Osteoarthritis of the knee joint is a common cause of chronic disability worldwide, affecting an estimated 654 million individuals globally and contributing to healthcare expenditure across developed and developing nations.⁽¹⁾ In India, ICMR epidemiological surveys estimate a knee OA prevalence of 22–39% among adults over 40 years, with musculoskeletal disorders accounting for a substantial proportion of disability-adjusted life years lost nationally.⁽²⁾ Region-specific clinical outcome data from semi-urban and rural Indian populations — communities with distinct occupational profiles, healthcare access patterns, and socioeconomic determinants — are limited in published literature.

Davangere, a Tier-2 city in Central Karnataka, has a workforce dominated by agriculture and one of India's largest handloom and textile industries, resulting in repetitive mechanical joint loading from early adulthood. Farmers, weavers, construction workers, and daily wage labourers constitute the majority of the working-age population and likely develop OA earlier and with greater functional disability relative to sedentary urban cohorts.⁽³⁾ Healthcare-seeking behaviour is further shaped by geographic access barriers and economic constraints, likely resulting in delayed presentation and a higher burden of inadequately managed disease at first consultation.

Intra-articular HA injection was developed to restore the viscoelastic properties of osteoarthritic synovial fluid. Its proposed mechanism extends beyond mechanical lubrication: exogenous HA reduces pro-inflammatory cytokines including IL-6 and TNF-alpha, stimulates endogenous HA synthesis, and may promote cartilage matrix synthesis.^(4,5) The 2012 Rutjes et al. systematic review questioned the clinical significance of HA benefits in heterogeneous populations, while the 2015 Richette et al. meta-analysis reported benefit in selected early-stage patients.^(6,7) This divergence has been attributed in part to pooling of mixed-grade populations in earlier trials; the present study restricts enrolment to Grade 1–3 disease.

Several gaps are noted in the existing literature: most HA trials use a 6-month primary endpoint, which may not capture longer-term effects; PASS outcomes are infrequently reported in Indian OA studies; MCID-based responder analyses are uncommon in Indian literature; and HA outcomes have not been characterised in the semi-urban Karnataka population. This study reports 12-month follow-up, MCID-based responder classification, and PASS outcomes in an early-stage OA cohort from Davangere district.

