Preventing progression from arthralgia to arthritis: targeting the right patients

Abstract

Early treatment is associated with improved outcomes in patients with rheumatoid arthritis (RA), suggesting that a 'window of opportunity', in which the disease is most susceptible to disease-modifying treatment, exists. Autoantibodies and markers of systemic inflammation can be present long before clinical arthritis, and maturation of the immune response seems to coincide with the development of RA. The pre-arthritis phase associated with symptoms such as as joint pain without clinical arthritis (athralgia) is now hypothesized to fall within the aforementioned window of opportunity. Consequently, disease modulation in this phase might prevent the occurrence of clinically apparent arthritis, which would result in a persistent disease course if untreated. Several ongoing proof-of-concept trials are now testing this hypothesis. This Review highlights the importance of adequate risk prediction for the correct design, execution and interpretation of results of these prevention trials, as well as considerations when translating these findings into clinical practice. The patients' perspectives are discussed, and the accuracy with which RA development can be predicted in patients presenting with arthralgia is evaluated. Currently, the best starting position for preventive studies is proposed to be the inclusion of patients with an increased risk of RA, such as those identified as fulfilling the EULAR definition of 'arthralgia suspicious for progression to RA'.

Figure 4. EULAR definition of arthralgia suspicious for progression to rheumatoid arthritis (38)

AUC: area under receiver operating characteristic curve; sens: sensitivity; spec: specificity; MCP: metacarpophalangeal; RA: rheumatoid arthritis A sensitive definition requires the presence of at least three items. A specific definition requires the presence of at least 4 items. The reported AUC and sensitivity were calculated in a validation study with the clinical expertise of a group of European expert rheumatologist that evaluated patients in their own practices as reference.(38)

Figure 5. Research agenda

PPV: positive predictive value; RA: rheumatoid arthritis; ACPA: anti-citrullinated peptide antibodies; DMARD: disease modifying anti-rheumatic drugs

Figure 1. Schematic view of rheumatoid arthritis development over time in relation to level of inflammation; it is presumed that disease modifying treatment initiated in the phase of arthralgia may prevent progression to persistent arthritis and rheumatoid arthritis (as indicated with the blue line)

Figure 2. Willingness of persons at risk for RA to take preventive medication, and factors influencing this willingness, schematic representation of data published by Finckh et al (25)

The black line is based on the reported results that 7%, 30% and 38% of persons at risk of rheumatoid arthritis (RA) were willing to take medication if the risk on RA was set at respectively 1%, 20% and 38%.(25) Qualitative studies have shown that persons prefer to receive a yes/no answer on whether or not they will progress to RA (–24) and therefore, if the risk on RA was 100% the willingness of taking medication was set at 95%. Low risk on severe adverse events (SAEs) (≤10%) and high risk reduction of developing RA (≥20%) significantly increased the willingness to take preventive medication which is schematically depicted by the grey lines; reported odds ratios for willingness to take preventive medication were around 4 if risk on SAEs was low and around 7 if the risk reduction of developing RA was high; the odds ratios here depended also on the absolute chance on RA development.(25)

Figure 3. Different approaches of identification of persons at risk of rheumatoid arthritis

RA: rheumatoid arthritis; MSK: musculoskeletal; GP: general practitioner ^a All numbers in this figure are based on data from the Leiden University Medical Centre (LUMC), the only referral center in a health care region of 400,000 inhabitants, and for some calculation combined with data from the local GP network practices in this health care region (RNUH-LEO).(33) ^b According to NIVEL and the local GP network practices (33,39), the yearly incidence of any non-traumatic musculoskeletal symptom was 294/1,000 (based on ICPC codes L1-L20, L84-L93 and T92 in the period 2009-2013 (40)). In a region of 400,000 inhabitants, there will be approximately ˜112,000 novel consultations for MSK symptoms per year. ^c 3,200 novel referred patients are seen per year at the rheumatologic outpatient clinic of the LUMC; we assumed that they all have MSK symptoms. Of these, 70 were newly diagnosed with RA within the first year (average data based on data of the Leiden Early Arthritis Cohort (the only referral centre in a healthcare region of 400,000 inhabitants) of the period 2009-2013 (41). Thus, yearly risk of 70/3200=2.1%. ^d At this outpatient clinic, 145 CSA-patients were identified in 1.8 year (36); this is 80 per year. ^e 75% of these CSA-patients had a positive EULAR definition and 22% progressed to RA.(42) As a reference, of all CSA-patients 17% progressed to RA within one year.(11) ^f Based on an incidence of 25/100,000/year in the general population.(32) ^g Calculations were based on published data from local GP network practices (33,43); these practices are part of the referral region of the LUMC. The total population here is 44,350 patients. Based on the incidence of consultations for MSK symptoms as reported at ^B, it is estimated that approximately 13,000 consultations for MSK complaints were performed in the GP practices yearly. During 2009-2013, 43 polyarthritis cases and 5 oligoarthritis cases were observed and confirmed.(43) Thus, an incidence of 10.2 per year per 13,000 MSK complaints consultations. This is a yearly risk of 0.0008% for this group of patients. There are no data on the number of patients in primary care that the GPs considered as suspicious for arthritis, there is also no data on the outcome of this group.