8 1 1.2 1.4
DMARDs Biologic therapy Creatinine – mean
p=0.003
63.493 100.361
0 20 40 60 80 100 120
DMARDs Biologic therapy eGFR – mean
p<0.00001

Figure 23. The values in serum creatinine present changes after 6 months of treatment with
different by molecule type s

Patients with treatment with rituximab showed an estimated filtration rate ‘higher than
patients ” with other biological tharapies (eGFR 97.037 mL/min/1.73 m2 vs. 90.933 mL/min/1.73
m2). Even thou, the significance was not statistically increased (p = 0.218) (figure 24).

Figure 24. A higher eGFR present in p atients with rituximab treatment compared with other
biological therapies

0.667 0.713
0.7 0.729
0.628 0.733 0.736
0.721
0.56 0.58 0.6 0.62 0.64 0.66 0.68 0.7 0.72 0.74 0.76
Rituximab Infliximab Adalimumab Etanercept
Creat 1
Creat 2
97.037
90.933
86 88 90 92 94 96 98
Rituximab Others* eGFR
p = 0.218

It was observed a statistical correlation of serum creatinine “with inflammation indicators
like ESR (p<0.000001) and CRP (p = 0.01) in case of group treated biologically .

Discussions

According to studies, renal involvement appears in patients with RA mo re often “during
the first 10 –15 years disease and also, ‘a significant percentage of patients ” with this kind of
rheumatic disease without baseline nephropathy “progressed to CKD over time [9] ”.
Usually, the kidney disease in patients with rheumatoid arthritis may be considered a
“secondary renal disease ”, caused by glomerulonephritis, to therapies with pot ential
nephrotoxicity , amyloidosis or to comorbidities that are associated (like arterial hypertension )
[10-13].
There are also many studies that are enlightening the implication of chronic inflammation
in the occurrence of renal involvement. The progressi ve decrease in the renal function may be a
result of s ystemic inflammation , and knowing this, the use of ‘ anti-inflammatory biologic
agents ’ such as TNF -α antagonists, could have a good therapeutic potential in to “preventing
CKD progression in RA ”[14].
Patients with RA may present a renal disease determined by the chronic use of a nti-
inflammatory drugs. In our study it was observe d an assoc iation in the “use of glucocorticoids
and the decrease of renal function expressed by lower eGFR in the cohort ’ that was using such
anti-inflammatory therapy. Many may take into consideration that the situation of patients with
such chronic recommendations is indicating a higher disease activity or the relation with
comorbidities and by this is increasing the risk of CKD, ”resulting in rapidly declining renal
function. ”Corticosteroids were found to be correlated with the increased risk of a low estimated
glomerular filtration rate (eGFR) < 45 mL/min/1.73 m2 in patients with RA [12].

It was observed a higher value for e GFRs in NSAID users “compared with nonusers
(eGFRs, 89.3 ± 23.9 vs 81.2 ± 10.2 mL/min/1.73 m2; P = 0.005). ” Considering this observation,
it can be introduced the idea of a protective role of NSAIDs for the occurrence of CKD, in
compar ance with the use of corticosteroids. This theory is only extrapolated, because the result
could be influenced by the better kidney function at the baseline or by the presence of fewer co
morbidities in analyzed patients .
‘The increased averages for antibodies, like rheumatoid factor and anti -cyclic
citrullinated peptides antibodies in the group that receiv ed biological therapy should be
extremely attentive analy zed with direct relation with indications of therapeutical plan. ‘The high
risk of evolution to permanent destructive disease given by high titers of antibodies, makes those
patients more prone into receiving a potentially remissive therapy like anti -TNF a gents, than
seronegative forms. ’”The potent anti -inflammatory response can be visible in our study by
analyzing the inflammatory indicators like ESR and CRP, which themselves are correlating with
a better renal function in this cohort.
“The superior result s of filtration rates in the biologically treated patients, is effectively
underlying the implications of chronic inflammation into developing chronic kidney disease.
Evaluation at a subsequent later measurement after enrollment in the study sustains the
importance if th e suppression for inflammation. ”
“”The evolution of renal function was little different in the patients using different types
of biologic agents, even if they are belonging to the same category . “ In the study, the most
efficient into “preve nting effects of chronic inflammation ” was the CD20 antibody (rituximab),
therapy that provided proper filtration rates , and the patients had a good evolution under
treatment.

The study presented in here is limited considering using CKD -EPI equation and th e
values of serum creatinine level in “the evaluation of renal involvement ”. There have been
former “larger studies ”that are considering that all these equations are only estimative, are
underestimating the renal function and “have not been validated in ca se of RA patients [15] ”.
Another important thing is that all the patients were Caucasians, and this represents a limitation
considering no “extension to other ethnic groups. There will be needed exten ded trials for
approving and generaliz ing results for th e characteristics of renal involvement in rheumatoid
arthritis.

Conclusions
It seems that the c hronic kidney involvement in patients with rheumatoid arthritis is more
a result of chronic inflammat ion and represents a n entity apart of abnormal protein dep osits or
the effects of drugs on renal function. Exploration of the risk of reduced kidney function in
diseases that are immune -mediated, implicitly in rheumatoid arthritis is sustained by the positive
effect of biological anti -inflammatory therapies.