Post Chikungunya Arthritis: A Real Diagnostic and
Therapeutic Challenge
Muhammad IshaqGhauri, Muhammad ShariqMukarram, Ashok
Kumar, Amir Riaz, UroojRiaz, MashoodIqbal
Jinnah Medical College Hospital,
Department of Internal Medicine, Karachi, Pakistan.
Correspondence to: Dr. Muhammad ShariqMukarram,
Email: shariq.msm@gmail.com, ORCiD: 0000-0002-3952-7710
https://doi.org/10.36570/jduhs.2020.1.890
ABSTRACT
Objective:
To evaluate the response of disease modifying anti rheumatic drugs (DMARDs) on
patients diagnosed with post chikungunya inflammatory arthritis attending
outpatient department of Rheumatology, Jinnah Medical College Hospital,
Karachi, Pakistan.
Methods:This
prospective case series study was conducted at Rheumatology clinic of Jinnah
Medical College Hospital in Karachi, Pakistan from January - June 2017 after a
serious Chikungunya outbreak in November 2016. All patients diagnosed with
Chikungunya viral fever who had joint pain refractory to non-steroidal
anti-inflammatory drugs(NSAIDs) were evaluated. All eligible patients were
given a trial of DMARDs along with systemic steroids (tapering) for 6 months.
Clinical response and inflammatory burden were evaluated using theDisease
Activity Score (DAS 28).
Results:Of
112 patients,more than half the population, 65/112 (58%) was in acute flare of
disease at the beginning of study and interestingly not a single patient had
high disease activity (DAS >5.1) at the end of 6 months. Patients who went
into disease remission were able to lead a pain free life, while those with a
relatively higher DAS28 were still struggling with the disease. The overall response
to the therapy was eloquent. None of the patient remained in active flair by
the end of 6 months. The mean DAS significantly decline at 6 months as compared
to the baseline DAS (2.79 +-0.89 vs. 4.96 +-1.11 respectively, p-value
<0.001)
Conclusion:
Chikungunya virus can lead to symmetrical inflammatory
arthritis that phenotypically mimics Rheumatoid arthritis but is not primarily
Rheumatoid arthritis. The pathogenesis of the disease process is still under
study. It is concluded that there is a significant role of DMARDs in treating
arthritis associated with CHIKV which can be used in controlling the
inflammation and disease progression.
Keywords:Chikungunya
(CHIK), Arthritis, Disease modifying anti rheumatic drugs (DMARDs),
Non-steroidalAnti-inflammatory drugs (NSAIDs), Disease activity score 28 (DAS
28)
INTRODUCTION
Chikungunya virus is an arbovirus belonging to
family, Togaviridae and genus Alphavirus is transmitted to humans by infected
Aedes mosquitoes. After mosquito bite, the virus enters the skin and blood
stream. Initial replication takes place in dermal fibroblasts after which the
virus spreads through the blood to different organs including liver, spleen,
lymph nodes, brain, muscle and joints. The viremic period in vertebrate host
may last 2 to 10 days after acquiring the infection. The virus was first
described during a febrile illness outbreak in Makonde in 1952, a province of
Tanzania. The word Chikungunya is derived from the Bantu Language which means
that which bends up and this refers to the position adopted by patients due to
severe joint pain.1
Various risk factors that contribute to the spread
of Chikungunya have been identified including rise in urbanization, weak
healthcare framework in developing countries and a change in climate with augmentation
of mosquito vectors.2Chikungunya fever was initially misdiagnosed as
dengue before the twentieth century. The virus reached Western hemisphere with
an outbreak on Island of Saint Martin in 2013.3
Since a re-emergence of this virus in year 2004, it
has spread into new locations such as Europe and has led to countless cases
throughout countries and around the Indian Ocean.4
Karachi, a city in Pakistan, suffered a similar
massive outbreak in November 2016 in which more than 30,000 people were affected
by the virus. Clinically, it initially presents with sudden onset fever,
polyarthralgia, rash, headache, nausea, fatigue and myalgia. The disease itself
is self-limiting, joint pain can be persistent for months and even years in
some cases.5
At present there are no vaccines or anti-viral drugs
for the prevention and treatment of CHIK viral infection. However, multiple
drugs are under trial. Treatment remains symptomatic with analgesics,
anti-pyretic and NSAIDs.6
METHODS
This
prospective case series study was carried out at the Rheumatology clinic of
Jinnah Medical College Hospital in Karachi, Pakistan, over a period of 6
months, from January - June 2017 after a seriousChikungunya outbreak in
November 2016.
