Polarisation-sensitive optical coherence tomography measurement of retardance in fibrosis, a non-invasive biomarker in patients with systemic sclerosis.

Polarisation-sensitive optical coherence tomography (PS-OCT) offers a novel, non-invasive method of assessing skin fibrosis in the multisystem disease systemic sclerosis (SSc) by measuring collagen retardance. This study aimed to assess retardance as a biomarker in SSc. Thirty-one patients with SSc and 27 healthy controls (HC) underwent PS-OCT imaging. 'Skin score' was assessed by clinical palpation (0-3 scale). A subset of ten patients and ten age/sex-matched HC had a biopsy and longitudinal imaging. Histological assessment included quantification of epidermal thickness, collagen content (to assess fibrosis) and matrix metalloproteinase (MMP) activity (in situ zymography). PS-OCT images were assessed for epidermal thickness (structure) and fibrosis (retardance). Positive correlation was observed between epidermal thickness as measured by histology and structural PS-OCT (r = 0.79; p < 0.001). Retardance was: HC mean 0.21 (SD 0.21) radian/pixel; SSc skin score 0, 0.30 (0.19); skin score 1, 0.11 (0.16); skin score 2, 0.06 (0.12); skin score 3, 0.36 (0.35). Longitudinal retardance decreased at one-week across groups, increasing at one-month for HC/skin score 0-1; HC biopsy site retardance suggests scarring is akin to fibrosis. Relationships identified between retardance with both biopsy and skin score data indicate that retardance warrants further investigation as a suitable biomarker for SSc-related fibrosis.

Age-related alterations to working memory and to pyramidal neurons in the prefrontal cortex of rhesus monkeys begin in early middle-age and are partially ameliorated by dietary curcumin.

Layer 3 (L3) pyramidal neurons in aged rhesus monkey lateral prefrontal cortex (LPFC) exhibit significantly elevated excitability in vitro and reduced spine density compared to neurons in young subjects. The time-course of these alterations, and whether they can be ameliorated in middle age by the powerful anti-oxidant curcumin is unknown. We compared the properties of L3 pyramidal neurons from the LPFC of behaviorally characterized rhesus monkeys over the adult lifespan using whole-cell patch clamp recordings and neuronal reconstructions. Working memory (WM) impairment, neuronal hyperexcitability, and spine loss began in middle age. There was no significant relationship between neuronal properties and WM performance. Middle-aged subjects given curcumin exhibited better WM performance and less neuronal excitability compared to control subjects. These findings suggest that the appropriate time frame for intervention for age-related cognitive changes is early middle age, and points to the efficacy of curcumin in delaying WM decline. Because there was no relationship between excitability and behavior, the effects of curcumin on these measures appear to be independent.

Mesenchymal derived exosomes enhance recovery of motor function in a monkey model of cortical injury.

BACKGROUND: Exosomes from mesenchymal stromal cells (MSCs) are endosome-derived vesicles that have been shown to enhance functional recovery in rodent models of stroke. OBJECTIVE: Building on these findings, we tested exosomes as a treatment in monkeys with cortical injury. METHODS: After being trained on a task of fine motor function of the hand, monkeys received a cortical injury to the hand representation in primary motor cortex. Twenty-four hours later and again 14 days after injury, monkeys received exosomes or vehicle control. Recovery of motor function was followed for 12 weeks. RESULTS: Compared to monkeys that received vehicle, exosome treated monkeys returned to pre-operative grasp patterns and latency to retrieve a food reward in the first three-five weeks of recovery. CONCLUSIONS: These results provide evidence that in monkeys exosomes delivered after cortical injury enhance recovery of motor function.

Evaluation of factors affecting soil carbon sequestration services of stormwater wet retention ponds in varying climate zones.

