We retrospectively evaluated 441 RA patients who
were followed up at our Rheumatic Diseases Followup
Clinic. The patients’ final examinations, disease
activities, and functional status revealed statistically
significant improvement compared with their initial
states. Radiological damage did not progress, and
the majority of patients had drug compliance. A
meaningful correlation was found between the final
HAQ levels and the Larsen scores when compared with
the number of tender and swollen joint.
The purpose of RA therapy is to put the disease
into remission within a short period of time and
maintain it for an extended period, thus preventing the
emergence of complications and freeing the patient for
daily life activities. One of the early arthritis evaluation
recommendations published by the EULAR in 2007
contains the number of sensitive and swollen joints, global evaluation of the patient and the doctor, followups
in one to three month intervals, requisition of
X-rays every six to 12 months in order to determine
structural damage, and the employment of a functional
measurement instrument, such as the HAQ, in disease
activity monitoring.8
The aim of the follow-ups is to be able to control
disease activity, identify any drug side effects, see the
deformities in the joints and take appropriate measures
to help the patient deal with them, evaluate any
accompanying psychological problems and provide
counseling if needed, and increase the patients’
compliance with the disease and the therapy.2
In our study, the female/male ratio was about 4/1.
This ratio is in keeping with previous studies.9,10
Sany et al.10 in their study with French RA patients
found the average age of disease onset to be 44 years
old, and our study had a similar age of 42.
The delay between the disease onset and diagnosis
in RA is reported to be nine months on average.11 We
found this time to be longer. This data might suggest
that patients referred with joint complaints should
be examined with particular attention paid to the
possibility of RA.
Erosions, which are the signs of structural damage
in RA, occur during the initial two-year early period of
the disease. Radiological erosion was found in 59.3% of
the patients in our study. Another study showed that
75.2% of the patients had erosion.12
Our study found the rheumatoid nodule rate to be
7.5%. In another study conducted in our country, the
nodule rate was again found to be 7.5%.9 Carmona
et al.13 reported the nodule rate in Spanish patients
to be 24.5%. This data possibly suggests that RA
presents with fewer nodules in Turkey and that the
disease presents differently in various geographical
regions.
Our study found extra-articular involvement
to be 21.5%, but we evaluated nodule presence as
a result of extra-articular involvement, which can cause an increased extra-articular involvement rate.
The study of Calgüneri et al.14 similarly reported
extra-articular involvement to be 38.4%. In order
of frequency, they found rheumatoid nodules in
18.1% of the patients, secondary Sjögren’s syndrome
in 11.4%, pulmonary involvement in 4.8%, Livedo
reticularis in 4.8%, Raynaud's phenomenon in 3%,
carpal tunnel syndrome in 2.8%, vasculitis in 1.3%,
amyloidosis in 1.1%, and Felty syndrome in 0.3%.14
In our study, pulmonary involvement was found to
be the most common type of involvement other than rheumatoid nodules. These were followed by the
presence of secondary Sjögren’s syndrome and eye
and hematological involvements.
In our study, 29.5% of cases showed no hand or leg
deformities. Baysal et al.15 in their study, found the
most common form of leg deformity to be pes planus,
whereas we found the most common form to be hallux
valgus. This data reveals the need for the use of an
orthosis that prevents and corrects deformities in order
to increase patient functionality.
Hypertension was the most frequently presented
disease with our RA patients. It has been reported that
the incidence of hypertension increases in RA patients
compared with the general population. This is most
likely triggered by inflammation.16
Rheumatoid factor was found to be positive in
60-80% of RA patients.17 In the aforementioned study
by Calgüneri et al.,14 68.3% of patients were found
to be RF positive, whereas RF positivity was 72.2%
in the multi-centered study of Bodur et al.9 In our
study, RF positivity was 59.4%, which is lower than
in previous studies. The lower rate of RF positivity
most probably comes from the calibration difference
between laboratories.
Therapeutic approaches to RA have undergone
changes over time with a better understanding of the
efficacies and side effects of available drugs and the
introduction of new therapy agents. Combination
therapy was preferred in the RA patients that we
followed. The steroid usage rate in our cases was
found to be lower than other studies.9 Although there
have been patients who used small-dose steroids for
extended periods at our clinic, they are normally used
as a ‘‘bridge therapy’’ until signs emerge of the efficacy
of the DMARDs. Therefore, only a minority of our
patients used steroids for extended periods.
