Table 4 Qualitative synthesis of results and overview of evidence

Tenderness/pain

Eich et al, [35]

Knee: 0% after 1 month (no significance value given)

One patient experienced focal cutaneous atrophy and a possible ruptured popliteal cyst

Weak evidence for IACIs decreasing pain in the knee as 2 studies show a reduction of pain

Weak evidence for IACIs decreasing pain in lower leg joints overall as 3 studies show a reduction of pain

Huppertz et al, [38]

Knee: 33.3% after 7 weeks (no significance value given)

Not Specified

Laurell et al, [24]

Ankle: Pain regression/partial improvement = 92.5% (no specific data included, only percentages) after 4 weeks

Local subcutaneous atrophy in 3 patients at 4 injection sites

Inconclusive due to lack of studies

(No significance value given)

Swelling

Eich et al, [35]

Knee: 27.3% after 1 month (no significance value given)

One patient experienced focal cutaneous atrophy and a possible ruptured popliteal cyst

Weak evidence for IACIs decreasing swelling in lower leg joints overall as 2 studies show a reduction in swelling

Huppertz et al, [38]

Knee: 0% after 7 weeks (no significance value given)

Not Specified

Synovitis

Papadopoulou et al., [40]

Number of joints in remission vs.

0.9% of injected joints suffered from skin hypopigmentation or subcutaneous atrophy.

Weak evidence for IACIs decreasing synovitis in the knee, ankle and STJ as 2 studies for each joint showed a reduction of synovitis.

Weak evidence for IACIs decreasing synovitis in lower leg joints overall as 3 studies show reduction of synovitis

Number of joints with synovitis flare: Knee = 79.2% vs. 20.8% (p < 0.001); Ankle = 54.8% vs. 45.2% (p = 0.14) STJ = 65.5% vs. 34.5% (p < 0.0001); MTPJ = 85.7% vs. 14.2% (p = 0.008); IPJ = 90.0% vs. 10.0% (p = 0.0003).

“A few” patients developed flushing or redness of the cheeks 24-48 hrs post-injection.

Inconclusive evidence for MTPJ and IPJ due to lack of studies

Overall mean relapse time 0.5 yrs (IQR 0.3-1.3 yrs) vs. mean remission time 0.9 yrs (IQR 0.6-1.9 yrs).

Ravelli et al., [41]

Knee: continued resolution at 6 months = 69%

One patient suffered from subcutaneous atrophy at the injection site.

Reoccurrence/relapse = 31%

(no significance value given)

Remedios et al., [42]

Clinical synovitis vs. MRI pannus:

Not Specified.

Tibiotalar: 84.6% vs. 84.6%; STJ: 23.1% (definite) vs. 46.2% (no significance value given)

Mean duration of effect (guided vs. unguided) (weeks): 38.3 vs. 13.9 (no significance value given)

Effusion

Huppertz et al, [38]

Knee: 13.3% after 7 weeks (no significance value given)

Not Specified

Inconclusive due to lack of studies

Hyperthermia

Eich et al, [35]

Knee: 18.2% after 1 month (no significance value given)

One patient experienced focal cutaneous atrophy and a possible ruptured popliteal cyst

Inconclusive due to lack of studies

Sustained clinical response

Al-Wahadneh, [31]

Knee: 30/30 = 100% maintained resolution at 3 months (no significance value given)

1/24 (4%): short-lived pain and erythema, 2/24 (8%): subcutaneous atrophy resolved dramatically after one year, 2/24 (8%): asymptomatic periarticular calcification.

Weak evidence for IACIs decreasing clinical signs and symptoms in the knee, ankle and STJ as 11, 4 and 2 studies respectively showed sustained clinical response.

Weak evidence for IACIs decreasing clinical signs and symptoms in lower leg joints overall as 21 studies show sustained clinical response

Inconclusive evidence for midfoot due to lack of studies

Allen et al, [35]

Knee: 18/48 = 37.5% relapse at 6 months (no significance value given)

Subcutaneous fat atrophy at injection site in one patient.

Beukelman et al, [26]

Knee: 1.4 yrs of resolution before relapse (SD ± 1.0)

53%: subcutaneous atrophy or hypopigmentation at injection site.

STJ: 1.2 yrs of resolution before relapse (TH + TA) (SD ± 0.9)

Earley et al, [33]

Knee: Excellent/Good Outcome: 92.8% vs.

2/23 had areas of subcutaneous atrophy at injection site.

