Time to Deal with Rheumatoid Cachexia: Prevalence, Diagnostic Criteria, Treatment Effects and Evidence for Management

Cachexia is an early result of rheumatoid arthritis (RA) (rheumatoid cachexia, RC), characterised mainly by involuntary loss of fat-free mass. RC is apparent in 1–67% of patients with RA, depending on the diagnostic criteria applied and the method used for the assessment of body composition. RC is associated with increased inflammation and disability, lower health perception, and greater mortality risk. These changes in body composition are driven by the inflammation process, the low levels of physical activity, the underlying testosterone deficiency and hypogonadism, and the pharmacotherapy required for RA. Chronic inflammation enhances resting energy expenditure as a response to stress, inducing an energy deficit, further propelling protein turnover. The use of corticosteroids and tumour necrosis factor α (TNF-α) inhibitors tend to increase fat accumulation, whereas other disease-modifying antirheumatic drugs (DMARDs) appear to induce increments in fat-free mass. The present review presents all information regarding the prevalence of RC, diagnostic criteria, and comorbidities, as well as the effects of pharmacotherapy and medical nutrition therapy on body composition of patients with RA.


EPIDEMIOLOGY: PRIMARY RESEARCH ON THE PREVALENCE OF RC
Several case-control studies evaluated muscle-mass loss in patients with RA against healthy controls, with many evaluating sarcopenia, or myopenia instead of cachexia.Giles and associates 31 revealed that RA status is associated with greater odds of sarcopenia, excess in BF, and sarcopenic obesity in women, but not men.Distinct body composition phenotypes were more evident among patients in the normoweight BMI category.Furthermore, specific RA characteristics, such as increasing joint deformity, patient-reported disability scores, elevated c-reactive protein (CRP) concentrations, rheumatoid factor sero-positivity, and a lack of current treatment with disease-modifying antirheumatic drugs (DMARDs) were associated with abnormal body composition phenotypes. 31Ecici 32 noted that 31.5% of the newly diagnosed, treatment-naive patients with RA exhibited sarcopenia, with a greater prevalence among men.Furthermore, 3 months of DMARD treatment appeared to reduce this prevalence, although grip strength was further reduced since diagnosis. 32n the other hand, in a Chinese population, Lin et al. 33 evaluated the prevalence of myopenia in patients with RA against age-and sex-matched, healthy controls.Compared with the control arm, patients with RA with normal BMI exhibited a higher rate of myopenia and overfat, and a greater BF as a percent of body weight (BW).Table 1 details the primary studies assessing the prevalence of RC among patients with RA.Most studies had a cross-sectional design, 12,18,[34][35][36][37][38][39] one was a one-year prospective cohort 17 and the remaining were case-control studies, with the control group comprising either of healthy participants [40][41][42] or RC-free patients with an RA diagnosis. 22,43Among patients with an RA diagnosis, the overall prevalence of RC ranged from 1% in the Netherlands 35 to 67%. 12 In a recent meta-analysis, Santo 17 calculated the pooled prevalence of RC at 19% (95% confidence intervals [CI]:07-33%), with a greater prevalence (29%) among studies using dual-energy x-ray absorptiometry (DXA) as the method for assessing body composition.However, in this meta-analysis, one study using the exact same sample was included twice (from two dis-tinct publications), 44,45 indicating a unit-of-analysis issue according to the Cochrane Collaboration. 46Moreover, several studies identified herein, were not included in the aforementioned meta-analysis, as the ones conducted by Hugo, 41 Roubenoff, 12 Santillán-Díaz, 22 Müller, 40 Pineda-Juárez, 39 and the most recent ones published by Santo, 47 Ångström 38 and Papichev. 37The wide CI suggested by Santo and associates 17 meta-analysis reflect the great heterogeneity of the pooled studies, the variety in disease progression observed in participants and the different methodology used to assess RC.Collectively, the available research indicates that studies of better quality are required to assess the prevalence of RC.
Diagnostic criteria for RC Diagnostic criteria for RC differed greatly between studies (Table 2), with several researchers adopting the Engvall et al. 18 criteria, some diagnosing RC using the Elkan et al. 44 criteria and others tailoring their own criteria for RC diagnosis. 40According to Engvall, 18 RC is diagnosed in patients with RA having a fat-free mass (FFM) below the 10 th sex-and ethic-specific percentile and a fat mass index (FMI) exceeding the 25 th percentile.The Elkan 44 criteria appear to be more liberal, diagnosing RC in every patient with RA exhibiting a FFM below the 25 th percentile, in parallel to an FMI exceeding the 50 th percentile.Ångström and associates 38 and Hugo et al. 41 compared the two diagnostic criteria and revealed a greater prevalence of RC when the Elkan 44 criteria were applied.Müller and associates 40 adopted their own criteria, diagnosing RC in patients with ALM/height 2 <20 th percentile for sex and ethnicity and BF (as a % of BW) >25% for men and >35% for women.Pineda-Juárez 39 diagnosed RC in their sample using bioelectrical impedance vector analysis (BIVA).Van Bokhorst and associates 35 applied the stricter staging system for general cachexia suggested by Evans et al. 48These incorporate BW loss (exceeding 5% in the previous 12 months or less in the presence of underlying illness) as the primary criterion, corroborated towards a diagnosis by three of the remaining criteria, namely a) low fat-free mass index (FFMI < 10 th percentile), b) low muscle strength, c) fatigue, d) anorexia, and e) abnormal biochemistry regarding CRP, hemoglobin and IL-6 concentrations (Table 2).The researchers concluded that these criteria do not appear to be clinically useful for the identification and diagnosis of RC, mainly due to the low percentage of patients with RA exhibiting BW loss, although they may be of use for other patient groups with frequent cachexia.Consensus criteria for cachexia, defined as severe loss of BW, muscle and fat mass, were developed by the European Society for nutrition and metabolism (ESPEN), but none of the studies on RA patients have applied these criteria. 49Furthermore, cachexia is a distinct entity from RC, thus specific diagnostic criteria are required.Among the methods used to assess body composition in the identified primary studies, DXA was the most popular one, applied in 8 studies, 18,[36][37][38][40][41][42]44,45,47 followed by bio-electrical impedance analysis (BIA). 12,35,39,44,45Skinfolds were only applied by Lombard et al., 34 using the Durnin and Womersley and Siri equations for the calculation of BF and body density, respectively.Elkan and associates 44,45 additionally compared BIA to DXA and reported that the two methods appear to have a good relative agreement, however, the limits of agreement are wide, indicating that the use of BIA may be restricted for RC diagnosis in clinical practice.