Study Design and Setting This was a prospective single-arm cohort study conducted at the Department of Orthopaedics, Bapuji Hospital and Chigateri General Hospital, JJM Medical College, Davangere, Karnataka, India, over one year. Ethical clearance was obtained from the Institutional Ethics Committee, JJMMC (IEC-13-2026). All participants provided written informed consent in their preferred language (Kannada or English). Sample Size Sample size was estimated for a single-arm cohort with VAS as primary outcome (paired comparison, baseline vs. 6 months), assuming MCID of 2 points, SD = 2.5, alpha = 0.05 (two-tailed), and power of 80% — yielding a minimum of 22 subjects. Accounting for 30% dropout, the target was 40 subjects. Forty-two patients were enrolled, all completing 12-month follow-up (attrition: 0%). Inclusion and Exclusion Criteria Inclusion Criteria: • Adults aged 18–65 years • Knee OA diagnosed per ACR clinical classification criteria • Symptoms >3 months, inadequately controlled by prior conservative management • K-L Grade 1, 2, or 3 on standing weight-bearing plain radiographs • Written informed consent and willingness to comply with 12-month follow-up Exclusion Criteria: • K-L Grade 4 or secondary OA (post-traumatic, infective, metabolic, or congenital) • Intra-articular corticosteroid injection at the treatment site within preceding 1 month • Septic arthritis, inflammatory arthropathy, or crystal arthropathy • Seropositivity for HIV, Hepatitis B, Hepatitis C, or COVID-19 • Bleeding or coagulation disorders, previous knee surgery, or concomitant ipsilateral knee pathologies Intervention Protocol All eligible patients received three intra-articular 1% w/v HA injections — a high molecular weight cross-linked hylan polymer — at 2-week intervals on an outpatient basis. Injections were performed via the superolateral approach under strict aseptic conditions by a single designated orthopaedic surgeon to ensure technique standardisation. Pre-injection aspiration was performed when joint effusion was clinically present. All patients received standardised post-injection care including analgesics, static quadriceps exercises, and range of motion physiotherapy. Outcome Measures Primary Outcomes: Pain was assessed using the Visual Analogue Scale (VAS, 0–10, higher = more pain). Functional status was assessed using the Knee Injury and Osteoarthritis Outcome Score Pain subscale (KOOS Pain, Kannada validated version, 0–100, higher = less pain), assessed at baseline, 3, 6, and 12 months. MCID thresholds were pre-specified as ≥2 points or ≥30% reduction for VAS, and ≥8 points improvement for KOOS Pain.(10) Patients were classified as Full Responders (MCID achieved on both outcomes), Partial Responders (MCID on one), or Non-Responders (neither). Secondary Outcomes: Patient Acceptable Symptom State (PASS) was assessed at 6 and 12 months using a validated single-item question regarding acceptability of the current knee state if it were to persist indefinitely (Yes/No).(11) Serum ESR (Westergren method, mm/hr) was measured at baseline. Serum CRP was classified as Low (<3 μg/L) or High (>3 μg/L) per laboratory reference range. Adverse events were documented at every visit. Standing weight-bearing radiographs were obtained at baseline; repeat imaging at 12 months was not part of this study protocol. 2.6 Statistical Analysis All analyses were performed using SPSS v26.0. Normality was assessed by the Shapiro–Wilk test. All VAS and most KOOS distributions were non-normal; non-parametric tests were applied throughout. Trends across time points used the Friedman test. Pairwise comparisons (each follow-up vs. baseline) used the Wilcoxon signed-rank test with Bonferroni correction (adjusted alpha = 0.017). Effect sizes were reported as Cohen's d. ESR correlation with outcome changes used Spearman's rank correlation. CRP High vs. Low group comparisons used Mann-Whitney U. PASS change from 6 to 12 months used McNemar's test. K-L subgroup comparisons used Mann-Whitney U and chi-square. Occupational category comparisons used the Kruskal-Wallis test. Age, BMI, and symptom duration as predictor variables were assessed by Spearman's correlation. Significance threshold: p<0.05.

Forty-two patients were enrolled and all completed 12-month follow-up (attrition: 0%). Baseline characteristics are summarised in Table 1. Mean age was 52.0 ± 7.7 years (range 35–65); 24 patients (57.1%) were male. Mean BMI was 24.4 ± 4.7 kg/m². Median symptom duration was 24 months (IQR 18–30), reflecting delayed healthcare-seeking in this population. Mean baseline ESR was 20.6 ± 11.1 mm/hr; 14 patients (33.3%) had elevated CRP (>3 μg/L).

Table 1 : Baseline demographic and clinical characteristics (n=42).

The K-L grade and occupational category distributions are shown in Figures 2 and 3. Grade 2 disease was most common (50.0%), followed by Grade 1 (31.0%) and Grade 3 (19.0%). Heavy manual labour was the predominant occupational category (57.1%), reflecting the agricultural and handloom-dominated workforce of the Davangere district.

Figure 2: Distribution of Kellgren–Lawrence radiological grade (n=42).

Figure 3: Distribution of occupational category (n=42).

All VAS distributions were non-normal (Shapiro–Wilk p<0.001 at all time points), and a statistically significant overall trend was observed across the four time points (Friedman χ²=105.31, p<0.001). KOOS Pain scores were similarly non-normally distributed at 3, 6, and 12 months, with a statistically significant overall trend (Friedman χ²=118.46, p<0.001). As shown in Figure 1, mean VAS declined progressively from 6.07 ± 1.14 at baseline to 4.45 ± 1.05 at 12 months, while mean KOOS Pain improved progressively from 41.90 ± 3.16 to 49.98 ± 2.25 over the same period. All pairwise comparisons versus baseline were statistically significant after Bonferroni correction for both outcomes, with large and increasing effect sizes across time points (VAS Cohen's d: 1.72 at 3 months, 3.03 at 6 months, 3.33 at 12 months; KOOS Cohen's d: 3.23, 3.77, and 3.93 respectively). The mean KOOS improvement of 8.07 points at 12 months crossed the pre-specified MCID threshold of 8 points at the group level.