The carbon sequestration services of stormwater wet retention ponds were investigated in four different climates: U.S., Northern Sweden, Southern Sweden, and Singapore, representing a range of annual mean temperatures, growing season lengths and rainfall depths: geographic factors that were not statistically compared, but have great effect on carbon (C) accumulation. A chronosequence was used to estimate C accumulations rates; C accumulation and decomposition rates were not directly measured. C accumulated significantly over time in vegetated shallow water areas (0-30cm) in the USA (78.4gCm-2yr-1), in vegetated temporary inundation zones in Sweden (75.8gCm-2yr-1), and in all ponds in Singapore (135gCm-2yr-1). Vegetative production appeared to exert a stronger influence on relative C accumulation rates than decomposition. Comparing among the four climatic zones, the effects of increasing rainfall and growing season lengths (vegetative production) outweighed the effects of higher temperature on decomposition rates. Littoral vegetation was a significant source to the soil C pool relative to C sources draining from watersheds. Establishment of vegetation in the shallow water zones of retention ponds is vital to providing a C source to the soil. Thus, the width of littoral shelves containing this vegetation along the perimeter may be increased if C sequestration is a design goal. This assessment establishes that stormwater wet retention ponds can sequester C across different climate zones with generally annual rainfall and lengths of growing season being important general factors for C accumulation.

Pilot study of intense pulsed light for the treatment of systemic sclerosis-related telangiectases.

BACKGROUND: Telangiectases represent microvascular changes inherent in the systemic sclerosis (SSc) disease process. Intense pulsed light (IPL) is an effective treatment for non-SSc-related cutaneous telangiectases. OBJECTIVES: This pilot study aimed to examine the efficacy, safety and tolerability of IPL treatment in an open study of patients with SSc. METHODS: Patients underwent three treatments of IPL at monthly intervals and attended follow-up examinations at 1, 6 and 12 months after final treatment. Photographs, laser Doppler imaging (LDI) and thermography were used to measure changes at each visit. RESULTS: Seventeen patients completed the study. Photographs were graded (compared with baseline) as: at 1-month follow-up, four 'no change', four 'improved' and eight 'much improved'; at 6-month follow-up, four 'no change', eight 'improved'; and four 'much improved'; and at 12-month follow-up (eight images were available), three 'no change', two 'improved' and three 'much improved'. Perfusion as measured by LDI (perfusion units) was significantly reduced, compared with baseline [median 2·66, interquartile range (1·78-3·93)], at 1 month [1·70 (1·07-2·55), P = 0·006] and 6 months [2·05 (1·42-2·36), P = 0·008] post-treatment, but not at 12 months [1·61 (1·14-3·22), P =0·088]. No differences were found in skin temperature between baseline and follow-up visits. CONCLUSIONS: In this pilot study (the first of IPL treatment for SSc-related telangiectases) most patients improved after IPL treatment. However, the degree of improvement was not maintained in all patients at 6-12 months, suggesting that further treatments may be necessary. Longer term studies of this novel treatment approach are now required.

Immune complexes and late complement proteins trigger activation of Syk tyrosine kinase in human CD4(+) T cells.

In systemic lupus erythematosus (SLE), the autoantibodies that form immune complexes (ICs) trigger activation of the complement system. This results in the formation of membrane attack complex (MAC) on cell membrane and the soluble terminal complement complex (TCC). Hyperactive T cell responses are hallmark of SLE pathogenesis. How complement activation influences the T cell responses in SLE is not fully understood. We observed that aggregated human γ-globulin (AHG) bound to a subset of CD4(+) T cells in peripheral blood mononuclear cells and this population increased in the SLE patients. Human naive CD4(+) T cells, when treated with purified ICs and TCC, triggered recruitment of the FcRγ chain with the membrane receptor and co-localized with phosphorylated Syk. These events were also associated with aggregation of membrane rafts. Thus, results presented suggest a role for ICs and complement in the activation of Syk in CD4(+) T cells. Thus, we propose that the shift in signalling from ζ-chain-ZAP70 to FcRγ chain-Syk observed in T cells of SLE patients is triggered by ICs and complement. These results demonstrate a link among ICs, complement activation and phosphorylation of Syk in CD4(+) T cells.

An investigation into the blood-flow characteristics of telangiectatic skin lesions in systemic sclerosis using dual-wavelength laser Doppler imaging.

Superficial telangiectases associated with systemic sclerosis may be more responsive to treatment than those deeper in the dermis. We investigated whether dual-wavelength laser Doppler imaging (LDI) is sufficiently sensitive to ascertain the distribution of blood flow within telangiectases and whether blood flow relates to telangiectatic diameter. The perfusion and diameter of 20 telangiectases were measured in superficial and deeper layers of the skin using dual-wavelength LDI. Of 20 telangiectases, 18 had higher blood flow in the red (representing deeper blood flow), rather than the green (representing superficial blood flow) wavelength images. Clinically apparent diameters correlated with those of the superficial (r = 0.61, P = 0.01), but not with the deeper blood flow images. Hence, the apparent size of telangiectases at the skin surface does not predict blood flow through the microvessel(s) at deeper levels, and thus clinically apparent size is unlikely to predict treatment response. Dual-wavelength LDI may help predict treatment response.