RC and sex
According to Engvall, 18 RC appears to affect predominately women, however, the great majority (83%) of participants in his study were women.On the other hand, Table 1 indicates that women consist of the predominant sex in all of the primary studies, 17 without necessarily demonstrating a greater prevalence of RC. 36,44,45 It should be kept in mind that RA affects more women than men and that body composition changes during menopause, peri-and post-menopausal status is associated with greater loses in ALM and LBM, in general. 50According to the longitudinal Study of Women's Health Across the Nation (SWAN) cohort, the transition to menopause is associated with a double rate of BF accumulation, whereas the use of hormone replacement therapy (HRT) does not appear to predict changes in body composition independently. 51Overall, the transition to menopause and its distinct hormonal changes are considered as an important contributors to predisposing women to sarcopenia and osteoporosis, further aggravating the low physical activity levels. 50On the other hand, a recent meta-analysis 52 suggested that the observed changes in the body composition of women are the result of ageing alone, with menopause possibly contributing only to the decrease in leg FM and the concomitant increase in central fat deposition.On the flip side, analysis of the University of California San Francisco (UCSF) cohort 53 suggested that the LBM deficits observed in RA are greater among men, due to testosterone levels.In men, testosterone levels consist of an important regulator of muscle mass, and according to research, testosterone concentrations decrease in men with an RA diagnosis. 54][56] According to Cutolo and Straub 57 , oestrogens act in both enhancing and inhibiting immune reactions, whereas androgens and progesterone exhibit anti-inflammatory and immunosuppressive effects 57,58 and for this, RA has been 3 2022 274 MEDITERRANEAN JOURNAL OF RHEUMATOLOGY 33  3  2022   suggested to be more severe in men compared to women.Moreover, the phenomenon of androgen-to-oestrogen conversion (intracrinology) is enhanced in inflamed tissues and RA in particular, 59,60 indicating why androgen concentrations are frequently low, whereas on the other hand, oestrogens levels remain normal in patients with RA. 57 These changes prompted researchers to propose androgens and progesterone as favourable therapeutic options in RA. 57 In conclusion, both sexes appear predisposed to altered body composition levels, either as a result of RA (men in particular), or the ageing process and some aspects of the menopause transition (women).