Poor/Re-injected: 7.2% at 3 months (No significance value given)

Eberhard et al, [34]

Knee Median Relapse (months)

Not Specified.

TH: 11.1 +/- 0.81

TA: 7.95 +/- 0.95

(p = 0.0072)

Hertzberger-ten Cate et al, [36]

Knee: resolution maintained in 70% of knees for >6 months (No significance value given)

2/21 patients suffered a small atrophic lesion at the injection site.

1/21 patient suffered a red and painful knee the day following injection (resolved by local ice application).

Sustained clinical response (cont’d)

Honkanen et al, [37]

Knee: overall probability of sustained clinical response was higher for TH then MP after 6-8 weeks (p > 0.0005)

Not Specified.

Laurell et al, [24]

Ankle pain Regression/Partial Improvement = 92.5% (no specific data included, only percentages) after 4 weeks (No significance value given)

Local subcutaneous atrophy in 3 patients at 4 injection sites.

Lepore et al, [39]

Knee: mean remission time = 13.9 months (range = 0-54 months) (no significance value given)

10% (3 patients) subcutaneous lipolysis with spontaneous regression.

Marti et al, [19]

Mean duration of remission until flare in months (range): knee = 8.0 (0-27); ankle = 4.5 (0-13); STJ = 3.5 (0-11); midfoot = 1 (0-3) (no significance value given)

Systemic effects of glucocorticoids in 7 patients (one flushed cheeks, three increased appetite, three mood changes).

Mean follow-up time of joints with ongoing remission in months (range):knee = 27.2 (1-69); ankle = 18.2 (1-39); STJ = 13; midfoot = n/a (no significance value given)

Local side effects in 12 patients (14 skin atrophies combined with hypopigmentation).

Remedios et al., [42]

Clinical synovitis vs. MRI pannus:

Not Specified.

Tibiotalar: 84.6% vs. 84.6%; STJ: 23.1% (definite) vs. 46.2% (no significance value given)

Mean duration of effect (guided vs. unguided) (weeks): 38.3 vs. 13.9 (no significance value given)

Sustained clinical response (cont’d)

Sornay-Soares et al., [44]

Knee: continued resolution in 76.9% knees at 6 months

No adverse effects were recorded.

(no significance value given)

Zulian et al., [46]

Knee and Ankle: continued resolution at 6 months

2 patients in each group developed skin atrophy at the injection site.

TH: 81.4%

2 patients experienced reversible apnoea (<20secs duration) during the induction phase of sedation.

TA: 53.3%

(p = 0.001)

Joint ROM

Balogh et al., [30]

Knee: BM = 0 degree difference vs. TH = 13 degrees difference at 42 days (no significance value given)

Mild skin atrophy in 1/23 who was injected with TH

Weak evidence for IACIs increasing ROM in the knee as 3 studies show improvement

Weak evidence for IACIs increasing ROM in lower leg joints overall as 5 studies show improvement

Eich et al, [35]

Knee: 66.7% improvement after 1 month (no significance value given)

One patient experienced focal cutaneous atrophy and a possible ruptured popliteal cyst

Huppertz et al, [38]

Knee: 92.9% improvement after 7 weeks (no significance value given)

Not Specified

Laurell et al, [24]

Ankle: 95% improvement after 4 weeks

Local subcutaneous atrophy in 3 patients at 4 injection sites

Inconclusive due to lack of studies

(No significance value given)

Cahill et al., [25]

STJ: 89.5% returned to normal ROM within 13 weeks (no significance value given). Mean duration of improvement = 1.2 SD ±0.9 yrs.

Subcutaneous atrophy or hypopigmentation in 53%

Inconclusive due to lack of studies

Leg length discrepancy

Eich et al, [35]

Improvement after 1 month: 100% (no significance value given)

One patient experienced focal cutaneous atrophy and a possible ruptured popliteal cyst

Weak evidence for IACIs decreasing LLD as 3 studies show reduction

Sherry et al., [43]

Mean difference in leg length for early intervention vs. control:

Not Specified

0% (±0) vs. 1.0% (±1.4) (p = 0.005)

over mean follow up of 4 months (SD ± 11 months)

Verma et al., [45]

Mean Lower Leg Difference (cm): ↓ 0.22 at 6 and 12 weeks (no significance value given).

No adverse effects were recorded.