The
inclusion was all adult patients aged more than 18 years of either gender
having positive sign and symptoms of polyarthritis, synovitis, ESR>30 and
normal levels of serum Beta HCG in females of child bearing age, excluding
underlying pregnancy. Whereas patients having oligoarthritis, prior history of
Rheumatoid arthritis, positive RA factor, positive anti CCP and females with
elevated levels of serum Beta HCG were excluded from the study. Upon
ultrasonography 2 females with elevated levels of serum Beta HCG were found to
be 5 weeks and 7 weeks pregnant, respectively. ESR, CRP, RA factor and Anti CCP
levels were determined of all patients, using standard assays.
Disease
burden was calculated using the disease activity score (DAS) 28 score and
patients were classified accordingly. (Table 1)
|
Table
1: Categories of disease activity score (DAS) |
|
|
Score |
Disease Activity Score |
|
<2.6 |
Remission |
|
2.6-3.19 |
Low Disease Activity |
|
3.2-5.1 |
Moderate Disease Activity |
|
>5.1 |
High Disease Activity |
All patients
were evaluated for their joint pain which persisted after chikungunya
infection, refractory to NSAIDs. Diagnostic evidence of infection, for all
patients, was obtained already either by PCR technique during the acute stage
or by the presence of anti CHIK antibody (IgM/IgG) as detected by ELISA> Out
of these 264 patients, 112 were included in the study who fulfilled the
inclusion criteria.
These
selected patients were now diagnosed as having Post chikungunya inflammatory arthritis and were treated with
synthetic DMARDs, Leflunomide (20mg/day) andHydroxychloroquine (200mg twice
daily) along with systemic steroids (10mg/day) which were tapered and stopped
at 6 weeks. The steroids were given to relieve the acute pain until the slow
acting DMARDs come into action.Female patients of childbearing age were asked
to abstain from pregnancy for at least the next 6 months and practice safe
contraception.
All
patients were followed over a period of 24 weeks (6 months) and were monitored
through DAS 28 score, calculated at Day 1 (beginning of treatment), 3rd
month and 6th month respectively.
IBM
SPSS Statistics for Windows, version 21 was used for data analysis. Descriptive
statistics were explored using mean +-SD for quantitative variables like age
and DMARDs whereas frequency and percentages for qualitative variables like
gender and DAS score. Paired t-test was applied to see the mean difference of
DAS score at day 1 and 6 months of the treatment. p-value<0.05 was
considered as significant.
RESULTS
A
total of 112 patients were included. Out of these 71 (63.3%) were females and
41 (36.5%) were males with moderate disease activity (mean +- SD DAS 4.96 +-
1.11). Amongst female population, 46 (64.8) were of childbearing age with serum
Beta HCG within normal limits.
The
DAS 28 on initiation of the therapy revealed more than half the population, 65
(58%) to be in acute flare of the disease (DAS >5.1). No patient was in
remission (DAS<2.6), 15 (13.4%) had low disease activity (DAS 2.6-3.19)
while 32 (28.6%) had moderate disease activity (DAS 3.2-5.1). On 3rd
month, 19 (17%) patients went into remission and the number of patients having
flare of the disease dropped down significantly to 18 (16%). At this point 27
patients (24%) had low DAS and 48 (42.3%) had moderate DAS. (Table 2) DAS score
at the end of 6th month revealed a significant (p-vale < 0.001)
response with none of the patient having high grade disease and the highest
number of patients, 43 (38.4%), were seen in remission. The number of patients
left with low and moderate disease were 41 (36.6%) and 28 (25%) respectively.
Overall, patients were left with low disease activity (mean +- SD DAS 2.79 +-
0.89) at the end of our study. (Table 3)
Although
the therapy was not discontinued after 6 months, we concluded our study as the
duration of therapy is still not decided.
a.
Paired t test applied
b.
Significant
DISCUSSION
The present study was conducted during CHIK viral
outbreak in Karachi, Pakistan. Patients
included in this study were those who presented with polyarticular inflammatory
joint pain. Multiple studies worldwide
have shown that CHIK virus leaves a long lasting burden, typically involving
the musculoskeletal system. A 6 year retrospective case series conducted in
Reunion Island showed 94 out of 159 patients, who were previously free from any
articular disorder, acquired rheumatological diseases including Rheumatoid
arthritis, spondyloarthropathies and undifferentiated polyarthritis.7
A
similar findinglike current study was reported from Saint Martin where an old age
woman acquired severe joint pain after CHIK viral fever, affecting multiple
joints (more than 10), not responding to NSAIDs and steroids. She was later
diagnosed with seronegative, nondestructive, post chikungunya rheumatoid
arthritis, treated with synthetic DMARD Methotrexate.8
Two
phases of the illness have been recognized: acute viremic phase followed by
chronic arthritis. Management of acute period remains symptomatic while that of
the latter phase is determined by understanding the underlying disease process;
whether the chronic arthritis is secondary to the persistence of viral
infection or due to a post infectious inflammatory process.9
Interleukin-17 in particular is responsible for chronic joint pain and
stiffness, stimulating the upregulation of other inflammatory cytokines like
Interleukin-1, Interleukin-6 and TNF α.10 Patients who
fulfilled the inclusion criteria of our study were those suffering from chronic
phase of the illness.
