Abstract
Objective Calcium pyrophosphate deposition (CPPD) disease prevalence is similar to that of gout and osteoarthritis (OA), yet CPPD outcomes research greatly lags behind research in these other forms of arthritis. We compared validated patient-reported outcome measures in patients with CPPD vs gout and OA.
Methods Patients with CPPD were recruited from Brigham and Women’s Hospital from 2018 to 2022. Presence of CPPD manifestations (acute calcium pyrophosphate [CPP] crystal arthritis, chronic CPP inflammatory arthritis, and/or OA with CPPD) was confirmed by medical record review. Baseline surveys included the Gout Assessment Questionnaire version 2.0, modified to ask about “pseudogout” rather than “gout”; Routine Assessment of Patient Index Data 3 (RAPID-3); and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). We compared responses in patients with CPPD against published gout and OA cohort studies.
Results Among 47 patients with CPPD, the mean age was 71.9 years and 51% were female. Sixty-eight percent had at least 1 episode of acute CPP crystal arthritis, 40% had chronic CPP inflammatory arthritis, and 62% had OA with CPPD. Pain visual analog scale scores during a flare were similar in CPPD (mean 6.8 [SD 1.9]) and gout (mean 6.7 [SD 2.6]; P = 0.78). Patients with CPPD reported significantly greater unmet treatment need than patients with gout (P = 0.04). RAPID-3 scores in CPPD (mean 8.1 [SD 5.6]) were lower than in gout (mean 12.1 [SD 6.2]; P < 0.01) and similar in OA (mean 6.8 [SD 6.1]; P = 0.30). Patients with CPPD had significantly worse WOMAC stiffness scores than patients with mild OA, and significantly better WOMAC function scores than patients with severe OA.
Conclusion Patients with CPPD may experience pain comparable to that in gout and OA and reported substantial unmet treatment needs.
- calcium pyrophosphate dihydrate
- chondrocalcinosis
- gout
- osteoarthritis
- outcome assessments
- quality of life
Calcium pyrophosphate deposition (CPPD) disease is a common crystalline arthritis that affects an estimated 8 million to 10 million Americans.1 Despite this substantial prevalence, research on CPPD lags far behind that in other forms of arthritis and targeted treatments do not exist. CPPD has several distinct, nonexclusive manifestations as described in the European Alliance of Associations for Rheumatology (EULAR) 2011 terminology recommendations.2 Acute calcium pyrophosphate (CPP) crystal arthritis, historically called “pseudogout,” is characterized by acute onset of self-limited swelling in the joint often accompanied by warmth, redness, and pain. Chronic CPP crystal inflammatory arthritis, previously called “pseudorheumatoid arthritis,” manifests as chronic pain and inflammation most commonly affecting the metacarpophalangeal joints, knees, or wrists. Osteoarthritis (OA) with CPPD is characterized by a joint showing both presence of CPPD and changes characteristic of OA, often in joints atypical for primary OA.
Prospective cohort studies have provided fundamental knowledge about common arthritides, including gout and OA.3-5 Studies using validated patient-reported outcome measures (PROMs) improve our understanding of the lived experience with disease. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) has been validated in OA cohorts and provides information about joint pain, stiffness, and function, whereas the Gout Assessment Questionnaire version 2.0 (GAQ 2.0) has been validated in gout cohorts and provides information on numerous outcomes.6,7 The Multi-Dimensional Health Assessment Questionnaire (MDHAQ) and the embedded Routine Assessment of Patient Index Data 3 (RAPID-3), which have been validated in rheumatoid arthritis (RA) cohorts, are frequently used in OA and gout cohort studies.8,9
We compared PROMs in a prospectively recruited CPPD cohort against previously published gout and OA cohorts that reported the same PROMs to contextualize the burden of CPPD.
METHODS
Study design and participants. Participants were prospectively recruited from the Brigham and Women’s Hospital Arthritis Center, Boston, USA. An initial cohort was recruited from 2018 to 2021 for a research study comparing imaging modalities in CPPD.10 The participants were identified through an electronic health record (EHR) search for patients with recent synovial fluid crystal analysis demonstrating CPP crystals and acute inflammatory arthritis documented in clinical notes.
