Efficacy of combination DMARD therapy vs. hydroxychloroquine monotherapy in chronic persistent chikungunya arthritis: a 24-week randomized controlled open label study Vinod Ravindran & George Alias
Clinical Rheumatology Journal of the International League of Associations for Rheumatology ISSN 0770-3198 Clin Rheumatol DOI 10.1007/s10067-016-3429-0
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Author's personal copy Clin Rheumatol DOI 10.1007/s10067-016-3429-0
ORIGINAL ARTICLE
Efficacy of combination DMARD therapy vs. hydroxychloroquine monotherapy in chronic persistent chikungunya arthritis: a 24-week randomized controlled open label study Vinod Ravindran 1,2 & George Alias 1
Received: 12 September 2016 / Revised: 18 September 2016 / Accepted: 20 September 2016 # International League of Associations for Rheumatology (ILAR) 2016
Abstract In a proportion of patients, chikungunya arthritis (CA) might run into a chronic persistent phase. The treatment for this phase is not very clear. In this randomized parallel group open label study of 24 weeks duration, we evaluated the efficacy of DMARD combination in persistent CA. Consecutive 139 patients with persistent CA (persistent arthritis for >1 year after the chikungunya fever either in 2008 or 2009 fulfilling epidemiological criteria for CA) were screened. Of these patients who were already taking hydroxychloroquine (HCQ) and had active arthritis were randomized to receive either fixed-dose combination therapy (methotrexate 15 mg/day, sulfasalazine 1 g/day, and HCQ 400 mg/day) or continue with HCQ 400 mg/day (dose optimized) monotherapy. Both groups received oral prednisolone up to 6 weeks. Assessments at every 4 weeks were carried out for primary efficacy (disease activity score; DAS ESR 28) and secondary efficacies, HAQ—Indian version and pain VAS100mm. Seventy-two patients were randomized (37 combination therapy, 35 monotherapy). Both groups were well matched in all respects. At 24 weeks, the combination therapy group showed significant improvement in both disease activity (mean ± SD DAS28; 3.39 ± 0.87 vs. 4.74 ± 0.65, p < 0.0001) and disability (mean ± SD HAQ; 1.4 ± 0.31 vs. 1.88 ± 0.47, p < 0.0001). At the study end, pain VAS was significantly less in the combination therapy group (46 ± 6.13 vs. 60.8 ± 11.6, p < 0.0001). Three patients withdrew from the combination group (inefficacy; 2, adverse event; 1) and seven from monotherapy (inefficacy; 7). This * Vinod Ravindran
[email protected]
1
Department of Rheumatology, PVS Hospital, Calicut, India
2
Centre for Rheumatology, Calicut, Kerala 673009, India
study provide evidence that for chronic persistent CA combination DMARD therapy with methotrexate, sulfasalazine and HCQ is superior to monotherapy with HCQ. Keywords Arbovirus . Epidemic . Methotrexate . Musculoskeletal . Viral arthritis
Introduction Chikungunya (CHIK) infection is mainly endemic to tropics [1]. Since late 2000, several countries have experienced epidemics of CHIK infection which is predominantly a self-limiting, severely painful, febrile, arboviral musculoskeletal illness, though many infected will remain asymptomatic [1–4]. Due to international travel, many non-endemic countries have also come across patients suffering from chikungunya arthritis (CA) [5]. Outbreaks have been reported in Italy [6] and in 2014 in the Caribbean where over 10,000 confirmed/ suspected cases were reported [7]. In the acute phase, the arthralgias are predominantly peripheral involving ankles, wrists, and phalanges and can be disabling [2, 8]. In about 10–20 %, CA might run into a persistent polyarticular phase which may even resemble rheumatoid arthritis (RA) [8, 9]. The acute phase of CA is generally managed with nonsteroidal anti-inflammatory agents and/or hydroxychloroquine (HCQ) [2, 5, 10]. However, the therapy of the chronic persistent CA is not very clear and many patients continue to receive HCQ without any evidence of same benefit as in the acute phase. Given the fact that chronic persistent CA is very disabling and has the potential to damage the joints in a similar way as RA, it appears logical to consider aggressive therapy with Disease-Modifying Anti-Rheumatic Drugs (DMARDs) [9, 11]. Though attractive, such approach in the management of chronic persistent CA has not been
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formally appraised in a controlled study yet. The primary objective of this prospective study was to evaluate the efficacy of DMARDs combination in the chronic persistent CA.
