Pairwise association of upper extremity musculoskeletal conditions: large population investigation from PERSIAN cohort study

Background People with one area of upper extremity musculoskeletal conditions (UEMSCs) may have other. We aim to determine how frequent is the ipsilateral coexistence of common UEMSCs apparent on interview and examination. Methods This is a large population cross-sectional study conducted as part of the PERSIAN cohort study int Mashhad University of Medical Sciences (MUMS). The study aimed to evaluate individuals for symptoms and signs of the following conditions: carpal tunnel syndrome (CTS), lateral epicondylitis (LE), trapeziometacarpal osteoarthritis (TMC OA), DeQuervain’s tendinopathy, trigger digit (TD), ganglion cyst, and rotator cuff tendinopathy (RCT). The primary outcomes of the study are (1) to determine the side-specific relative risk of each UEMSC coexisting with the second condition, and (2) to identify predictive factors of each UEMSC using side-specific multivariate logistic regression analysis. Results We conducted a study involving 4737 individuals from the staff of MUMS and found significant pairwise associations among UEMSCs on a side-specific basis. Women had more chance of having DeQuervain’s disease (β = 6.3), CTS (β = 3.5), ganglion cyst (β = 2.5), TMC OA (β = 2.3), and RCT (β = 2.0). Each condition (dependent variable) was associated with others (predictors) as follows: CTS: RCT (β = 5.9), TMC OA (β = 4.7), TD (β = 2.9), and LE (β = 2.5). TMC OA: LE (β = 6.4), TD (β = 5.4), RCT (β = 4.3), and CTS (β = 4.1). LE: RCT (β = 8.1), TMC OA (β = 6.4), and CTS (β = 2.5). DeQuervain’s disease: TD (β = 13.6), RCT (β = 4.5), and LE (β = 3.8). TD: CTS (β = 8.8), ganglion cyst (β = 7.6), DeQuervain’s disease (β = 5.7), and TMC OA (β = 4.3). RCT: LE (β = 5.8), TMC OA (β = 5.5), CTS (β = 5.2), and DeQuervain’s disease (β = 4.3). Ganglion cyst: TD (β = 4.8). Conclusion Our study reports significant increased frequency of the UEMSCs among patients who already have one of the diseases, in a large sample size study. Level of Evidence Level II (Differential Diagnosis/Symptom Prevalence Study).


Introduction
Prevention of upper extremity musculoskeletal conditions (UEMSCs) is of significance through understanding their common risk factors.Tendinitis, synovitis, tenosynovitis, osteoarthritis, DeQuervain's disease, epicondylitis, and carpal tunnel syndrome are common UEMSCs.Epidemiological research has discovered strong correlations between these diseases and physical risk factors causing strain [1][2][3].
Carpal tunnel syndrome (CTS), a widely recognized condition with a high prevalence, has prompted investigations into potential association with other upper extremity conditions [4].CTS has been found to exhibit associations with lateral epicondylitis (LE) [5,6], shoulder and cervical pain [7,8], and has notably been observed to co-occur with LE in surgically treated patients [9].LE, commonly known as tennis elbow, demonstrates correlations with DeQuervain's disease, CTS [9,10], and rotator cuff tendinopathy (RCT) [11], potentially indicating shared underlying mechanisms.Biomechanical factors, such as prolonged non-neutral wrist posture, may account for the relationship between CTS and conditions like LE [12].Additionally, there is another study reporting notable relationships between CTS and trapeziometacarpal osteoarthritis (TMC OA) [13].The presence of CTS alongside TMC OA in surgical cases underscores the need for proactive identification and simultaneous treatment to minimize postoperative complications.Furthermore, shared risk factors prompt the investigation of trigger digit's intriguing association with CTS, revealing genetic insights that shed light on potential localized mechanisms [14].In light of these complex association networks, the study hypothesizes an evaluation of the concurrent occurrence of these upper extremity musculoskeletal conditions.
Shared local [15], psychosocial [16,17], biomechanical (occupational) [12,18], metabolic [19], and genetic [14,20] factors, as well as a previous history of upper extremity injury, are hypothesized underlying contributors to the concomitant UEMSCs.By estimating the likelihood that two UEMSCs would develop concurrently, we may focus on high-risk individuals and use physical examinations for early detection and secondary prevention (screening).We herein study the 4737 personnel of the PERSIAN Cohort Study in Mashhad University of Medical Sciences (MUMS) who underwent clinical assessment (history and physical examination) for UEMSCs, to investigate the likelihood of concurrent two upper limb conditions in a large population of healthcare staff.Doing this cross-sectional study, we inquire about the relative risk of common UEMSCs for the second disease existence in side-specific basis.

Setting and population
This study uses the data gathered in (Removed due to Blinding).The study protocol has received approval from the institutional review board of the (Removed due to Blinding), and adheres to the criteria outlined in the Helsinki declaration.Prior to the study, all participants provide their informed consent, and they are free to decide at any time whether to continue participating or not.Patients enrollment process and study design are reported here [21] in details (Fig. 1).