The Brigham CPPD (BRIC) Registry was established in 2022 to facilitate longitudinal studies in patients with symptomatic CPPD disease. Potential BRIC Registry participants were identified from January 2022 to October 2022 by applying a published EHR-based machine learning algorithm with a positive predictive value of 81% for acute CPP crystal arthritis.11 Patients with chronic CPP crystal arthritis and OA with CPPD were identified by screening the EHR for radiology reports documenting chondrocalcinosis on conventional radiography. We reviewed the EHR for all potential participants to confirm presence of symptomatic CPPD disease; those with asymptomatic chondrocalcinosis were not recruited. Participants were recruited in sequential waves following chart review. All consecutively reviewed patients with symptomatic CPPD disease were invited to participate in the BRIC Registry. Acute CPP crystal arthritis was defined by EHR documentation of acute inflammatory arthritis symptoms in a joint with synovial fluid CPP crystals and/or chondrocalcinosis on conventional radiograph. Chronic CPP crystal inflammatory arthritis was defined by EHR documentation of persistent joint inflammation not attributable to RA or another known inflammatory arthritis, with presence of synovial fluid CPP crystals and/or chondrocalcinosis in the affected joint(s). OA with CPPD was defined by presence of radiographic chondrocalcinosis in at least 1 painful joint documented in the EHR. These manifestations were not mutually exclusive, and a board-certified rheumatologist (SKT) verified that potential participants had at least 1 symptomatic manifestation (see Figure 1). Participants provided written informed consent before the start of any study procedures.
Distribution of CPPD manifestations in this cohort (N = 47). CPP: calcium pyrophosphate; CPPD: calcium pyrophosphate deposition disease; OA: osteoarthritis.
Instruments. As validated PROMs for CPPD have not been developed, we adopted validated outcome measures from OA and gout. At the time of BRIC Registry enrollment, participants completed baseline surveys including a “pseudogout questionnaire” (details described in the next paragraph), additional questions about acute CPP crystal arthritis flares and medication use, the WOMAC, and the MDHAQ. Participants recruited to the study comparing imaging modalities completed the same “pseudogout questionnaire” as BRIC Registry participants and had consented to use of their responses in future CPPD research.
The “pseudogout questionnaire” is a modified version of the GAQ 2.0 originally developed by Takeda and adapted with permission.6 Modifications included replacing “gout” with “pseudogout” throughout and altering questions about urate-lowering therapy to ask about “medication.” The GAQ 2.0 includes the Gout Impact Scale (GIS), rephrased here as the “CPPD Impact Scale” which includes 5 subscores (disease concern overall, medication side effects, well-being during attack [flare], concern during attack [flare], and unmet need) that evaluate the effect of the disease on an individual on a scale of 0 to 100 with 100 indicating the greatest negative effect. The GAQ 2.0 also includes a pain visual analog scale (VAS) 0 cm to 10 cm score to describe pain during flares and asks the number of joints involved in a typical flare.
The WOMAC includes 3 subscores (pain, stiffness, and function) each with a different range; notably, reporting ranges vary between studies.7,12 For the present study, we adopted the following previously published WOMAC score ranges: pain, 5 to 25; stiffness, 2 to 10; and function, 17 to 85.13 Higher values indicate worse pain, stiffness, or function.
The MDHAQ can be used to calculate the RAPID-3, a PROM assessing 3 factors (ie, pain, function, and patient global estimate of status) and is used in a variety of rheumatic diseases. RAPID-3 score ranges from 0 to 30, with 30 representing the most severe effect on patients.
Participants were also asked to select from a list of common CPPD treatments those that they had ever used and those currently taken. Additionally, participants could write in additional medications used to treat their CPPD.
Statistical analysis. For each outcome measure, we used t tests to compare responses from patients with CPPD against historical gout and OA cohorts. t tests were employed given that published data reported means and SDs, rather than medians and IQRs. For comparison of the GAQ 2.0, we used published data from a large gout cohort reported by Hirsh et al.4 For comparisons of PROMs in OA, we used data from Woo et al, because they published separate WOMAC measurements for mild and severe OA using the ranges listed above (see Instruments).13 Woo et al classified OA as mild or severe based on the American College of Rheumatology criteria for functional limitation (“mild” meaning able to perform activities of daily living with or without limited ability to participate in hobbies, and “severe” meaning limited ability to partake in hobbies and work and/or self-care activities14). We used RAPID-3 scores from patients with gout and OA reported by Castrejón et al as a comparator for our CPPD cohort.9 A 2-tailed P < 0.05 was considered significant. Analyses were conducted using SAS v9.4. The Mass General Brigham institutional review board approved all aspects of this study (protocols 2018P002919 and 2021P002962).