Disease activity and disease duration Epidemiology
According to Fukuda, 61 the continuation of inflammation appears to be essential for the decrease in muscle protein to occur in RC.Elevation of disease activity increases BMI through an increased deposit of FM, with a parallel decrease in visceral muscle being observed.As a result, research in Morocco revealed that greater disease activity and duration were associated with the prevalence of RC, 36 whereas Engvall 18 suggested that DAS28 correlated negatively with the LBM of patients.Uutela 62 further verified this, by showing that poorer muscle performance composite score (MPCS) was associated with greater disease activity in patients with RA.Further evidence was also provided early on by Roubenoff, 12 who reported that LBM was associated with the number of swollen joints and a more recent study showing that disease activity was associated with changes in body composition, indicating the importance of aiming for remission when treating RA. 47 On the other hand, the greatly heterogenous pooled data by Santo 17 failed to reveal the existence of a relationship between disease activity and duration with the prevalence of RC, in line with the results of Santillán-Díaz's 22 underpowered study.Thus, it is logical to assume that the lack of a relationship between disease activity and RC in these studies is probably the result of lower methodological quality.

Interventions
Since proinflammatory cytokines, and particularly TNF-α, are important inducers of RC, 13,63 it is logical to expect that a reduction in inflammation (including TNF-α), would attenuate RC. 5 However, a treat-to-target therapeutic approach with tight control in RA failed to attenuate RC. 5 According to Lemmey, 5 a possible explanation is that RC occurs early in the course of RA, probably even during the preclinical phase.This is indicated by the fact that muscle atrophy and decline in muscle strength are already present before the onset of pain and swelling in patients with RA. 64 In the same vein, RC was associated with erythrocyte sedimentation rate (ESR) at the time of diagnosis 38 and a similar degree of muscle depletion in patients with early RA, 6,65 as well as in those with established RA. 66 Nevertheless, BF appears to accumulate with disease duration, 6 as a possible result of therapy.