Study design
During a cross-sectional study, one trained orthopedic surgery resident PGY 2/4 (who received training from Dr. A.M., the senior hand surgeon, before the commencement of the study) took history and did physical examination of enrolled individuals to detect the upper extremity conditions, including CTS, LE, trapeziometacarpal joint osteoarthritis (TMC OA), DeQuervain's disease, trigger digit (TD), ganglion cyst, and rotator cuff tendinopathy (RCT).We made a brief self-reported questionnaire and a physician clinical assessment for the orthopedic evaluation of the PERSIAN Cohort Study in Mashhad University of Medical Sciences (MUMS).Diagnosis were made clinically based on history and physical examination, as described in Table 1.Each criterion related to a history question or a diagnostic physical examination test has 1 score.For each condition, diagnosis was made if the person fulfilled all the determined criteria (Table 1).For each condition, people were dichotomized into two groups of "Yes" for those who diagnosed having the disease (positive for all criteria), "No" for those who diagnosed not having the disease (negative for all criteria).Suspicious cases that we could not diagnose the disease or not (positive for some criteria) were excluded from the study.

Descriptive data
The mean age of the study population was 43.5 years, and men-to-women ratio was close to 1.Most of the individuals were married (86.7%), with bachelor degree (45.1%).Nurses and midwives comprised the highest proportion of the population, accounting for 19% (Table 2).

Statistical analysis and outcomes
We used SPSS software (version 26) to perform statistical analysis.Descriptive statistics were reported as mean, standard deviation (SD), and prevalence (%).The relative risk (RR), its p value, and 95% confidence interval were calculated.Statistical significance was two-tailed at p value < 0.05.The primary outcomes of the study are (1) to determine the side-specific relative risk of each UEMSC coexisting with the second condition, and (2) to identify predictive factors of each UEMSC using side-specific multivariate logistic regression analysis.To answer these, we considered limbs as the samples (each individual as two samples).

Diseases prevalence
According to Fig. 1, RCT had the most prevalence (6.9 percent) among studied musculoskeletal conditions.

Carpal tunnel syndrome (CTS)
The RR for all upper extremity conditions was significant among patients with CTS, except for ganglion cyst and Dupuytren's contracture.Women have 3.54 times more chance to have CTS.Individuals with LE, TMC OA, RCT, and TD are 2.5, 4.7, 6, and 2.9 times more likely to have concomitant CTS on their ipsilateral limb, respectively (Table 3).

TMC osteoarthritis (TMC OA)
The RR for all upper extremity conditions was significant among patients with TMC OA, except for ganglion cyst and Dupuytren's contracture.Women have 2.31 times more chance to have TMC OA.Every one-unit increase in the age year led to 1.02-times increase in TMC OA existence.Individuals with LE, CTS, RCT, DeQuervain's, and TD are 6.4,4.1, 4.3, 17.2, and 5.4 times more likely to have concomitant TMC OA on their ipsilateral limb, respectively (Table 4).

Lateral Epicondylitis (LE)
The RR for all upper extremity conditions was significant among patients with LE, except for ganglion cyst and Dupuytren's contracture.Women have 1.62 times more chance to have LE.Every one-unit increase in the age year led to 1.03-times increase in LE existence.Individuals with TMC OA, RCT, and CTS are 6.4,8.1, and 2.5 times more likely to have concomitant LE on their ipsilateral limb, respectively (Table 5).

DeQuervain's disease (DeQ)
The RR for all upper extremity conditions was significant among patients with DeQuervain's disease, except for Dupuytren's contracture.Women have 6.LE, TD, RCT, and TMC OA are 3.8, 13.6, 4.6, and 22.7 times more likely to have concomitant DeQuervain's disease on their ipsilateral limb, respectively (Table 6).

Trigger digit (TD)
Except for Dupuytren's contracture, the RR of all conditions was significant among patients with TD.Every oneunit increase in the age year led to 1.05-times increase in TD existence.Individuals with CTS, TMC OA, DeQuervain's, and ganglion cyst are 8.8, 4.3, 5.7, and 7.6 times more likely to have concomitant TD on their ipsilateral limb, respectively (Table 7).

Rotator cuff tendinopathy (RCT)
The RR of all upper extremity conditions was significant among patients with RCT, except for ganglion cyst and Dupuytren's contracture.Every one-unit increase in the age year led to 1.03-times increase in RCT existence.
Women have 2 times more chance to have RCT.(Table 8).Individuals with TMC OA, CTS, LE, and DeQuervain's are 5.5, 5.1, 5.8, and 4.3 times more likely to have concomitant RCT on their ipsilateral limb, respectively (Table 8).

Ganglion cyst
The RR for TD and DeQuervain's disease was 5.4 and 8.5, respectively (P value = 0.003) among patients with ganglion cyst.Women have 2.57 times more chance to have ganglion cyst.Individuals with TD are 4.8 times more likely to have concomitant ganglion cyst on their ipsilateral limb (Table 9).