RESULTS
Among 47 participants with CPPD, the mean age was 71.9 years and 51% were female (Table 1). Thirty-two (68%) had at least 1 episode of acute CPP crystal arthritis, 19 (40%) had chronic CPP inflammatory arthritis, and 29 (62%) had OA with CPPD (Figure 1). Participants in this cohort most often had > 1 CPPD manifestation; when only 1 manifestation was present, acute CPP crystal arthritis was the most frequent. Medications ever used for CPPD disease included colchicine (53%), oral glucocorticoids (GCs; 49%), intraarticular GC injections (49%), and nonsteroidal antiinflammatory drugs (43%). Four (9%) participants had a history of gout in addition to CPPD and 29 (62%) had OA (Table 1).
Baseline characteristics of 47 CPPD participants.
Of the 29 participants with OA and CPPD, 100% had at least 1 painful joint with radiographic OA in that joint and 21 (72%) had OA and chondrocalcinosis in the same joint (see Supplementary Table S1 for distribution of involved joints, available from the authors upon request). Radiographic OA severity, defined by the degree of joint space narrowing, was mild in 10/29 (34%), moderate in 5/29 (17%), and severe in 14/29 (48%). Twenty-one (72%) participants with OA and CPPD had knee and/or hip OA and of those, 1 reported an acute flare within 1 week of completing the WOMAC. Eighteen (62%) participants with OA and CPPD had synovial fluid aspirated previously, of which 16 (89%) were positive for CPP crystals.
Per manual EHR review, 14 participants had no documented episode of acute CPP crystal arthritis. However, 9 of these 14 participants self-reported at least 1 episode (flare) in their lifetime.
Comparison to OA. Among 574 patients with OA in Woo et al’s cohort, 47.2% were aged ≥ 70 years, 76.3% were female, and knee (82.2%) and hip (10.1%) were the most common sites. OA severity was mild in 219 (38.2%) and severe in 290 (50.5%); the remainder had a prosthetic joint and were not included in the present analyses. WOMAC joint stiffness scores were worse in patients with CPPD (mean [SD]; 4.7 [1.7]) than those with mild OA (3.9 [1.7]; P < 0.01) and similar to those with severe OA (4.9 [1.9]; P = 0.52; Figure 2). RAPID-3 scores were similar in patients with CPPD and patients with OA (P = 0.30). Patients with CPPD reported similar WOMAC physical function (P = 0.79) and pain scores (P = 0.38) compared to those with mild OA. Patients with severe OA had worse WOMAC pain (P < 0.01) and physical function (P < 0.01) than patients with CPPD.
Comparison of PROMs in CPPD vs gout and OA. Figures present mean and SD (whiskers) for each outcome measure; for all measures, higher values indicate worse scores. CPPD Impact Scale data were available for 40/47 CPPD participants and WOMAC data were available for 41/47 CPPD participants. CPPD is shown as black dots throughout, and statistically significant results are presented using brackets. (A) Comparisons of Gout/CPPD Impact Scale subscores range 0 to 100 for each of 5 elements. Gout data are from Hirsch et al.4 (B) Comparisons of WOMAC pain, stiffness, and physical function subscales in CPPD participants vs OA data from Woo et al.13 CPPD: calcium pyrophosphate deposition disease; OA: osteoarthritis; PROM: patient-reported outcome measure; WOMAC: Western Ontario and McMaster Universities Osteoarthritis Index.
Comparison to gout. Among 297 patients with gout in Hirsch et al’s cohort (of which 294 had GIS data), mean age was 62.2 years, 9.8% were female, and nearly half (49.7%) had ≥ 3 gout flares in the past year. Patients with CPPD reported a significantly greater unmet treatment need score (47.7 [27.0]) than patients with gout (38.2 [21.4]; P = 0.04; Figure 2). A greater number of joints was involved on average during gout flares (5.2 [6.9]) than during flares of acute CPP crystal arthritis (2.1 [2.2]; P < 0.01). However, when comparing VAS scores for pain during flare, patients with gout (6.7 [2.6]) and CPPD (6.8 [1.9]) reported similar pain levels during flares (P = 0.78). Results from the GIS indicated that patients with gout and CPPD experienced similar disease concern overall for their gout/CPPD (P = 0.61). Patients with gout and CPPD also expressed similar lack of well-being during attack (P = 0.78). However, patients with gout expressed significantly greater concern during attacks (P < 0.01). Patients with gout also had significantly higher RAPID-3 scores (12.1 [6.2]) compared to patients with CPPD (8.1 [5.6]; P < 0.01).