Comorbidities associated with RC
5][36] However, it should be noted that RC does not appear to increase cardiovascular disease (CVD) risk. 19According to Masuko, the exact role of RC in increasing cardiovascular risk and clinical prognosis in RA is not clearly understood. 67However, when patients with RC and RC-free ones were compared, no differences were observed regarding classical or novel risk factors for cardiovascular disease (CVD), the prevalence of established CVD, or 10-year CVD mortality risk. 38,43,67According to Elkan, 68 low physical activity levels in RA are associated with increased CVD risk, irrespective of body composition.In an early case-control study of patients with RC, muscle density decline was associated with numerous inflammatory factors. 69RA disability was associated with adverse changes in body composition, with health assessment being inversely related to the ALM. 70However, RC and disability have only been evaluated by Roubenoff and associates, 12 in the first recorded study evaluating the prevalence of RC.No other research has evaluated RC and disability together thus far.Despite the lack of research identifying comorbidities in RC, given that cachexia is a major factor for increased mortality risk, prompt interventions are required to prevent fatal metabolic abnormalities. 67eumatic drugs, body composition and RC Table 3 details all primary studies investigating changes in body composition parameters in patients with RA, following individual medication interventions, or combination therapeutic schemes.Methotrexate (MTX) monotherapy is the first line DMARD agent for DMARD-naïve patients with RA. 71,72 It is yet unknown if MTX monotherapy for RA, 71,72 is beneficial for RC. 67Santillán-Díaz 22 and associates suggested that MTX administration with concomitant folic acid (FA) supplementation may protect against the development of RC.FA is a known cofactor in the metabolism of homocysteine, and low homocysteine levels are associated with greater muscle degradation, reduced muscle strength and lower physical function. 73,74n the other hand, oral nutrient supplementation (ONS) with FA has been shown to reduce homocysteine concentrations during MTX therapy. 75n a comparative effectiveness study, Marcora and associates 65 compared the use of TNF blocking agents (etanercept, ETA) to MTX among patients with RA and showed that the latter induced a 14% increase in FFM TITLE compared to a 44% increase observed in the ETA arm.Both therapies were effective in controlling disease activity and improving physical function.Chen and associates 76 compared subcutaneous injections of ETA against non-biological DMARDs for 1 year and observed a greater BW gain, hyperuricemia prevalence, decreased fasting plasma glucose-dependent insulinotropic polypeptide (GIP) concentrations, and loss of post-oral glucose suppression of plasma leptin concentration in the ETA arm.In a similar trial, Engvall 77 compared treatment with a combination of DMARDs against MTX plus anti-TNF (infliximab, IFX) for a total of 2 years.IFX therapy induced an increment in BF mass, whereas a similar effect was not achieved with the DMARDs combination, despite the fact that both treatments resulted in akin reductions in disease activity.This indicated that the accumulation of FM appears to be drug-specific.In a small sample of women with an RA diagnosis, Serelis 78 evaluated the effect of IFX compared to adalimumab (ADA), on the body composition and adiponectin levels of participants.One year of intervention failed to induce any changes in LBM and FM and no differences were noted in the lumbar spine BMD of participants.On the other hand, anti-TNF treatment for 1-year increased serum adiponectin concentrations significantly.In a similar trial, Toussirot 79 administered three different anti-TNF agents (IFX, ETA, or ADA) to patients with RA and ankylosing spondylitis (AS).After two years of follow-up, a gain in BMI was recorded and an increase in visceral and android fat among patients with RA.Collectively these trials suggest that anti-TNF agents are not effective in increasing muscle mass and are associated with greater FM as compared to csDMARD alone, in particular regarding fat accumulated in the trunk. 24,65owever, an epidemiological analysis of the Veterans Affairs RA (VARA) registry 80 revealed that MTX was associated with a reduced risk of BW loss, whereas prednisone or anti-TNF therapies were not associated with changes in the BMI or the risk of BW loss, independent of other factors.According to Santillán-Díaz, 22 this MTX-induced positive metabolic balance can explain its effects on the immune response effects, namely the extracellular increase in adenosine, and the inhibition of the transcription factor NFκB, the endothelial and inflammatory cell function, the T-cell function regulation. 81,82rednisolone, is a GC, reducing inflammation and improving physical function rapidly and effectively, thus, frequently used as a first-line treatment in RA as part of a combination therapy with other DMARDs.Konijn et al. 30 investigated the effect of two different prednisolone doses, a high-dose and a step-down regimen on the body composition of patients with early RA.Both prednisolone regimens increased total body mass, through an accumulation of FM.However, fat redistribution from peripheral to central tissues was not recorded, contra-dicting the previous assumption of rapid adverse effects of prednisolone on the body composition of patients with RA.On the other hand, Lin et al. 33 revealed that when patients with a normal BMI were considered, approximately 18.2% exhibited myopenia overlapping with overfat.Moreover, in this normoweight subgroup of patients with RC, the worst radiographic scores and highest rates of previous GC treatment and hypertension diagnosis were also exhibited. 33Compared to the patients not exhibiting myopenia and overfat, the normoweight ones with RA on previous GC treatment exhibited a higher rate of myopenia, overlapping with overfat. 33In concert to this observation, Hugo and associates 41 noted that low levels of physical activity and treatment with GCs was associated with increased nutritional complications among patients with RA, including RC and metabolic syndrome.A more recent study conducted in Russia 37 suggested that the median cumulative dose of oral GC in patients with RC appears to be higher, although the finding was not statistically significant.Nevertheless, an early study 36 had also reported a greater steroid cumulative dose among patients with RC, indicating that changes in body composition are also therapy-driven.Apart from TNF-α blockers, other anti-inflammatory agents are often employed in the management of RA.Tournadre and associates 83 evaluated the effect of TCZ treatment, a humanized anti-IL-6 receptor monoclonal antibody, on the body composition and metabolic profile of patients with RA.After one year of treatment with TCZ, BW was significantly increased without any observed changes in the FM.Between months 6-12 of treatment, an increase in appendicular lean mass and skeletal muscle mass index was observed, with a redistribution of BF.The trunk/peripheral fat ratio was decreased and subcutaneous adipose tissue was increased.No changes were noted regarding blood pressure, waist circumference, fasting glucose concentrations, or the atherogenic index of participants.These findings were also confirmed by a French multicentric study, the évolution des ADIpokines et de la composition corporelle chez les patients atteints de Polyarthrite Rhumatoïde et recevant un traitement par Tocilizumab (ADIPRAT) phase IV open-label clinical trial. 84n the ADIPRAT, 84 patients with RA were administered intravenous TCZ (8 mg/kg monthly), as administered in daily practice, with the option to decrease TCZ dosage to 4 mg/kg at the rheumatologist's discretion and the possibility to reduce GCs intake whenever deemed required.After one year of intervention, an increase in adiponectin concentrations was noted, especially at the onset of the treatment.Furthermore, TCZ induced significant gain in LM, BMI and waist circumference, while FM remained unchanged.Schultz and associates 85 evaluated the administration of TCZ in 11 patients with rheumatic diseases (no further information was provided), who were diabetes-free.TCZ treatment for 3 months significantly decreased the homeostatic model for insulin resistance (HOMA-IR), and increased serum adiponectin concentrations.Serum triglycerides, LDL and HDL tended to be increased, whereas lipoprotein (a) levels were lowered post-treatment. 85Finally, Fioravanti 86 evaluated TCZ administration (8 mg/kg TCZ IV, once every 4 weeks) as monotherapy, or on top of MTX treatment for a total 6 months.ESR, CRP, DAS28-ESR and health assessment questionnaire (HAQ) were improved in both arms.In parallel, total cholesterol concentrations were increased and chemerin was decreased in both arms.Furthermore, a variety of methodological issues are apparent in research.Overall, it is difficult to define the exact effect medications have on RC, as most of the studies are either comparing different medication regimens, as it is unethical to leave the patients without medication.Moreover, several trials [83][84][85] used control arms comprising of patients not receiving any medication, whereas one trial used healthy controls as comparators 24 .With regard to the participants included in the aforementioned research items, the majority of studies used patients with RA, medication-naïve or on medication, with active or inactive RA, where changes in body composition were recorded during the course of intervention.Only the trial conducted by Schultz 85 used patients with RC as the patient pool for their intervention.

