Study design
This was a double-blind, crossover randomized controlled trial. Patients were randomized to receive either MTX or placebo (PBO) by subcutaneous (sc) injection during an initial treatment period of three months, followed by a ‘wash-out’ phase of two months and a crossover second treatment period of three months (Figure 1). Period durations of three months’ treatment were selected to capture the relatively slow-acting anti-inflammatory effects of MTX and usual natural fluctuations of the disease. Once monthly, patients were examined, asked to fill out questionnaires and had routine blood tests.
Study population and recruitment
We intended to study the subset of CPPD arthropathy patients presenting with recurrent clinical manifestations of acute mono- or oligoarthritis (‘pseudogout’), or persistent polyarthritis. We enrolled all consecutive patients from the Rheumatology Departments of several university hospitals (Geneva, Dublin, Zurich) and regional hospitals (La Chaux-de-Fonds and Yverdon) who met the inclusion criteria and accepted to enter the study. The inclusion criteria were:
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Definite CPPD disease using the McCarty diagnostic criteria [9].
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Recurrent mono- or oligoarthrits (‘pseudogout’) (at least three flares/six months) or persistent polyarthritis.
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Unsatisfactory response to at least one NSAID or low-dose glucocorticoids (defined by the patient), OR contraindication to NSAIDs and glucocorticoids (defined by the physician).
The exclusion criteria were:
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A contraindication to MTX treatment: hepatic failure, important alcohol consumption, severe renal failure, hematological disease, acute infection.
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A diagnosis of an alternative rheumatic condition: rheumatoid arthritis, connective tissue disease, psoriatic arthritis, gout or any other chronic or recurrent disease associated with oligo- or polyarthritis.
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Inability to fill out a questionnaire in the local language.
The study was approved by the local ethics committees (Geneva, Lausanne, Bern, Zurich, Switzerland and Mater Misericordiae University Hospital, Dublin, Ireland) and the Swiss federal health authorities (Swissmedic). Informed consent was obtained from all participants. The trial was registered (EudraCT N°: 2007-003479-37, ISRCTN79343755) [10].
Randomization/blinding
Patients were randomized to either MTX or PBO in balanced blocks of six by means of a random number generator. The medication codes were kept in sealed envelopes until the end of the study. Both patients and the investigators were blinded to the treatment group assignment.
Intervention
Patients were randomized to receive either MTX or PBO during an initial treatment period of three months, followed by a ‘wash-out’ period of two months, and a subsequent treatment period of three months with the alternative regimen. Patients were started on MTX therapy with 7.5 mg the first week, which was increased to 15 mg/week if tolerated. All patients also simultaneously received folic acid supplementation (5 to 10 mg/week) to reduce side effects, as recommended. Patients received their first sc MTX injection by a nurse and were taught how to perform sc injections themselves. Subsequent MTX injections were self-administered with commercially available pre-filled syringes (Metoject™, Gebro Pharma AG, Liestal, Switzerland) [11]. Identical pre-filled syringes containing NaCl 0.9% were produced and packed by the hospital’s pharmacy. New medications were provided at each visit and exchanged for unused medications, to assess compliance by syringe count.
Patients were allowed to use concomitant medications as judged best by their physicians, without modifications during the study (from three days before T0, to T +8). In addition, treatment of CPPD arthropathy flares with a three-day course of NSAIDs, a three-day course of oral glucocorticoids (≤30 mg/d of equivalent prednisolone) or a three-day course or increase of colchicine was allowed. Intra-articular injections of glucocorticoids or high doses of oral glucocorticoids (>30 mg/day) were not allowed.
Outcome measures
The primary outcome was disease activity score based on 44 joints (DAS44). The DAS44 is a validated assessment tool of disease activity in rheumatoid arthritis (RA) that has been used in many other chronic arthritides. The DAS44 is a composite outcome measure including the number of swollen joints, the number of tender joints and the erythrocyte sedimentation rate (ESR).
Computation of the DAS44 [12]:
The number of tender and swollen joints was assessed by the physicians at the beginning and at the end of each treatment period during the medical examination. ESR was measured at regular intervals on each blood test. General health was evaluated using a Lickert scale ranging from 0 to 10 by the physician.