Methods Patients This was a prospective randomized parallel group open label study of 24 weeks duration. Between March and June 2010, consecutive consenting adult patients with chronic persistent CA (defined as persistent arthritis for >1 year) after the CHIK fever fulfilling following WHO case definition [12] of confirmed case either in 2008 or 2009 were screened: Chikungunya fever is confirmed if the patient meets one or more of the following findings irrespective of the clinical presentation: & & &
Virus isolation in cell culture or animal inoculations from acute-phase sera Presence of viral ribonucleic acid (RNA) in acute-phase sera as determined with RT-PCR Presence of virus-specific IgM antibodies in single serum sample in acute phase or 4-fold increase in virus-specific IgG antibody titer in samples collected at least 3 weeks apart
For this, history was obtained to establish the typical narration of fever and medical records were reviewed including the results of serology done at that time. Of these patients who had active disease (defined as those who had three or > swollen and six or > tender joints and ESR >28 mm/h) [13] and were already on HCQ therapy were randomized. Simple randomization was carried out using computer generated random numbers and allocation was concealed by using sealed envelopes. Assessments At baseline, assessments included complete blood count (CBC), erythrocyte sedimentation rate (ESR), liver function tests, serum creatinine, rheumatoid factor (RF), anticitrullinated peptide antibodies (ACPA), and X-rays of hands and feet. Primary efficacy was disease activity measured by the disease activity score (DAS28 ESR) [14]. Proportion of patients achieving the European League Against Rheumatism (EULAR) good response was also recorded [15]. Secondary efficacies were disability measured by Health Assessment Questionnaire-Indian version (HAQ) [16] and pain measured on visual analog scale-100mm (VAS) [17]. ESR, alanine transaminase (ALT) and CBC were done at four weekly intervals and at the study end serum creatinine was also repeated. All assessments were repeated every 4 weeks by the same assessors.
Treatment One group received triple combination therapy (at fixed dose of methotrexate 15 mg/week, sulfasalazine 1 g daily, and HCQ 400 mg daily) and the other continued with monotherapy with HCQ (dose optimized to 400 mg/day). As per the protocol, a switch to injectable methotrexate, subcutaneously once weekly was to be made for those reporting intolerance to oral methotrexate. Both groups were treated for 24 weeks. Both groups received oral prednisolone (initial dose; 7.5 mg daily, tapered off and discontinued at 6 weeks). Paracetamol and anti-inflammatory medications as rescue medications were monitored. Statistical analyses Statistical differences in means were assessed using unpaired Student’s t test. Proportions were compared using Fisher’s exact test. All tests were two tailed, and p < 0.05 was considered significant. The required sample size of 35 per group was estimated to provide 80 % power at 5 % significance level assuming a dropout rate of 10 %. Data management and per protocol analyses were carried out using the statistical package for social sciences, version 17.0. Ethical approval Necessary approvals were obtained from the ethics committee of our institution. Informed written consent was obtained from all patients prior to their enrolment in this study.
