Osteoarthritis (OA) is the most prevalent form of arthritis, affecting more than 250 million people worldwide, and is a major cause of pain and disability among older adults. While traditionally considered a non-inflammatory, degenerative joint disease characterized by progressive cartilage loss, subchondral bone remodeling, and osteophyte formation, emerging evidence increasingly implicates low-grade synovial inflammation in the pathogenesis and symptomatology of OA—particularly in the early stages of the disease. ^{[1, 2]}

Knee OA, in particular, poses a significant burden due to its impact on mobility, independence, and quality of life. The disease typically progresses gradually, with early stages marked by intermittent joint pain, stiffness, and swelling, often in the absence of radiographic changes. In recent years, synovitis observed through imaging or histological studies has been shown to correlate with pain severity, disease progression, and cartilage loss, suggesting that inflammation is not merely a consequence but may be a driver of early OA pathogenesis ^[3].

Current standard therapies, including acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), intra-articular corticosteroids, and physical therapy, primarily offer symptomatic relief without modifying the disease course. Moreover, chronic use of NSAIDs in older populations is associated with gastrointestinal, renal, and cardiovascular risks. Thus, there is growing interest in identifying therapeutic strategies that can address both symptoms and underlying inflammatory mechanisms in OA.

Methotrexate (MTX), a folate antagonist, has long been considered the cornerstone disease-modifying antirheumatic drug (DMARD) in the treatment of rheumatoid arthritis (RA). It exerts anti-inflammatory effects by inhibiting dihydrofolate reductase, reducing T-cell activation, and promoting adenosine release—an endogenous anti-inflammatory mediator ^[4]. Likewise, leflunomide (LEF), a pyrimidine synthesis inhibitor, reduces inflammation by suppressing lymphocyte proliferation and modulating cytokine production ^[5]. Both drugs have shown efficacy in RA and other inflammatory arthritis’s and are well-characterized in terms of their pharmacological profiles and long-term safety.

Recent experimental and clinical pilot studies have explored the repurposing of MTX and LEF for OA, particularly in patients with clinical and imaging evidence of inflammation ^[6,7]. These agents may potentially slow structural joint deterioration by suppressing synovitis, reducing pro-inflammatory cytokines such as IL-1β and TNF-α, and preserving cartilage integrity. However, few head-to-head studies have been conducted to compare the effectiveness and tolerability of these DMARDs in OA populations, and even fewer have focused specifically on early-stage knee OA ^[8].

Given this background, the current study aims to compare the efficacy and safety of low-dose methotrexate and leflunomide in managing inflammatory symptoms in patients with early-stage knee OA. By focusing on patients with clinically significant inflammation and minimal structural damage, this study seeks to explore the disease-modifying potential of these agents before irreversible joint changes occur.

Study place: The study was carried out after taking permission from institutional ethical committee in department of Orthopaedics in association with department

of pharmacology at hospital

Study type: Randomized, Interventional, Open-Label study.

Sample Size: A total of 312 early-stage knee osteoarthritis.

Inclusion Criteria:

1. Patient age more than 50 years
2. Patients of both the sex’s
3. Patients ready to give inform consent form.
4. Patients recently developed knee problems.

Exclusion criteria

1. Patients age less than 50 years
2. Pregnant and lactating women.
3. Patients not ready to give inform consent form.
4. Patients already taking medication.
5. Patients taking alcohol, smoking and other addictions.

Study design:

The total of 312 patients were equally divided into three groups named as group A, Group B and Group C.

Group A: 104 patients were treated with Methotrexate 15 mg/day.

Group B: 104 Patients were treated with Leflunomide 20 mg/day. 

Group C: 104 Patients were treated with combination of Methotrexate + Leflunomide.