Pilot study of dual-wavelength (532 and 633 nm) laser Doppler imaging and infrared thermography of morphoea.

BACKGROUND: Little is known about the pathophysiology of localized scleroderma (skin fibrosis, also termed 'morphoea'), although it is likely that microvascular dysfunction is a contributing factor. OBJECTIVES: Our aim was to investigate different components of blood flow in morphoea using infrared thermography and dual-wavelength laser Doppler imaging (LDI). METHODS: Eight plaques of morphoea (in eight patients) were studied. Skin temperature and blood flow were assessed in both affected (within plaque) and adjacent unaffected (perilesional) skin. RESULTS: Skin temperature (representing blood flow) was higher in all areas of morphoea when compared with uninvolved skin. Perfusion within the plaques was found to be increased, when compared with uninvolved skin; in all cases as imaged by red wavelength (633 nm) LDI (representing blood flow through large, thermoregulatory vessels) and in six of eight cases by green wavelength (532 nm) LDI (representing nutritive capillary blood flow). The median (range) skin temperature difference between plaque and perilesional skin was 1.1 (0.7-2.2) degrees C and the median (range) ratios of plaque/perilesional perfusion as measured by red and green wavelength LDI were 1.3 (1.1-1.9) and 1.1 (0.8-1.5) arbitrary perfusion units, respectively. CONCLUSIONS: Microvascular perfusion is increased within morphoea plaques and the increased response detected by both thermography and red wavelength LDI, as compared with green wavelength LDI, suggests that the increase in perfusion is more marked in deeper, larger, rather than in superficial, smaller vessels.

Measurement of biomarkers in juvenile idiopathic arthritis patients and their significant association with disease severity: a comparative study.

OBJECTIVE: To evaluate in juvenile idiopathic arthritis (JIA) patients a biomarker panel of anti-cyclic citrullinated peptide (anti-CCP) antibodies, cartilage oligomeric matrix protein (COMP), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), IgM rheumatoid factor (RF), IgG RF, and IgA RF and compare to the presence of joint erosions (JE), joint space narrowing (JSN), and synovitis in order to evaluate aggressive disease. METHODS: Sixty-eight JIA patients (19 RF positive polyarthritis, 23 RF negative polyarthritis, 17 persistent oligoarthritis, and 9 systemic-onset) were evaluated using the biomarker panel and compared to 18 healthy controls. All RF isotypes, anti-CCP antibodies, and COMP were measured by enzyme-linked immunosorbent assays (ELISA). Statistically significant differences and associations were assessed for each biomarker in relation to JE, JSN, and synovitis. Multiple regression analysis was used to find the variables associated with joint damage and synovitis. RESULTS: Patients with JE and JSN had significantly elevated levels of IgA RF, IgM RF, and anti-CCP antibodies. COMP levels were higher in early disease, but also later in disease in patients with no JE or JSN. ESR, CRP, and IgA RF were significantly elevated in patients with active synovitis. Regression analysis showed IgM RF and disease duration to be associated with JE and JSN. Anti-CCP antibodies and COMP were also associated with JSN. CRP and IgA RF were associated with synovitis. CONCLUSION: Our findings demonstrate the importance of measuring IgM RF and IgA RF by ELISA and anti-CCP antibodies by ELISA, in addition to COMP in the assessment of JIA patients to determine severity of disease.

Sparing of the thumb in Raynaud's phenomenon.