Results A total of 139 patients were screened. All these patients had virus-specific IgM antibodies in single serum sample in the acute phase. Of these 72 patients fulfilling both inclusion criteria were randomized (37 to combination DMARDs therapy, 35 to HCQ monotherapy) (Fig. 1). Both groups were well matched in all respects (Table 1). A very small proportion of patients were positive for RF but none were positive for ACPA or had typical erosions of RA on x-rays. Nineteen percent (7/37) of patients in the combination DMARDs group and 14 % (5/35) in the HCQ monotherapy group fulfilled the ACR/EULAR2010 classification criteria for RA (p = 0.754) [18]. On the whole, many patients were on 200 mg/day of HCQ and dose optimization (to 400 mg/day) at the study beginning was required in 20 out of 35 patients in the HCQ monotherapy group. Improvement in all measured parameters were noted at the first assessment at 4 weeks (Table 2); however, in the combination therapy group, significant improvement in disease activity (mean ± SD DAS28 ESR at 8, 16, and 24 weeks were
Author's personal copy Clin Rheumatol Fig. 1 Chart showing study participants flow
3.66 ± 0.77 vs. 4.91 ± 0.69, 3.46 ± 0.86 vs. 4.79 ± 0.62, and 3.39 ± 0.87 vs. 4.74 ± 0.65, respectively; p < 0.0001 for each) was observed (Fig. 2). EULAR good response was achieved in 30 patients (85 %) in the combination group compared to only 5 (14 %) in the HCQ monotherapy group. In addition, low disease activity (LDA, i.e., DAS28 ESR ≤3.2 to >2.6) was achieved in 19 (54 %) patients in the combination therapy group (Table 2). Self-reported disability also improved significantly in the combination therapy group (mean ± SD HAQ at 8, 16, and 24 weeks were 1.54 ± 0.63 vs. 1.97 ± 0.57, 1.33 ± 0.48 vs. 1.9 ± 0.08, and 1.14 ± 0.31 vs. 1.88 ± 0.47, respectively, p < 0.0001 for each) (Fig. 2). At the study end, pain VAS was significantly less in the combination therapy group (46 ± 6.13 vs. 60.8 ± 11.6, p < 0.0001). Table 1 Demographics and disease related variables in the groups
Three patients withdrew from the combination group (inefficacy; 2, AE; 1) and seven from monotherapy (inefficacy; 7) (Fig. 1). The withdrawals for inefficacy in the HCQ monotherapy group took place after the second assessment, i.e., 8 weeks. In the combination DMARDs group, one patient withdrew due to nausea. The use of NSAIDS and paracetamol as rescue medicines was much more in the HCQ monotherapy group (data not shown).
Discussion Chikungunya viral infection is an interesting clinical entity due to its potential to cause severe disability due to chronic involvement of the musculoskeletal system in a sizable
Characteristics
Combination group (n = 37)
Monotherapy group (n = 35)
p
Age (years, mean ± SD) Female (%) RF positive, n (%) ACPA positive, n (%) Erosions DAS28 ESR (mean ± SD) HAQ (mean ± SD) Pain VAS (mm; mean ± SD)
54.05 ± 6.67 65 2 0 0 5.36 ± 0.94 1.94 ± 0.08 64.32 ± 1.75
56.6 ± 7.64 69 3 0 0 5.07 ± 0.88 1.97 ± 0.08 62.57 ± 2.05
0.136 0.933 – – – 0.186 0.770 0.518
Author's personal copy Clin Rheumatol Table 2
Key parameters over time in both groups
Characteristics
Week 0
Week 4
Week 24
Comb
Mono
Comb
Mono
Comb
Mono
SJC, median (range) TJC, median (range)
5 (3–7) 8 (6–9)
5(3–7) 7(6–9)
5(3–6) 7 (6–9)
5(3–6) 6(6–9)
0 (0–2) 3 (0–4)
4(3–6) 4(4–8)
ESR, median (range)
40 (32–65)
38 (30–67)
31 (26–56)
32(28–60)
DAS28, mean ± SD LDA, n(%)
5.36 ± 0.94 0
5.07 ± 0.88 0
5.00 ± 0.13 0
4.9 ± 0.69≠ 0
25(20–44) 3.39 ± 0.87 19 (54 %)
36 (26–55) 4.74 ± 0.65≠ 0
Comb; combination therapy; Mono; monotherapy; SJC, swollen joint count; TJC, tender joint count; ESR; erythrocyte sedimentation rate; DAS28, Disease Activity Score; LDA, low disease activity ≠