DISCUSSION
By comparing PROMs in a clinic-based CPPD cohort to those in published gout and OA cohorts, we identified similarities and differences between the patient experience of these common forms of arthritis. Patients with CPPD reported greater unmet treatment needs than patients with gout. Although gout flares typically involved a greater number of joints than flares of acute CPP crystal arthritis, the patient experience of pain during flares was similar. Joint stiffness was greater in CPPD than mild OA. Scores obtained from the RAPID-3, a tool that has not been validated in CPPD, were similar in CPPD and OA, but lower in CPPD than in gout. Taken together, these findings paint a picture of CPPD as a disease with several manifestations that causes painful flares as severe as gout, despite fewer involved joints. Outside of acute CPP crystal arthritis flares, patients with CPPD reported worse joint stiffness but joint pain and function similar to those in patients with mild OA.
That patients with CPPD reported greater unmet treatment need than patients with gout is not surprising, as targeted medications for CPPD are lacking and only a small number of randomized trials have tested treatments commonly used for CPPD.15-17 Our findings underscore the need for development of targeted treatments. Additionally, patients with CPPD reported significantly greater joint stiffness than patients with mild OA, raising questions about whether inflammation related to CPP crystals contributes to worsened stiffness. In addition, these data demonstrate that gout and acute CPP crystal arthritis flares have a similar effect on patients both physically and psychologically.
The patient-reported outcomes collected for this study are in alignment with candidate outcome domains to be measured in CPPD identified by Fuller et al.18 These potential domains, including articular manifestations, function, and analgesic use, were developed by the Outcome Measures in Rheumatology working group by interviewing patients with CPPD and their caregivers, healthcare professionals, and stakeholders.18
Discordance between patients and the EHR in regard to history of acute CPP crystal arthritis flares was common. In a gout study conducted by Gaffo et al, this was also noted as patients and physicians disagreed about the presence of a gout flare at 30% of clinic visits.19 Although the cause of this discrepancy is unclear, these findings highlight the need for a validated definition of acute CPP crystal arthritis flare with input from patients and clinicians.
Among CPPD participants, there was marked heterogeneity in ever use and current use of medications. There have been very few randomized clinical trials of treatments for acute or chronic CPPD, which contributes to the lack of standardization of treatments. Approximately half of our cohort reported use of GCs for CPPD treatment, raising concerns about potential GC-related toxicities in this older adult population.
Limitations of this study include small sample size, which precluded the performance of subgroup analyses to evaluate specific manifestations of CPPD. Validated outcome measures for CPPD do not yet exist, so we used validated PROMs from comparable diseases (OA and gout). At the time of study initiation, classification criteria for CPPD were not established, so we employed the EULAR 2011 definitions for specific manifestations.2 A small percentage of patients in the CPPD cohort also had gout and a moderate percentage had OA, raising the possibility that these comorbid arthritides affected responses to PROMs; we chose to retain these participants in the analysis to reflect the real-world co-occurrence of CPPD with gout, OA, and other rheumatic musculoskeletal diseases. Improvement of OA treatment since publication of Woo et al’s study in 2004 may have also influenced the comparison of PROMs between our present day CPPD cohort and the historical OA cohort. Finally, questions on the modified version of the GAQ 2.0 specifically asked about “pseudogout” rather than “gout,” although it is possible that participants were unable to distinguish between the two.
To our knowledge, this is the first prospective CPPD cohort attempting to quantify symptom severity as assessed by PROMs. Ongoing recruitment to the BRIC Registry will facilitate collection of longitudinal data on CPPD disease. In conclusion, patients with CPPD may experience similar levels of pain during acute flares as in gout and similar physical limitation as in mild OA. These data support the need for targeted treatment strategies in CPPD and interventions to reduce physical limitations.
Footnotes
This study was supported by the National Institutes of Health (grants K23 AR075070 and L30 AR070514).
The authors declare no conflicts of interest relevant to this article.
- Accepted for publication April 4, 2023.
- Copyright © 2023 by the Journal of Rheumatology