Secondary outcomes included the number of acute arthritis flares for the acute recurrent forms, and disease and pain levels (visual analog scale (VAS)) for the chronic forms, which have been shown to be sensitive to change in other arthritides
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Acute arthritis flares: Acute arthritis flares (‘pseudogout flares’) are an important outcome as these are one of the most easily recognized concerns of patients. However, flares have not yet been well defined in the arthritis literature [13]; we therefore only recorded the number of subjective arthritis flares and let patients judge what is or is not a ‘flare’ or an ‘attack’. We considered transient increases in concomitant glucocorticoids as a flare equivalent.
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Pain: Pain was measured using a VAS of the target joints.
Safety: We monitored MTX side effects according to published guidelines [14]. All patients were required to have a recent blood test prior to enrollment to check liver function tests, hepatitis serology (<1 year), blood cells and renal function. A baseline chest X-ray was also performed. All patients had their liver function tests, blood cell count and creatinine tested at monthly intervals. Other potential side effects were monitored at monthly intervals. Among others, patients were specifically asked about nausea, vomiting, abdominal pain, diarrhea, cutaneous affections, mucous ulcerations, cough and dyspnea.
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Other secondary outcomes: Included patient’s global assessment, function of the target joints, ESR and serologic markers of inflammation (blood tests), duration of morning stiffness, number of tender and swollen joints, number of analgesic pills, cumulative dose of glucocorticoids, NSAIDs or colchicine and safety [13]. Patient’s global assessment of their general health was evaluated using a Lickert scale ranging from 0 to 10. Functional impairment were determined by asking the patient to assess function in the involved joints (3 = total disability, 2 = movement possible, 1 = weight bearing possible, 0 = painless full function [13]). We also recorded the length of morning stiffness in minutes, and number of analgesic, and anti-inflammatory pills taken during the previous week. The type of clinical presentation of CPPD arthropathy was based on the number of synovitic joints on the physical examination during the three-month treatment period: one swollen joint was classified as a monoarticular presentation, between two and four swollen joints as an oligoarticular presentation, and more than four swollen joints as a polyarticular presentation. The persistence of the clinical presentation was based on the assessment of the enrolling physician (presence of pseudogout flares) and the duration of patient’s physical impairment by his arthritides (>50% of days impaired classified as chronic arthropathy).
Analysis
We calculated the sample size based on published data on DAS44 changes in trials with MTX in RA, with the goal of being able to detect a difference at least as large as the effect size of a moderate clinical response (0.6 points, EULAR response criteria) [15]. Assuming a matched analysis (crossover design) and a type one error of 5%, 28 pairs would be needed to reject the null hypothesis with a statistical power of 80%.
Efficacy analyses were performed on the intent-to-treat basis. Patients lost to follow-up after enrollment were assumed not to have benefitted from the intervention and a last observation carried over procedure was used to impute the missing follow-up assessments. Individual questionnaire scores, measured at monthly intervals, were correlated and thus an analysis for repeated measure analysis was performed. It is not known precisely when the therapeutic efficacy of MTX emerges in CPPD arthropathy. Based on our pilot study [6], we estimated that the therapeutic efficacy would appear within the three first months after treatment initiation. In order to analyze the DAS44 responses over time for both groups (PBO and MTX), we use a marginal longitudinal model, which consists of modeling parametrically the marginal mean of the responses as well as the correlations between individuals. Since both groups are similar at baseline by design, the marginal expectation of the response depends only on a group effect (MTX vs. PBO), a quadratic time trend specific to each period (in order to capture the natural evolution over time), and the DAS44 at baselines (T0 and T +5, see Figure 1), and an interaction period - treatment group [16].
We tested the possibility of a carry-over effect for patients who received MTX as their first treatment by adding the treatment sequence into the model. We also analyzed the possibility of effect modification by type of CPPD arthropathy (monoarticular vs. polyarticular presentation). All analyses were conducted with the R statistical software (R version 2.15.2) [17].