Discussion
The primary objective of our study was to assess the concurrent presence of musculoskeletal conditions in the upper extremity.Conducting a large population-based Table 1 Diagnosis criteria 1 Compression test: The examiner placed direct pressure for 30 s over the carpal tunnel (median nerve) between the thenar and hypothenar eminence while the patient's forearm was in the supination position.Any numbness or paresthesia in the median nerve's distribution was indicated as a positive test result.This test is 87% sensitive and 95% specific for CTS 2 Finkelstein test: The Finkelstein test is the standard provocative test for determining the presence of DeQuervain's disease.The patient was instructed to make a fist by actively flexing their thumb to the maximum extent.In order to stretch the muscles in the first extensor compartment, the patient then deviates his or her wrist to the ulnar side.If the patient reports pain in the wrist's first extensor compartment, the test is considered positive 3 Grind test: The thumb grind test is used to evaluate TMC joint arthritis and the health of the basal joint.The examiner conducted the grind test by holding the patient's thumb's metacarpal bone and rotating it in a circle while applying light axial force.A typical complaint from a patient with thumb joint arthritis is a sudden, acute pain at the CMC joint, which may also be accompanied by crepitus; this indicates a positive test 4 Hawkins test: The examiner places the patient's arm shoulder in 90 degrees of shoulder flexion with the elbow flexed to 90 degrees and then internally rotates the arm.The test is considered to be positive if the patient experiences pain with internal rotation.This test is 62-92% sensitive, and 25-100% specific for rotator cuff tendinopathy (impingement syndrome) study, we aimed to investigate the pairwise associations among clinically diagnosed upper extremity musculoskeletal conditions and their prevalence patterns.Notably, our findings reveal a substantial association among the clinically diagnosed UEMSCs.Among the studied UEMSCs, RCT emerges as the most prevalent condition, with a prevalence of approximately 7%, consistent with prior literature [22].RCT's prominence is also reflected in its status as the most commonly identified work-related upper extremity (UE) condition in a systematic review [23].Risk factors for this condition includes age, dominant arm, and trauma history [24].We observed significant associations between RCT and CTS, as individuals with RCT are nine times more likely to have CTS.This association is also observed in another study reporting patients experiencing rightsided RCT having a notable odds ratio of 2.12 for rightsided CTS [25].
We have found that among people with CTS, the RR for LE and RCT is 9.6 and 8.8, respectively.The intricate relationships within the UEMSCs network extend to the structural and biomechanical dimensions.Wee TC et al. provide insights into shared pathophysiology, as common extensor tendon (CET) sonographic abnormalities in CTS patients without clinical symptoms of LE suggest a potential association [26].Moreover, the biomechanical implications of prolonged non-neutral wrist posture, as observed in lateral epicondylitis (LE), raise questions about the potential bidirectional influence between CTS and other orthopedic conditions [12].LE reported in 33% (vs.13% in our study) of patients with surgically treated CTS [9].Among risk factors for women with CTS, tennis elbow had the OR of 1.73 (95% CI 1.34-2.22)[27].Among 512 manual laborers, CTS prevalence reported as 6.6 percent, and this prevalence increased among those with rotator cuff tendinopathy and epicondylitis to 13.3% (vs.22% in our study) and 20.7% (vs.25% in our study), respectively [25].However, it is also possible that CTS is the initiating condition that causes the onset of other problems.TD and CTS frequently coexist, linked by shared systemic risk factors like diabetes, rheumatoid arthritis, and hypothyroidism.A substantial percentage of patients with idiopathic trigger digit also exhibit CTS [19].Recent genome-wide association studies emphasize genetic connections, specifically implicating the DIRC3 gene and IGF-1 signaling, underlining the localized mechanisms contributing to their co-occurrence [14].The concept of "Basal joint pain syndrome" is proposed to address the complex interplay between TMC OA and associated skeletal or soft tissue diseases, highlighting the need for concurrent treatment [28].In fact,  65% of patients required at least one additional surgical procedure, and 75% received therapy for associated musculoskeletal issues before, during, or after arthroplasty surgery [28].It is worth noting that maintaining prolonged and specific postures, such as in professions like dentistry, is associated with thumb osteoarthritis [29].Similar to our results, CTS showed to be 39% (vs.27% in our study) prevalent among patients who surgically treated for TMC OA [13].The reason could be the conjunction of bone architectural changes in CTS and reduced space owing to flexor tenosynovitis.Given the notable association, special effort should be taken to detect or rule out coexisting carpal tunnel syndrome in patients scheduled for basal joint surgery so that, if present, it can be treated concurrently, reducing the risk of postoperative morbidity and delayed symptoms.

Limitations
This study possesses several strengths, notably a substantial sample size and comprehensive clinical evaluations.However, it is not without its limitations.Para-clinical tests of imaging or electro-physiologic  The observation of significant co-occurrence of musculoskeletal conditions within the upper extremity among non-care seeking individuals underscores the importance of employing comprehensive care for both diagnosing and treating these musculoskeletal conditions.

Table 5
Lateral epicondylitis (LE) Ipsilateral association of LE with other upper limb orthopedic conditions (N = 198)

Table 7
Trigger digit (TD) Ipsilateral association of TD with other upper limb orthopedic conditions (N = 80)

Table 9
Ganglion cyst (GC) Ipsilateral association of GC with other upper limb orthopedic conditions (N = 68)