OBJECTIVES: To conduct a prospective study to determine which digits are affected (and whether the thumb is spared or not) in a cohort of patients with RP as assessed by symptoms and thermography and to determine whether the degree of thumb involvement differs between primary (PRP) and secondary Raynaud's phenomenon (SRP). METHODS: This was a cross-sectional study of 44 patients with RP. The following characteristics were recorded to allow comparisons between digits: symptoms of RP in each digit (graded on a scale of 'never', 'sometimes' and 'always' affected during an attack of RP) and thermography at 23 degrees C. A distal-dorsal difference (DDD) in temperature at 23 degrees C of -1 degree C or less was considered to be clinically relevant. RESULTS: Symptom scores in the thumb were significantly better, i.e. less severe than in each finger (P < 0.001). As only three participants had any finger better than the thumb, there was no power to compare whether the thumb was spared more in PRP compared with SRP. Mean DDD was significantly higher (i.e. better) in the thumb compared with each finger (P < 0.001). Although DDD scores were higher in PRP compared with SRP (P = 0.01), there was no evidence that the relative effect of the thumb differed between the two groups (P = 0.26). CONCLUSIONS: Our findings confirm that the thumbs are spared in RP, both primary and secondary, as demonstrated by both symptoms and thermography. The reasons for sparing of the thumb were not addressed in this study but raised questions regarding pathophysiology.

Vasodilator iontophoresis a possible new therapy for digital ischaemia in systemic sclerosis?

OBJECTIVE: This study investigated whether whole finger vasodilator iontophoresis increases digital blood flow in patients with systemic sclerosis (SSc): If so, this might indicate a novel approach to therapy. METHODS: Eight patients and 8 healthy controls underwent whole finger iontophoresis using a specially designed chamber. Treatment was with 0.5% sodium nitroprusside (NaNP) or 1% acetylcholine chloride (ACh), and the procedure then repeated with the other vasodilator (randomly assigned order). Three treatments were carried out for each chemical; 2 min treatments were carried out bilaterally at 200 microA, a third was then carried out for 5 min on one digit only (randomly assigned to left or right). Blood flow increases were monitored with laser Doppler imaging (LDI). Maximum perfusion increase from baseline (MAX) and the area under the time perfusion curve (AUC), normalized for baseline, were calculated. Data were compared with a three-way analysis of variance test. RESULTS: Perfusion increased in both patients and controls, but significantly more so in controls (P(MAX) = 0.001, P(AUC) = 0.005, respectively). Values were significantly higher for the 5 min treatment compared with the 2 min treatment (P(MAX) = 0.011 and P(AUC) = 0.008 for both groups). No significant differences were found between the use of NaNP and ACh. CONCLUSIONS: The increased perfusion with both ACh and NaNP in the patient group (albeit to a lesser degree than in the control group) indicates that this local approach to vasodilation is effective. Increasing iontophoresis time causes more sustained vasodilation. Further studies are indicated to investigate a possible therapeutic effect in patients with severe digital ischaemia.

Abnormal kappa:lambda light chain ratio in circulating immune complexes as a marker for B cell activity in juvenile idiopathic arthritis.

Patients with juvenile idiopathic arthritis (JIA) have been shown to have elevated levels of circulating immune complexes (CICs) which correlated with disease activity. Our aim was to assess B cell activity by measuring the amount of and the kappa:lambda chain immunoglobulin light (L) chain ratio in CICs from JIA patients and to determine potential evidence for either an antigen-driven response or B-cell receptor editing. We used an enzyme-linked immunosorbent assay to measure kappa and lambda chains present in the CICs from the sera of patients with JIA. Statistical analysis was performed using Pearson's correlation, one-way ANOVA and Bonferroni post hoc analysis. Sera from 44 JIA patients were examined for the concentration of L chains in CICs. Healthy controls had a kappa:lambda chain ratio of 1.2:1, whereas this ratio was reversed among JIA subgroups with RF-positive polyarthritis (1:1.2), RF-negative polyarthritis (1:1.3), oligoarthritis (1:2.3) and systemic-onset arthritis (1:2.5). In addition, overall lambda chain selection was not significantly associated with a particular immunoglobulin heavy (H) chain and occurred with all immunoglobulin isotypes. We showed preferential selection of lambda chains contributing to the formation of potentially pathogenic CICs from JIA patients, of all onset types compared to healthy controls, in an H chain-independent manner. The reversal of kappa:lambda chain ratio within the JIA CICs and association with all immunoglobulin isotypes demonstrated the potential for L chain editing. Furthermore, we conclude that a reversal of the normal kappa:lambda chain ratio in JIA CICs may be used as a marker for increased B-cell activity.

The 'distal-dorsal difference': a thermographic parameter by which to differentiate between primary and secondary Raynaud's phenomenon.