Our study examined whether patients had drug
compliance and also looked at the underlying causes
for non-compliance. We found that 84.6% of the
patients we were able to question had complaints
about the dosage and administration period of the
prescribed drugs. In a study by Tuncay et al.,18 it was
observed that 11.6% of 86 RA patients followed for one
year were constantly noncompliant. In our study, the
higher number of patients might have increased the
noncompliance rate. A study that explored the factors
which underly drug noncompliance demonstrated that
patients neglected to take the drugs mostly due to
their side effects. Forgetfulness was the second most
common reason for noncompliance, with inefficacy
being the third and multiple drug use being the
fourth, The “termination of social security benefits”
or “inability to afford medicines” were underlying
socioeconomic factors for noncompliance. The study
by Tuncay et al.18 also found that forgetfulness was the
most common cause of patient noncompliance, with
the second reason being dyspeptic complaints. These
results show that forgetfulness is the most important factor in drug noncompliance in RA patients. Devising
charts to remind the patients to take their drugs or
having family member support could provide solutions
to this problem.
We also determined the number of patients in
our study who experienced drug side effects and the
types of side effects that afflicted them. More patients
(34.9%) were found to experience side effects due to
methotrexate (MTX) usage. Gastrointestinal (GIS) and
hepatic side effects are most frequently encountered in
MTX therapy.19 In our study, GIS side effects were found
to be the most frequent, depending on MTX usage, and
this was in agreement with the literature. The next most
common side effects were hepatotoxicity, pulmonary
involvement, mucosal ulceration, hematological side
effects, and pruritus. As a result, the MTX therapy
in 37.6% of the patients was discontinued, folic acid
was added to the therapy in 46.1% of patients, and
the subcutaneous MTX form was introduced in 9.7%
of the patients for cases of gastrointestinal tolerance.
Numerous studies, including a meta-analysis, exposed
that folic acid and folinic acid reduced nausea and
mucous membrane ulcerations, which are the primary
side effects of MTX.20 Administration of folic acid with MTX therapy in RA patients, started from the
onset of the disease, could prove to be effective in
reducing GIS side effects. Another alternative is the
introduction of the subcutaneous form of MTX.
In a study which focused on a five-year follow-up of
102 RA patients receiving sulfasalazine (SSZ) therapy,
the side effect rate was found to be 25.4%, with the
most common side effects being GIS in nature.21 In
our study, side effects were found with SSZ usage in
16.5% of patients, with those associated with GIS issues
being the most frequent. This type of therapy was
discontinued in 84% of cases observed with side effects,
and the dosage was reduced in the others.
The rate of side effects for leflunomide (LEF) was
6.3%. A study conducted in our country reported that
LEF was discontinued due to hematological side effects
and hepatotoxicity.22 In our study, hepatotoxicity was
found to be the most common side effect connected
with LEF usage, followed by pruritus and GIS side
effects.
The most severe side effect observed with
hydroxychlorochine (HCQ) is retinal toxicity, which
can result in loss of sight. Therefore, it should be
emphazed that patients with RA need to be examined
by an ophthalmologist prior to starting an antimalarial
therapy, and there should be subsequent
routine checks.23 In our study, we found that 4% of the
patients showed side effects with HCQ, 83.3% of which
were retinal toxicity. In these cases, HCQ therapy was
discontinued.
We also identified non-medical therapy practices
which had been recommended to the patients. A
study by Vliet Vlieland24 showed strong evidence
for the efficacy of exercise and less evidence for
joint protection programs, orthosis usage, and
electrophysical modalities. Our study found that
19.5% of the patients received a minimum of one
type of physical therapy throughout their disease
period. The rate of exercising patients remained as
low as 10.2%. The reason for the this might be lower
education levels. When diagnosed, patients should be
briefed and encouraged to exercise. The influence of
non-medical therapy practices need not be ignored
as they provide another link in the chain to aid the
patients. We found that 8.4% of the patients were
using orthosis, with the most common being insoles
for pes planus and hand-wrist splints for carpal
tunnel syndrome and ulnar drift.
Many studies have emphasized the importance of
regular evaluation, and it has been suggested that such an intensive follow-up allows for better evaluation
of the patients’ response to therapy and improved
results in disease activity, radiographic progression,
physical function, and quality of life.2,3 To follow
up our RA patients, we have been using morning
stiffness duration, number of sensitive and swollen
joints, global assessments of the patient and the doctor,
and pain level along with ESR and CRP values in
order to monitor disease activity. In this study, a
meaningful improvement was observed in morning
stiffness duration, pain level, patient global assessment,
and the number of sensitive and swollen joints in the
patients’ final follow-ups.
In the TICORA study, 55 RA patients were
intensively followed up while 55 others were followed
up in a routine fashion. They were monitored and
compared for a period of 18 months. As a result, an
improvement was found in sensitive joint, swollen
joint, pain level, ESR, and CRP as well as in patient
and doctor global assessments in both groups, with
the ratio being higher in the patients followed more
intensively.3
In the Computer Assisted Management in Early
Rheumatoid Arthritis (CAMERA) study, 299 RA
patients were followed up for a period of four years.