In
the chronic stage of the disease, arthritis can be present for weeks, months or
even years. It has a significant impact on the quality of life of a patient
with restriction of normal activities of daily life.11-13 Majority
of our patients attained remission by the end of 24 weeks but a certain number
population still had persistent joint pain because of which they had to
struggle with their daily chores.
A
study carried out in George Washington University found patients, infected with
CHIK virus, to have joint pain that can persist too as long as 20 months post
infection.14
Detection
of CHIK virus in blood can be done either by serology (IgM/IgG) or by PCR.15Polymerase
chain reaction (PCR) is a reliable test to detect the presence of virus only in
first seven days, after which it becomes undetectable. Five to ten days post
infection,IgM Antibody to the virus becomes detectable and remains positive to
a maximum of 2 to 3 months duration. Antibody IgG, like any other infection,
shows chronicity of the disease and remains positive for years.16
Therefore, as a general rule serology should not be checked in the first week
of illness.
We
presumed the post infectious arthritis, in our population, to be autoimmune in
origin. Based on this phenomenon we had decided to treat our patients with
DMARDs. Further evidence to this can be drawn from a cross sectional study,
which is one of the largest observational study that involved analysis of
synovial fluid of chikungunya arthritis patients. Fluid analysis did not detect
the presence of the virus. On the basis of these results, Dr. Chang explained
the arthritis being secondary to the induction of host autoimmunity which
justifies the role of immunomodulating drugs in its treatment.17Hydroxychloroquine(HCQ)
has been recommended by Brito and colleagues as first line treatment for chronic
chikungunya arthritis in a dose of 6mg/kg. However, they also suggested
escalating the therapy to a combination ofHydroxychloroquine (HCQ),
Sulfasalazine (SSZ), and Methotrexate (MTX) in patients with refractory
arthritis.18 The same triple therapy, as mentioned above, was found
to be superior to HCQ monotherapy in an open labelled trial where patients were
given MTX (15mg/week), SSZ (1000mg/day) and HCQ (400mg/day).19
Although combination therapy was more effective, contribution of SSZ separate
from MTX could not be established. The Brazillian Society of Rheumatology also
recommends use ofHCQ for the treatment of chronic joint symptoms following
chikungunya fever. It may be used alone or in combination with other DMARDs.20
Treatment of chronic Chikungunya arthritis in the above mentioned studies
include Methotrexate with Sulfasalazine combined with Hydroxychloroquine.
However, we combined Hydroxychloroquine(44mg/d) with Leflunomide (20mg/d),
which is an established drug in treatment of Rheumatoid arthritis and we found
this combination to be more efficacious when compared to the aforementioned
trials, as shown in the results.
The
choice of DMARDs to treat Chikungunya arthritis can vary, Mohini. A Ganiin her
study proves the efficacy of Methotrexate, Hydroxychloroquine and Sulfasalazine
in treating post Chikungunya inflammatory arthritis. These drugs were continued
for 2 years. Majority of patients in this study were positive for Anti-CCP.21
We did not include in our study patients who tested positive either for RA
factor or Anti-CCP in order to avoid the study from being biased. It is now
important to consider the diagnosis of Chikungunya in travelers, presenting
with symmetrical polyarthritis, returning from endemic areas.
This
study has certain limitation. Firstly, this study is a single center study with
a limited patient pool. Secondly, the major limitation is the uncertainty to
determine whether patients who achieved remission remained in the same state or
experienced disease progress in future. However, despite of these limitations,
this study highlighted the significant role of DMARDs in treating post
chikungunya inflammatory arthritis.
CONCLUSION
All patients diagnosed with Chikungunya
viral infection are recommended tofollow over a period of weeks to months in
order to evaluate the development of inflammatory arthritis. Based on our
results, we concluded that DMARDs have a remarkable role in treating post CHIK
inflammatory arthritis and reducing the disease progression. Due to lack of
enough clinical evidence, duration of the therapyhas yet not been decided.
AUTHORS
CONTRIBUTION:MIG and MSM
substantially contributed in the conception, designing, acquisition, analysis
and interpretation of the data, AK, AR, UR, MI drafted the manuscript, MIG
revised it critically for important intellectual content, All authors gave the
final approval
ETHICAL
APPROVAL: This study was approved by the research
ethical committee of Jinnah Medical College Hospital.
CONFLICT OF INTEREST: None declared
FUNDING:
None
Received:
January 02, 2020
Accepted: April
02, 20202
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