Figure 1: VAS and KOOS Pain trends over 12-month follow-up (n=42).

MCID achievement and responder classification at 6 and 12 months are summarised in Table 2 and Figure 4A. At 6 months, VAS MCID was achieved in 8 patients (19.0%) and KOOS MCID in 20 patients (47.6%), yielding 5 Full Responders (11.9%) and 18 Partial Responders (42.9%). At 12 months, both VAS and KOOS MCID were achieved in 26 patients (61.9% each), with Full Responders rising to 17 (40.5%) and Partial Responders remaining at 18 (42.9%). Non-Responders declined from 19 (45.2%) at 6 months to 7 (16.7%) at 12 months, representing 12 patients converting from Non-Responder status over the 6-to-12-month interval.

Table 2: MCID achievement and responder classification at 6 and 12 months.

MCID: VAS ≥2 points or ≥30% reduction; KOOS Pain ≥8 points. Full Responder: MCID achieved on both outcomes simultaneously.

Figure 4: Responder classification and PASS achievement at 6 vs. 12 months (n=42).

PASS was achieved by 21 patients (50.0%) at 6 months and 35 patients (83.3%) at 12 months (Table 3, Figure 4B). This increase of 33.3 percentage points was statistically significant (McNemar's test: p<0.001). Fourteen patients transitioned from non-acceptable to acceptable symptom state between 6 and 12 months, and no patient transitioned in the opposite direction, confirming that gains achieved at 6 months were fully maintained and extended through 12 months. Of the 7 patients (16.7%) who did not achieve PASS at 12 months, 4 were Non-Responders and 3 were Partial Responders.

Table 3: Patient Acceptable Symptom State (PASS) outcomes at 6 and 12 months.

*McNemar's test.

Baseline ESR showed no statistically significant correlation with VAS change at 6 months (Spearman's r = −0.063, p = 0.693) or KOOS change at 6 months (r = −0.240, p = 0.125). Patients with elevated CRP demonstrated a slightly lower mean VAS improvement at 6 months compared to those with normal CRP (1.07 vs. 1.25 points), though this difference was not statistically significant (Mann-Whitney U = 161.0, p = 0.176). Age was a statistically significant positive predictor of VAS improvement at 6 months (Spearman's r = 0.436, p = 0.004): older patients demonstrated greater pain reduction following HA injection. BMI showed no significant correlation with VAS change (r = 0.126, p = 0.428), nor did symptom duration (r = −0.051, p = 0.747) (Table 4).

Table 4: Spearman's correlation — predictor variables vs. VAS change at 6 months.

*p<0.05.

       Patients were divided into Grade 1–2 (n=34) and Grade 3 (n=8) subgroups for comparison. No statistically significant differences were observed in VAS improvement, KOOS improvement, or PASS rates at either 6 or 12 months (VAS change at 12 months: 1.59 ± 0.49 vs. 1.75 ± 0.43, p=0.413; PASS at 12 months: 82.4% vs. 87.5%, p=1.000), suggesting that within the early OA spectrum studied, radiological grade does not predict differential treatment response. Mean VAS improvement at 6 months did not differ significantly across the four occupational categories (Kruskal-Wallis H=3.782, p=0.286). PASS rates at 12 months by occupational category were: Heavy Manual Labour 83.3%, Moderate Manual Labour 100.0%, Sedentary 81.8%, and Professional 66.7% (the Professional group's lower rate should be interpreted cautiously given the small subgroup size, n=3).

      No serious adverse events were recorded across all 42 patients and 126 injection visits. The intervention was well-tolerated throughout. Minor transient injection site discomfort was reported in a small number of patients following individual injections, resolving within 24–48 hours without intervention. No cases of septic arthritis, haemarthrosis, anaphylaxis, or systemic reactions were documented.