Dietary treatments, body composition and RC
8][89][90][91][92] Medical nutrition therapy (MNT) in RA mainly aims in stimulating an overexpression of anti-inflammatory cytokines 93 and controlling RC, with tailored nutrition interventions focusing on overcoming impaired protein synthesis and reverting muscle catabolism.A total of four intervention studies have evaluated the use of ONS in body composition among patients with RA, using an RCT design (Table 4).Wilkinson 94 administered ONS against placebo as an add-on therapy for 12 weeks and revealed that although supplementation with creatine increased total and appendicular LM, it failed to improve isometric knee extensor and handgrip strength, and physical function.Marcora and associates 95 compared the results of two different amino-acid drinks administered for 12 weeks, one containing 3 g beta-hydroxy-beta-methylbutyrate (HMB, calcium salt), 14 g of L-arginine (ARG) and 14 g L-glutamine (GLN), diluted in 240 mL of water, drank twice/daily and a comparator drinks with a nitrogen (7.19 g/day) and calorie (180 kcal/day) balanced mixture of ARG (11 g), GLN (1.75 g), L-glycine (6.10 g) and L-serine (4.22 g), diluted in 240 mL of water, drank twice/daily.Dietary supplementation with HMB/GLN/ARG was not superior to placebo in the treatment of RC.However, both amino acid mixtures increased FFM, total body protein (TBP), arms and legs LM, and some measures of physical function.Aryaeian et al. 96 hypothesised that ONS with barberry extract might improve anthropometry and glycemia in patients with RA.Using a placebo-controlled design, they demonstrated that after 3 months BW, BMI, and conicity index increased similarly in both groups.On the other hand, BF (%), low-density lipoprotein (LDL), hips circumference, fasting plasma glucose (FPG), and systolic blood pressure were all decreased in the intervention arm compared to the placebo.Lovell 97 evaluated supplemental Calcium (Ca) intake on the bone mineral density (BMD) of patients with juvenile RA.The two treatment arms received 1,000 mg of Ca and 400 IU of vitamin D, or vitamin D alone, for a duration of two years.At 24 months, the mean BMD among the youngsters receiving Ca was greater, independently of sex, Tanner's puberty stage, medication adherence, or other factors.Finally, recent research on animals indicated that ONS with coriander 98 might have favorable effects in restoring muscle mass, however, this finding has not been verified on humans.In summary, with regard to the dietary supplements, amino acids appear to be promising in improving body composition and possibly attenuating RC although more research is required to validate the findings.Antioxidant supplements like barberry extract appear to target glycemia and by inference, an improvement in other metabolic factors, including anthropometry, may be noted.