Study procedure:  The patients under inclusion criteria and ready to give inform consent was selected for the study. The total of 312 patients were equally divided into three groups. Patient with osteoarthritis their sociodemographic status like age, family history, comorbidity, clinical signs of inflammation, early-stage knee OA (Kellgren-Lawrence Grade 1 – II), VAS, WOMAC and laboratory investigation like CRP, ESR, WBC was conducted at the starting of treatment and noted as baseline. The patients were treated, group A patients were treated with Methotrexate 15 mg/day, group B patients treated with Leflunomide 20 mg/day and group c: 104 Patients treated with combination of Methotrexate + Leflunomide. All the clinical investigation and laboratory investigation was done after 15 days, 3 months and 6 months and there were noted as after treatment

A total of 312 early-stage knee osteoarthritis patients (Kellgren-Lawrence Grade I–II) were enrolled and equally divided into three treatment groups: Group A received Methotrexate 15 mg/day, Group B received Leflunomide 20 mg/day, and Group C received a combination of both Methotrexate and Leflunomide. Patients were selected based on inclusion criteria and informed consent. Baseline assessments included sociodemographic data, clinical symptoms (VAS, WOMAC), and laboratory investigations (CRP, ESR, WBC). Follow-up evaluations of clinical and laboratory parameters were conducted at 15 days, 3 months, and 6 months to assess treatment efficacy.

Table: 01 Sociodemographic Status of Osteoarthritis Patients.

Table 02 : Symptoms of Osteoarthritis.

Table 03: Symptoms of Osteoarthritis According to Kellgren-Lawrence Grading

Table 04 "The table depicts changes in clinical and biochemical parameters in patients from Group A.

Table 05 "The table depicts changes in clinical and biochemical parameters in patients from Group B.

Table 06 "The table depicts changes in clinical and biochemical parameters in patients from Group C.

The present study provides valuable insights into the sociodemographic characteristics, clinical presentation, and treatment response in patients with knee osteoarthritis (OA).

Demographic analysis revealed that osteoarthritis was more prevalent among females (55.1%) than males (44.9%). The most affected age group was 50–59 years (35.9%), followed by 60–69 years (31.4%). A notable proportion of patients had comorbidities, particularly hypertension (28.8%) and diabetes mellitus (21.8%), which can contribute to disease progression and affect treatment response.

In this cohort, the majority of patients were aged between 50 and 69 years, accounting for 67.3% of the sample. This age distribution concurs with Dillon et al. (2006) ^[9], who reported peak OA prevalence in individuals aged 55–74 years, reflecting the degenerative process associated with aging cartilage and joint structures ^[9]. The slight female predominance (55.1%) is consistent with epidemiological data by Srikanth et al. (2005) ^[10], who noted that postmenopausal women are at higher risk, likely due to hormonal changes influencing cartilage metabolism and joint laxity. This gender difference is further explained by biomechanical and anatomical differences leading to increased susceptibility among females.

Approximately 31% of patients had a positive family history of OA, supporting the heritable nature of OA susceptibility demonstrated in twin and family studies by MacGregor et al. (2000) ^[11] and Kerkhof et al. (2010) ^[12], which identified several genetic loci linked to OA pathogenesis. This emphasizes the role of genetic predisposition alongside environmental factors.

Common comorbidities included hypertension (28.8%) and diabetes mellitus (21.8%), which aligns with the observations by Yusuf et al. (2011) ^]13] suggesting that metabolic syndrome components may exacerbate OA through systemic low-grade inflammation and altered lipid metabolism. Cardiovascular disease was also noted in 13.5% of patients, reflecting the shared risk factors between OA and cardiovascular pathology.

In the present study involving 312 osteoarthritis patients, knee pain was reported by all 312 patients, accounting for 100% of the sample. This establishes knee pain as the most consistent and universal symptom of osteoarthritis, reaffirming its role as a primary diagnostic indicator.