Outcomes improved between 6 and 12 months across all measures examined. Full Responder rates increased from 11.9% to 40.5%, PASS rates rose from 50.0% to 83.3%, and the proportion classified as Non-Responders fell from 45.2% to 16.7%, with no patient transitioning from PASS-positive to PASS-negative status between these time points. This pattern is consistent with the possibility that a 6-month endpoint, commonly used in viscosupplementation trials, may not capture the full extent of treatment response. A possible biological explanation is that stimulation of endogenous synovial HA production and anti-inflammatory cytokine modulation are gradual processes that may take 9–12 months to reach maximum effect.(4) The 2015 Richette et al. meta-analysis, which included trials with longer follow-up, also reported increasing benefit over time in early-stage patients.(7) These findings are consistent with that temporal pattern in this Indian cohort, though the single-arm design precludes attributing the improvement to HA alone. The mean group improvement in KOOS Pain at 12 months (8.07 points) exceeded the pre-specified MCID threshold of 8 points, indicating that the average patient improvement met the threshold for clinical relevance rather than reaching statistical significance alone. Combined with 61.9% of individual patients achieving KOOS MCID at 12 months, this finding is relevant to the concern raised by Rutjes et al. regarding sub-MCID improvements observed in mixed-grade populations, though direct comparison is limited by differences in study design and population.(6) Age showed a statistically significant positive correlation with VAS improvement (r=0.436, p=0.004): older patients in this cohort had greater pain reduction following HA injection. This finding runs counter to the expectation that older patients, who typically have more advanced disease, would respond less well. Possible explanations include greater inflammation-driven pain that is more responsive to HA's anti-inflammatory effects, reduced mechanical loading due to lower activity levels in older patients, or lower baseline analgesic use. This association would need to be replicated in other cohorts before it could inform patient selection. The PASS rate of 83.3% at 12 months reflects the proportion of patients who considered their symptom state acceptable at that time point. In the Davangere context — a working-age population with substantial occupational physical demand and limited access to surgical intervention — this proportion may be relevant to clinical decision-making around non-surgical management. No patient transitioned from PASS-positive to PASS-negative status between 6 and 12 months, which is consistent with maintained or extended benefit over that interval, though longer follow-up would be needed to assess durability beyond 12 months. The 50.0% PASS rate at 6 months was lower than at 12 months, suggesting that outcomes at the 6-month review may not represent the eventual treatment response. No statistically significant differences were observed between K-L Grade 1–2 and Grade 3 subgroups: within the early OA spectrum studied, treatment response did not differ by radiological grade. This is consistent with offering HA across Grade 1–3 patients without grade-based exclusion, though the subgroup sizes (n=34 vs. n=8) limit the power to detect smaller differences. Limitations This study has several important limitations. The single-arm design without a control group limits causal inference; a randomised controlled comparison with corticosteroid, PRP, or exercise therapy would provide higher-level evidence. Conducted at a single institution, findings may not be generalisable beyond the Davangere district context, though this is also the study's strength as a regionally specific contribution. CRP was recorded as binary rather than continuous, limiting biomarker analysis. Radiological follow-up was not performed at 12 months, precluding assessment of disease progression. Only the KOOS Pain subscale was administered rather than the full five-domain KOOS. The Professional occupational subgroup (n=3) was too small for meaningful inference.

In this cohort, intra-articular hyaluronic acid injection was associated with statistically significant, progressive improvement in pain and function in patients with early knee osteoarthritis over 12 months, with no serious adverse events recorded. Within the early OA spectrum (K-L Grade 1–3), treatment outcomes did not differ significantly across radiological grades. The 83.3% PASS rate at 12 months and the absence of serious adverse events are consistent with HA being a reasonable non-surgical option to consider for this working-age, high-occupational-demand Karnataka population, though the single-arm design limits causal conclusions about efficacy. Future studies should incorporate a randomised controlled comparison arm, full five-domain KOOS, continuous CRP measurement, 12-month radiological assessment, and follow-up beyond 12 months.

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