Metabolism, body composition and RC
According to Spies, 99 in RA, energy metabolism is regulated by chronic inflammation, not only with regard to energy supply, but additionally for immune response activation and control, through a variety of metabolic signals. 100,101hus, the existence of chronic, low-grade inflammation diverts energy and glucose metabolism from other systems in order to support the requirements for immune response activation. 102,103In the presence of a chronic pro-inflammatory environment, macrophages and lymphocytes switch from a resting state to a highly active one, pedaling the release of host-defense factors promoting phagocytosis and antigen production. 104To counterbalance this metabolic shift, lipid and protein catabolism increase for the production of ATP. 102The higher inflammatory cytokine production stimulates muscle catabolism 10 through the nuclear-factor κB (NK-κB)-dependent pathway, 105 increasing the whole-body protein turnover, triggering muscle loss and the development of cachexia. 106This net protein shortage further increases metabolic rate and in particular, resting energy expenditure (REE) in patients with RA. 12,13,24,107 However, total energy expenditure (TEE) levels appear lower compared to the rest of the population, mainly as a result of low physical activity levels. 108ITLE TEE consists of the sum of the thermic effect of food (TEF), REE and physical-activity energy expenditure (PAEE).With the TEF being dependent on the amount of consumed food, and TEE in RA appears to be mostly influenced by the REE and PAEE of patients.In this manner, the increased REE and the reduced PAEE are developing an energy deficiency environment, further driving the cachectic state. 109everal lines of evidence suggest that REE, disease activity and severity are inter-related in RA and RC.In all of these studies, REE was measured using indirect calorimetry. 107,110,111When REE is calculated using prediction equations instead of being measured, it is not associated with any score or biomarker of disease activity. 112On the other hand, RA-specific equations for the calculation of REE have been proposed, taking into account the levels of CRP. 113n the same vein, although malnutrition would be the logical sequence in this inflammatory environment, the use of standard malnutrition assessment tools seems to fail to detect the need for nutrition intervention in RA, as there may be an increase in FM. 45,88,114 This results in masking the identification of patients in higher risk for RC, since the assessment of cachexia is rarely performed in clinical practice.

Limitations of existing research
A major limitation in the available research on RC involves the diagnostic criteria applied.RA sensitive criteria are necessary for RC diagnosis although it appears that the use of different criteria, not specific to RA increase bias and do not allow for generalization or pooling of the primary studies.Thus, it appears that the need for conducting studies of better quality aiming to assess the prevalence of RC is apparent.

CONCLUSIONS
In 1873, Sir James Paget 115 first described RC; however, research on effective interventions to manage this important problem remains in infancy.It appears that the complex pathophysiology of RA, the adverse effects of polypharmacy in body composition, and the deteriorating metabolic alterations, develop a complex situation which becomes difficult to balance.Nonetheless, it appears that triage for RC identification should be performed as early as RA diagnosis, with constant monitoring of the condition thereafter, in order to better understand the mechanistic effects of RC and improve prognosis in affected patients.

Table 1 .
Primary studies assessing RC in patients with RA.

Table 1 .
Primary studies assessing RC in patients with RA.

Table 1 .
Primary studies assessing RC in patients with RA.

Table 2 .
Diagnostic criteria for rheumatoid cachexia used in the literature.

Table 3 .
Primary studies evaluating the effects of medication for RA on body composition and cachexia.

Table 3 .
Primary studies evaluating the effects of medication for RA on body composition and cachexia.

Table 3 .
Primary studies evaluating the effects of medication for RA on body composition and cachexia.