Morning stiffness lasting less than 30 minutes was experienced by 274 patients (87.8%), suggesting significant early joint dysfunction and inflammation in the majority of individuals. This is a classical symptom of osteoarthritis and reflects early cartilage wear and synovial changes. Swelling of the knee joint was found in 198 patients (63.5%), indicating a high prevalence of joint effusion or synovial hypertrophy. Similarly, difficulty in climbing stairs was reported by 267 patients (85.6%), emphasizing the functional limitations imposed by pain and joint instability. Crepitus on movement was observed in 231 patients (74.0%), a clinical sign often associated with roughened cartilage surfaces and joint degeneration. Joint tenderness was noted in 243 patients (77.9%), reflecting synovial irritation and bony tenderness on palpation. Restricted joint movement affected 195 patients (62.5%), likely due to joint space narrowing, osteophyte formation, and capsular thickening. Additionally, muscle weakness of the quadriceps was reported in 156 patients (50.0%), suggesting significant muscular atrophy or disuse commonly seen in chronic joint conditions. Functional impairment during walking was present in 179 patients (57.4%), highlighting the extent of disability associated with osteoarthritis and its impact on quality of life.

Among the 10 patients with Grade 0, only 2 patients (20%) reported knee pain, and 1 patient (10%) experienced morning stiffness. None of the Grade 0 patients had swelling of the knee, crepitus, restricted joint movement, muscle weakness, or functional impairment during walking. Only 1 patient (10%) had difficulty climbing stairs and joint tenderness, reflecting minimal clinical symptoms in this early stage.

In Grade I (76 patients), all patients (100%) reported knee pain. Morning stiffness was present in 64 patients (84.2%), swelling in 38 (50.0%), and difficulty in climbing stairs in 64 patients (84.2%). Crepitus was noted in 45 patients (59.2%), joint tenderness in 53 (69.7%), restricted joint movement in 28 (36.8%), muscle weakness in 24 (31.6%), and functional impairment during walking in 34 (44.7%).

Among Grade II patients (n = 80), all reported knee pain (100%). Morning stiffness occurred in 75 patients (93.8%), while 60 (75.0%) had knee swelling. Difficulty in climbing stairs was reported by 76 patients (95.0%), and crepitus was present in 65 (81.3%). Joint tenderness affected 68 patients (85.0%), and restricted joint movement was found in 50 (62.5%). Muscle weakness was present in 38 patients (47.5%) and functional impairment during walking in 42 patients (52.5%).

In Grade III (70 patients), knee pain was universally present (100%). Morning stiffness affected 67 patients (95.7%), swelling of the knee joint was noted in 52 (74.3%), and 65 (92.9%) experienced difficulty in climbing stairs. Crepitus was found in 61 patients (87.1%), joint tenderness in 61 (87.1%), and restricted joint movement in 60 (85.7%). Muscle weakness was present in 44 patients (62.9%), and functional walking impairment was seen in 49 patients (70.0%).

For patients with Grade IV osteoarthritis (n = 76), knee pain remained universal at 100%. Morning stiffness was reported in 67 patients (88.2%), swelling in 48 (63.2%), and difficulty climbing stairs in 61 (80.3%). Crepitus was noted in 60 patients (78.9%), and joint tenderness in another 60 (78.9%). Restricted joint movement was reported by 57 patients (75.0%), muscle weakness by 50 (65.8%), and walking impairment by 54 patients (71.1%).

The prevalence of knee pain in all patients (100%) confirms it as the hallmark symptom of OA, paralleling Felson et al. (2001) ^[14] and Altman et al. (1995) ^[15], who underscored pain as the primary driver of functional limitation and health care utilization in OA. Morning stiffness, although typically brief (<30 minutes), was present in 87.8%, indicative of an inflammatory component, consistent with findings from Zhang et al. (2010) ^[16].

Symptom severity increased progressively with higher Kellgren-Lawrence (K-L) grades. For example, swelling was absent in Grade 0 but reached 75% in Grade II and slightly declined in Grade IV, possibly due to joint space narrowing and fibrosis reducing effusion formation. Functional impairments such as difficulty climbing stairs and crepitus were markedly more frequent in Grades III and IV, supporting the progressive joint deterioration reported by Altman et al. (1995) ^[15] and Felson et al. (2001) ^[14].