p < 0.0001
1. LDA is DAS 28 ESR between 2.6 2. In either group none of the patients achieved remission i.e. DAS 28 ESR of < 2.6.
proportion of patients infected with it. The overall estimate for chronic persistent chikungunya arthritis (CA) is in the tune of 10–20 % with a wide range from 6 % lasting up to 3 years [9, 19] to 63 % in another series of 88 patients in the Reunion Island who were evaluated after a mean 18 months post CHIK fever [20]. In the chronic phase, some of these patients might fulfill the classification criteria for RA [8, 9, 21]. Like RA, its potential to cause joint damage and long-term disability is well documented [9, 11]. As the 2004–2011 CHIK epidemic alone has affected 1.4 to 6.5 million individuals in over 40 countries [22], the long-term disability and economic consequences of chronic persistent CA can rightly be perceived to be staggering. Though ribavirin and interferon-alpha have demonstrated in vitro activity against virus replication, so far no antiviral agent has been shown to be effective against human infection [23]. Our results provide evidence that in chronic persistent CA, treatment with combination therapy using methotrexate, sulfasalazine, and HCQ leads to substantial improvement in disease activity and also reduces disability and pain effectively. This benefit appears to be similar to what has been observed of therapy with combined DMARDs in RA [13, 24, 25]. A previous uncontrolled 16-week study involving
Fig. 2 Disease activity and disability at weeks 8th, 16th, and 24th. DAS disease activity score, HAQ Health Assessment Questionnaire
patients fulfilling only clinical criteria for CHIK fever and having persistent CA for >3 months used injectable MTX and HCQ and bridge therapy with glucocorticoids had also reported good clinical benefit in 149 patients who completed the study [26]. It might be worth speculating the reasons of such benefits of combined therapy in chronic persistent CA. While the acute illness is due to the viremia, the chronic synovitis is believed to be an immune-mediated phenomenon [27]. In both early and chronic persistent CA, levels of cytokines such as interleukin (IL)-6, IL- 8, IL-13, and tumor necrosis factor-α (TNF-α) have been reported to be elevated and chemokines such as monocyte chemoattractant protein (MCP)-1 and macrophage inflammatory protein (MIP)-1 also appear to play important roles in the pathogenesis of chronic arthritis in CHIKV infection [10, 28]. Some of the cytokines such as IL-6 and 13 persists in the chronic persistent phase [10, 29] and it is thought that virus persistence might be also be responsible [10, 27]. Methotrexate, sulfasalazine, glucocorticoids, and HCQ have a complex mechanism of action in RA involving modulation of several of the aforementioned factors; therefore, it is likely that they are somehow able to alter those immune responses in chronic persistent CA as well. We chose a fixed-dose combined therapy with methotrexate 15 mg/week, sulfasalazine 1 g/day, and HCQ 400 mg/day in the combination group and HCQ 400 mg/day in the monotherapy group and treated both groups for 24 weeks. Both group received oral prednisolone at 7.5 mg/day which was gradually tapered and discontinued at 6 weeks in both groups. The reason for choosing a fixed-dose DMARD combination was to allow a fair comparison with HCQ monotherapy with maximum allowed fixed dose of 400 mg/day. The dose of methotrexate at 15 mg/week has been used in several landmark trials in RA and leads to a predictable response in many [13, 24]. In clinical practice, however, we propose that clinicians consider the abovementioned DMARD’s doses at initiation but increase gradually (methotrexate up to 25 mg/day
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and sulfasalazine up to 3 g/day) aiming for either low disease activity (LDA) or remission (DAS 28 ESR swollen and six or > swollen joints and ESR >28 mm/h and as a group had DAS28 ESR of >5.1) and 22 did not. Despite dose optimization to 400 mg/day in the HCQ monotherapy group, improvement in key parameters though present were not significant highlighting the fact in the chronic phase the use of HCQ monotherapy may not be justified though some beneficial effect of HCQ monotherapy in both chronic [3] and acute [10, 30] phase of CHIK arthritis cannot entirely be ruled out. One of the limitations of our study is lack of standardization of the IgM essays done during the CHIK epidemic due to retrospective analysis of records to ascertain it. However, all patients had typical narration of CHIK fever during the epidemic involving several family members and had persistent articular symptoms thereafter. Other limitations include the un-blinded nature of assessments and use of outcome measures such as DAS 28 ESR and HAQ which have not yet been validated in CA. To the best of our knowledge, the present study is the first randomized controlled study appraising the DMARD therapy in chronic persistent CA. In conclusion, our data suggests that an aggressive approach using a combination of DMARDs is effective in chronic persistent CA. It is likely that such approach may be able to stop the progression to joint damage in CA; this aspect require longer studies using radiographic outcomes.
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Compliance with ethical standards Ethical approval Necessary approvals were obtained from the ethics committee of our institution. Informed written consent was obtained from all patients prior to their enrolment in this study.
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Disclosures None. Funding None.
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