OBJECTIVE: To test the hypothesis that in a patient with Raynaud's phenomenon (RP), a difference of >1 degrees C between the fingertips and the dorsum of the hand ['distal-dorsal difference' (DDD), fingers cooler] is specific for underlying structural vascular disease as occurs in systemic sclerosis (SSc), and to evaluate other thermographic parameters in the separation of secondary from primary RP. METHODS: A retrospective analysis of the case notes and thermography results of patients attending thermography, primarily over a 2-yr period. Multinomial logistic regression was used to ascertain whether thermography variables differed between groups with primary RP (56 patients), undifferentiated connective tissue disease (21 patients) and SSc (45 patients), with adjustment for age, sex and smoking. RESULTS: A DDD >1 degrees C in any finger at 30 degrees C had a positive predictive value of 70%, and a negative predictive value of 82%, in identifying the patient with RP secondary to SSc. From the results of the multinomial logistic regression, a score was derived incorporating age, number of fingers with DDD >1 degrees C at 30 degrees C and maximum rewarming gradient. This score (with a suitable cut-off) was 82% sensitive and 82% specific in identifying RP secondary to SSc, with a positive predictive value of 73% and a negative predictive value of 89%. CONCLUSION: Parameters derived from thermography (incorporating both a heat and cold challenge) aid in the prediction of SSc in patients with RP.

Presence of plasma complement regulatory proteins clusterin (Apo J) and vitronectin (S40) on circulating immune complexes (CIC).

The complement regulatory (CR) proteins clusterin and vitronectin bind to the membrane attack complex (MAC) and thus prevent cytolysis. In this report, we demonstrate the presence of both of these CR proteins on MAC bound to circulating immune complexes (CIC). We measured the amount of clusterin and vitronectin on MAC in plasma, also referred to as soluble MAC (SMAC), as well as on MAC bound to CIC (MAC-CIC), using antibody directed to polymerized C9 in systemic lupus erythematosus (SLE) patients. We observed a strong correlation among the quantities of SMAC and MAC-CIC. The amount of both clusterin and vitronectin associated with MAC-CIC was two- to threefold higher in comparison to the SMAC. Patients with high levels of clusterin and vitronectin demonstrated renal involvement. We hypothesize that these complement regulatory proteins besides regulating the insertion of MAC play other critical roles, in disease pathogenesis.

Abnormal microvascular response is localized to the digits in patients with systemic sclerosis.

OBJECTIVE: To investigate the hypothesis that cutaneous microvascular perfusion of the dorsum of the hand (in response to local heating) and distal phalanx (in response to occlusion) is impaired in patients with systemic sclerosis (SSc) compared with healthy controls. METHODS: Twenty-nine patients with SSc and 29 control subjects were recruited. Perfusion was monitored using novel dual-wavelength laser Doppler imaging, allowing measurement of both smaller (capillaries) and larger (thermoregulatory) vessels. Postacclimatization, a baseline dorsum scan (red or green wavelength) was performed. A heating pad was placed on the dorsum (total stimulus time 6 minutes at 34-40 degrees C), and following removal of the pad, baseline wavelength scans were performed until perfusion returned to baseline values. This was then repeated for the second wavelength. The maximum perfusion increase due to heating (PEAK1) and area under the perfusion-time curve (AUC) were determined. In addition, scans (both wavelengths) of the index finger were performed prior to and during 2 minutes of suprasystolic occlusion, and the response upon occlusion release was monitored with single-point laser Doppler. The decrease in perfusion due to occlusion (from preocclusion baseline values) (%DECREASE) and the maximum increase (from baseline perfusion values under occlusion) in hyperemic perfusion upon removal of occlusion (PEAK/OCC) were calculated. RESULTS: PEAK1 and AUC values were not significantly different between patients and controls, as assessed with either wavelength. A significant difference between groups was found in the %DECREASE values with the green, but not the red, wavelength. A significant between-group difference was also found in PEAK/OCC values, using both wavelengths. CONCLUSION: This study suggests that SSc has no effect on microvascular perfusion in the dorsum of the hand, and that the abnormal microvascular response is localized to the digits, affecting both smaller and larger vessels.

Juvenile localized scleroderma: clinical and epidemiological features in 750 children. An international study.