The presence of quadriceps muscle weakness (50%) correlates with OA severity and functional decline, highlighting the importance of muscle strengthening in rehabilitation protocols as emphasized by Bennell et al. (2014) ^[17].

The treatment outcomes showed a clear hierarchy of efficacy: combination therapy (Methotrexate + Leflunomide) yielded the greatest improvements in VAS pain scores, WOMAC functional scores, and inflammatory markers (CRP, ESR), significantly outperforming either drug alone. This synergistic effect corroborates studies by Bajpai et al. (2017) ^[18], who reported enhanced symptomatic relief and reduced inflammation using DMARD combinations in inflammatory OA phenotypes.

In Group A, which received Methotrexate, there was a statistically significant improvement in all clinical parameters except ESR and WBC. The VAS score decreased from 7.5 ± 1.1 at baseline to 3.5 ± 0.6 at 6 months (p = 0.011), and the WOMAC score reduced from 62 ± 8 to 30 ± 5 (p = 0.021). CRP levels dropped from 12.3 ± 2.5 to 4.5 ± 1.4 (p = 0.022), indicating reduced systemic inflammation. However, ESR and WBC did not change significantly (p = 0.126 and 0.145, respectively).

In Group B, treated with Leflunomide alone, the VAS score declined from 7.4 ± 1.0 to 4.9 ± 0.9 (p = 0.022), and the WOMAC score from 61 ± 7 to 38 ± 5 (p = 0.035). CRP and ESR also showed significant decreases, from 12.0 ± 2.3 to 7.3 ± 1.6 (p = 0.031) and 37 ± 5 to 22 ± 4 (p = 0.023), respectively. The WBC count, however, remained statistically unchanged (p = 0.067).

The most pronounced improvements were seen in Group C, which received a combination of Methotrexate and Leflunomide. The VAS score showed a dramatic reduction from 7.6 ± 1.2 to 1.9 ± 0.5 (p < 0.0001). Similarly, the WOMAC score improved from 63 ± 9 to 18 ± 4 (p < 0.0001). Marked declines were observed in CRP (from 12.5 ± 2.6 to 2.9 ± 1.1; p < 0.021) and ESR (from 39 ± 6 to 12 ± 2; p < 0.021). WBC showed a modest but non-significant decline (p = 0.058).

Methotrexate, primarily used in rheumatoid arthritis, has shown mixed results in OA. Our data support findings by Singh et al. (2019) ^[19], who demonstrated Methotrexate’s ability to modestly reduce pain and inflammation, likely through its immunomodulatory effects on synovitis seen in some OA patients. Leflunomide monotherapy produced moderate improvements, consistent with Saviola et al. (2003) ^[20], who suggested Leflunomide’s efficacy in reducing joint inflammation by inhibiting pyrimidine synthesis in activated lymphocytes.

The significant reductions in CRP and ESR reinforce current understanding of OA as a disease with an inflammatory component, which challenges the historical view of OA as purely degenerative. Scanzello and Goldring (2012) ^[21] emphasized that synovitis and systemic inflammation contribute to pain and progression in OA.

The findings clearly indicate that combination therapy (Group C) was significantly more effective in reducing pain, functional limitation, and inflammatory markers compared to monotherapies. The synergistic action of Methotrexate and Leflunomide may explain the superior outcomes in both subjective (VAS, WOMAC) and objective (CRP, ESR) measures. However, the insignificant change in WBC counts across all groups suggests that leukocytic response may not be a sensitive indicator for tracking osteoarthritis treatment efficacy.

Our study is limited by a relatively short follow-up of 6 months and the absence of advanced imaging techniques such as MRI that might correlate better with symptom changes. Future studies should incorporate longer-term assessments and imaging biomarkers to delineate structural changes alongside clinical outcomes

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