The patients were classified into two groups: patients
under a one-month interval intensive follow-up with
a computer-controlled system and patients under a
classical quarterly routine follow-up. Both groups were
treated with the same dosage of MTX. Two years later,
50% of the intensively followed patients and 37% of the
classically followed patients had been in remission for
at least six months. Sensitive joint, swollen joint, ESR,
and pain levels of both groups generally showed an
improvement.[25]
In the TICORA and CAMERA studies,3,25 a
meaningful improvement was detected in the ESR and CRP levels as well as for acute-phase reactants, but
in our study, only the CRP level showed significant
improvement. As ESR is dependent upon plasma
fibrinogen levels, it rises and improves later than CRP.
As CRP’s half-life is short, it is quickly restored to its
normal value once the inflammation is over.[26] These
results reinforce the view that the CRP level is more
valuable for inflammation follow-ups.
Our study struggled to produce answers to the
following questions: “How well did we treat the
patients?” and “What is our disease activity score
and remission rate at the end of the therapy?”. A
meaningful improvement was discovered in DAS28
scores compared with the scores at the onset of followup.
When we grouped our results according to the
EULAR disease activity criteria, it was found that
the rate of patients with high disease activity was
reduced in the final check-up compared with the
initial admission, that the rate of patients in moderate
disease activity remained nearly the same, and that
the patient rates in mild disease activity and remission
significantly increased. These findings demonstrated
that a large portion of the patients benefited from
therapy and follow-up, but some of them still needed
additional therapy. Even in early-stage RA, remission
rates do not go beyond 50-60% in the best series.
Besides, there is limited data on the sustainability of
remission.27 Future goals include finding the best
therapy for all patients and finding a cure for the
disease.
Our study found disease activity was lower in the
group with drug compliance. The high number of
patients and extended monitoring period in our study
also need consideration. This data might suggest drug
compliance is important in controlling disease activity
in RA; therefore, the patients need to be informed of
this in order to increase their participation in therapy.
In a study by Nyhäll-Wåhlin et al.,28 it was
demonstrated that the risk of extra-articular
involvement was higher during the two-year follow-up
after diagnosis with RA in patients with high disease
activity and disability and that these patients had worse
prognoses. Likewise, our findings showed that disease
activity was lower in the group with no extra-articular
involvement, thus extra-articular involvement should
be considered in patients with high disease activity.
The patients’ functional levels as well as their disease
activity levels need to be evaluated. The HAQ score is
the most important functional indicator in determining
“restrictedness”, loss of labor, and mortality in advance.
Therefore, it is one of the factors affecting prognosis
in early-stage RA.29 In the Combination Therapy
in Early Rheumatoid Arthritis (COBRA) study and
the Finnish Rheumatoid Combination Therapy (FINRACo)
trial study, it was demonstrated that there
were lower functional losses in five-year follow-ups,
depending on the combination therapy.30,31 Our data
also found a meaningful improvement in the patients’
functional disabilities after comparison of their HAQ
scores during their initial admission and final checkups.
Another study followed 191 RA patients for five
years, and the number of sensitive joints, pain level,
disease activity level, and radiological progression
along with ESR and CRP levels were found to be the
predictive factors on the HAQ score.32 In a study
by Başkan et al.33 it was found that there was a
relationship between the HAQ and disease time, pain
level, number of sensitive joints, Ritchie articular
index (RAI), and laboratory parameters (ESR, CRP)
in female patients, whereas male patients showed no
relationship between the HAQ and disease time and
laboratory parameters. There was only a relationship
with the Larsen scores. In our study, a meaningful
correlation was also found between the final check-up
HAQ score and a combination of the final Larsen score
and the number of sensitive and swollen joints. These
results may indicate that functional levels were most
affected by the number of sensitive and swollen joints.
In our study, the Larsen score was used to evaluate
radiological damage. No meaningful difference was
found in the increase between the change in our cases
at onset and the final Larsen scores. Radiological
progression was discontinued in 59.5% of our patients,
and radiological damage progressed in 29.3%. While
Kremer and Lee34 argued that long-term therapy with
MTX inhibits the radiographic progression of RA,
Pullar et al.35 reported that SSZ significantly reduced
joint destruction. However, Uğur et al.36 demonstrated in their cohort that radiological progression continued
after a one-year follow-up period and that joint damage
also continued to increase in patients who stayed in
remission.
Li et al.37 found a meaningful relationship between
disease time and the Larsen score. In another study,
a weak correlation was revealed between the HAQ
score and the Larsen score, whereas in a study done
in our country, the Larsen score was related to disease
duration in female patients and the HAQ in male
patients.33,38 However, in our study, we found that
the progression in the Larsen score increased parallel
to an extension in disease duration and found no
correlation between the change in the Larsen score
and the functional level at onset and change in disease
activity. In light of this data, despite today’s RA therapy
approaches, it is possible to conclude that radiological
progression is still inevitable in patients who are in the
advanced stages of the disease.
Declaration of conflicting interests
The authors declared no conflicts of interest with
respect to the authorship and/or publication of this
article.
Funding
The authors received no financial support for the
research and/or authorship of this article.
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