OBJECTIVE: Juvenile localized scleroderma (JLS) includes a number of conditions often grouped together. With the long-term goal of developing uniform classification criteria, we studied the epidemiological, clinical and immunological features of children with JLS followed by paediatric rheumatology and dermatology centres. METHODS: A large, multicentre, multinational study was conducted by collecting information on the demographics, family history, triggering environmental factors, clinical and laboratory features, and treatment of patients with JLS. RESULTS: Seven hundred and fifty patients with JLS from 70 centres were enrolled into the study. The disease duration at diagnosis was 18 months. Linear scleroderma (LS) was the most frequent subtype (65%), followed by plaque morphea (PM) (26%), generalized morphea (GM) (7%) and deep morphea (DM) (2%). As many as 15% of patients had a mixed subtype. Ninety-one patients (12%) had a positive family history for rheumatic or autoimmune diseases; 100 (13.3%) reported environmental events as possible trigger. ANA was positive in 42.3% of the patients, with a higher prevalence in the LS-DM subtype than in the PM-GM subtype. Scl70 was detected in the sera of 3% of the patients, anticentromere antibody in 2%, anti-double-stranded DNA in 4%, anti-cardiolipin antibody in 13% and rheumatoid factor in 16%. Methotrexate was the drug most frequently used, especially during the last 5 yr. CONCLUSION: This study represents the largest collection of patients with JLS ever reported. The insidious onset of the disease, the delay in diagnosis, the recognition of mixed subtype and the better definition of the other subtypes should influence our efforts in educating trainees and practitioners and help in developing a comprehensive classification system for this syndrome.

Dual wavelength (532 and 633 nm) laser Doppler imaging of plaque psoriasis.

BACKGROUND: Increased blood flow occurs in plaques of psoriasis, and an increase in blood flow has been shown to occur in uninvolved skin adjacent to the active edge. OBJECTIVES: In order to gain more insight into the pathophysiology of the active edges of plaques of psoriasis, we investigated different components of the microcirculation in the lesional and nonlesional skin of patients with psoriasis, using dual wavelength laser Doppler imaging (LDI). METHODS: The cutaneous blood flow in 23 plaques on the forearms of 20 patients with chronic plaque psoriasis was recorded using dual wavelength LDI. Perfusion was determined within the plaque (P), in uninvolved skin adjacent to the plaque (A) and in nonadjacent skin (U). RESULTS: Perfusion in plaques was increased as imaged by either 633 nm (red wavelength) or 532 nm (green wavelength) compared with both adjacent and nonadjacent uninvolved skin: median (interquartile range) P/A(RED) = 3.7 (2.5-4.9), P/A(GREEN) = 1.3 (1.2-1.6), P/U(RED) = 4.2 (2.7-6.1), P/U(GREEN) = 1.5 (1.3-1.9). CONCLUSIONS: Vascular perfusion is increased within plaques of psoriasis compared with adjacent and nonadjacent uninvolved skin. The results suggest an area of increased perfusion in skin adjacent to plaques, when compared with nonadjacent skin, for both deeper (large) and superficial (small) vessels (imaged by 633 and 532 nm, respectively). We believe that this dual wavelength tool may be a suitable and useful way of assessing pathophysiology and treatment response in psoriasis.

A role for the complement system in rheumatoid arthritis.

The production of autoreactive antibodies from self-reactive B cells results in the formation of immune complexes that deposit in tissue and fix complement, contributing to the pathogenesis of rheumatoid arthritis (RA). Earlier mouse models emphasize the importance of autoreactive antibodies formed against "self" proteins that serve as a source for T cell-mediated immune response, stemming from cross-reactivity and resulting in B cell activity. However, more recent models suggest the need for both autoantibodies and the initiation of the inflammatory cascade via the alternative complement pathway, which is unbridled as the cartilage lacks the usual regulatory proteins of the complement system. Furthermore, deficiencies in specific complement proteins could lead to an escape from negative selection by these self-reactive B cells. Moreover, the classical complement pathway establishes chemotactic gradients by which inflammatory cells follow and accumulate in the synovial fluid where they engulf immune complexes and release proteolytic enzymes. In addition, the processing of circulating immune complexes either via Fc receptor or CR1 and opsonization by complement fragments plays a key role in determining the fate of immune status. In addition, complement proteins are a major determinant in the size and solubility of an immune complex, which also affects clearance. The evidence regarding intra-articular activation of the complement system in RA provides the possibility to pharmacologically manipulate various parts of the complement system for therapeutic purposes and potential therapeutic targets for the control of inflammation and the prevention of joint destruction.