Circumference

Balogh et al., [30]

Mean Knee Joint Circumference (cm):

Mild skin atrophy in 1/23 who was injected with TH

Inconclusive due to lack of studies

BM = 1.0

TH = -1.7 after 1, 3, 7 and 42 days (no significance values given).

Imaging

Weak evidence for IACIs decreasing imaging findings in lower leg joints overall as 3 studies show improvement

MR imaging

Weak evidence for IACIs decreasing MRI detectable clinical signs and symptoms as 3 studies show detectable improvement

Effusion

Eich et al., [35]

Knee: 36.4% detected by MRI at 1 week and 1 month (no significance value given)

One patient experienced focal cutaneous atrophy and a possible ruptured popliteal cyst

Weak evidence for IACIs decreasing MRI detectable effusion as 2 studies show detectable improvement.

Huppertz et al, [38]

Knee and Ankle: 40.0% at 7 and 13 weeks (no significance value given)

Not Specified.

Pannus

Eich et al., [35]

Knee: 63.6% detected by MRI at 1 week and 1 month (no significance value given)

One patient experienced focal cutaneous atrophy and a possible ruptured popliteal cyst

Weak evidence for IACIs decreasing MRI detectable pannus as 3 studies show detectable improvement.

Huppertz et al, [38]

Knee and Ankle: 10.0% at 7 and 13 weeks (no significance value given)

Not Specified.

Remedios et al., [42]

Clinical synovitis vs. MRI pannus:

Not Specified.

Tibiotalar: 84.6% vs. 84.6%; STJ: 23.1% (definite) vs. 46.2% (no significance value given)

Mean duration of effect (guided vs. unguided) (weeks): 38.3 vs. 13.9 (no significance value given)

Popliteal cyst

Eich et al., [35]

Knee: 33.3% detectable at 1 week and 1 month (no significance value given)

One patient experienced focal cutaneous atrophy and a possible ruptured popliteal cyst

Inconclusive due to lack of studies

Destruction of articular cartilage/bone

Eich et al., [35]

Missing outcome data at 1 week and 1 month (no significance value given)

One patient experienced focal cutaneous atrophy and a possible ruptured popliteal cyst

Inconclusive due to lack of studies

Destruction of meniscus

Eich et al., [35]

100% (no ligament destruction reported) at 1 week and 1 month (no significance value given)

One patient experienced focal cutaneous atrophy and a possible ruptured popliteal cyst

Inconclusive due to lack of studies

Bone marrow oedema

Eich et al., [35]

None reported at 1 week and 1 month (no significance value given)

One patient experienced focal cutaneous atrophy and a possible ruptured popliteal cyst

Inconclusive due to lack of studies

Avascular necrosis

Eich et al., [35]

None reported at 1 week and 1 month (no significance value given)

One patient experienced focal cutaneous atrophy and a possible ruptured popliteal cyst

Inconclusive due to lack of studies

Uptake of contrast medium

Huppertz et al, [38]

Knee and Ankle: 20.0% detectable at 7 and 13 weeks (no significance value given)

Not Specified.

Inconclusive due to lack of studies

US imaging

Weak evidence for IACIs decreasing US detectable clinical signs and symptoms as 2 studies show detectable improvement

Joint effusion and/or pannus

Eich et al., [35]

Knee: 100% detectable after 1 week and 1 month (no significance value given)

One patient experienced focal cutaneous atrophy and a possible ruptured popliteal cyst

Inconclusive due to lack of studies

Popliteal cyst

Eich et al., [35]

Knee: 0% detectable after 1 week and 1 month (no significance value given)

One patient experienced focal cutaneous atrophy and a possible ruptured popliteal cyst

Inconclusive due to lack of studies

Synovial hypertrophy

Laurell et al., [24]

Talocrural joint = 87% regression vs. 13% no effect

Local subcutaneous atrophy in 3 patients at 4 injection sites.

Inconclusive due to lack of studies

Posterior-STJ = 95% regression vs. 5% no effect

Midfoot joints = 91% regression vs. 9% no effect (no significance value given).

Mean synovial thickness: statistically significant difference at 4 weeks (p < 0.001)

Synovial hyperaemia

Laurell et al., [24]

Talocrural Joint = 86% normalisation vs. 14% no normalisation

Local subcutaneous atrophy in 3 patients at 4 injection sites.

Inconclusive due to lack of studies

Posterior-STJ = 95% normalisation vs. 5% no normalisation

Midfoot Joints = 80% normalisation vs. 20% no normalisation (no significance value given) after 4 weeks.