We hypothesised that a sizeable number of OA patients in fact could have been diagnosed as RA patients if CRP was the primary diagnostic tool. We found that more than a third of the OA patients had CRPM and half had CRP levels corresponding to the levels observed in RA. Secondly, we hypothesized an inflammatory biomarker could be associated with an inflammatory endotype, associated with progression. Interesting only CRPM but not CRP was prognostic for progression of OA.
CRPM is a metabolite of C-reactive protein, which is released from the inflamed tissue after CRP has exerted its effect on its target cells [20, 21]. Both CRP and CRPM are reduced in response to anti-inflammatory treatments such as anti-IL1 or anti-IL-6 receptor antibodies [22, 23]. Presently, no subset analyses for identification profiles associated with progression in OA have been presented. In addition, the literature on CRP as both a biomarker for progression and diagnosis of OA is very contradicting with both positive and negative observations (ref ref). This is of interest in respect disorders like OA, as these disorders are not classically thought of as acute or systemic inflammatory diseases, however a subpart of patients may have an inflammatory endotype that could be associated with progression.
A decade ago, Kerkhof et al. . and Attur et al. , showed that specific genotypes linked with the IL-1β and IL-1 receptor antagonist were associated with radiographic severity of OA. They did not find an association with radiographic progression. These data was further substantiated a year later by Attur et al., that demonstrated that two distinct subgroups existed amongst OA patients where IL-1β expression was increased as compared to controls. This IL-1β endotype was associated with worse pain and function scores as well as radiographic progression. In the OAI-FNIH biomarker consortium, Kraus et al. found that blood markers of cartilage and bone remodelling as well as the inflammation-associated marker hyaluronic acid (HA) was associated with radiographic and pain progression [27, 28]. Of note, as in our investigation, the OAI study was designed to include both progressors and non-progressors, where all subjects had OA at baseline. These data clearly point in the direction of the existence of an inflammatory endotype in OA, and such endotype could be defined by specific risk associated polymorphism and the level of one or more biochemical or transcriptomics markers that assess inflammatory activity.
Progression in OA in clinical trial settings is commonly defined as changes to joint space width or increase in KLG over a time frame of one to three years. However, drivers of progression most likely have different origins amongst patients [1, 29, 30]. Thus, we know how the patients feel and function, but we don’t know why and what drive a worsening of disease. This may be key in understanding why certain drugs fail in development: if only 30% of the trial population will benefit from targeting as specific pathway, and with a plausible 50% response rates, the hurdle for documenting a clinical benefit is high, or impossible. Thus, there is a medical need for better subgrouping of patients by developing tools for endotyping. We propose that emphasis should be put on identifying sub-groups or subtypes of OA and to target drug development to each group followed by investigation of the efficacy . We have recently published that CRPM together with other markers of tissue turnover may further subgroup patients into different endotypes, and that these endotypes display different radiographic progression types in RA . Interestingly, we also included OA patients in the analysis that approximately 25% of the OA patients clustered with a subset of RA patients which were primarily in bone and cartilage markers, whereas about 10% of the patients clustered with RA patients that were high in bone, cartilage, macrophage and interstitial matrix turnover markers including CRPM. CRPM is most likely just one signal of many that could be investigated and combined to enable endotyping of patients and thereby better characterization of the patient profiles and planning of appropriate treatment regimen. CRPM have also recently been investigated in idiopathic pulmonary fibrosis  and spondyloarthropathy  and have been associated with progression. This may suggest that there is a general inflammatory endotype associated with progression of chronic tissue diseases, which may worthwhile investigating for the benefit of patients responding.
A limitation of the OA studies is that all patients have OA at baseline, in contrast to general demographic studies, thus the results cannot be extended to classification of CRPM as diagnostic biomarker (i.e. finding knee OA patients in a risk population). Instead, the analysis is limited to the identification of OA patients likely to develop bilateral and radiographic knee OA. Another limitation is the selection bias which is introduced in a well-defined trial protocol. From a clinical perspective the population was homogeneous, where most subject had KLG 2 and moderate to severe pain; subjects with mild or very severe pain were excluded, and thus the variation in the dataset is narrow and not representative of all types of patients.