Physiopathology of pain in rheumatology.

Pain is the main manifestation of many rheumatic diseases (be they overtly inflammatory such as rheumatoid arthritis or dysfunctional such as fibromyalgia) but, at least initially, the mechanisms involved in the genesis, amplification and chronicisation of the persistent pain characterising the various conditions can be very different. The main peripheral mechanism underlying acute nociceptive pain is a change in the activity of the nociceptors located in the affected anatomical structures (joints, tendons and ligaments), which makes them more sensitive to normally painful stimuli (hyperalgesia) or normally non-painful stimuli (allodynia). This physiopathological mechanism of peripheral sensitisation plays a primary role in rheumatic diseases characterised by acute inflammation, such as the arthritides due to microcrystals. In the case of chronic rheumatic diseases that do not regress spontaneously, functional and structural central nervous system changes cause a generalised reduction in the pain threshold that is not limited to the anatomical structures involved, thus leading to the appearance of hyperalgesia and allodynia in many, if not all body districts. This is the physiopathological basis of chronic, widespread musculoskeletal pain.

Chronic widespread pain in spondyloarthritis.

The pain associated with spondyloarthritis (SpA) can be intense, persistent and disabling. It frequently has a multifactorial, simultaneously central and peripheral origin, and may be due to currently active inflammation, or joint damage and tissue destruction arising from a previous inflammatory condition. Inflammatory pain symptoms can be reduced by non-steroidal anti-inflammatory drugs, but many patients continue to experience moderate pain due to alterations in the mechanisms that regulate central pain, as in the case of the chronic widespread pain (CWP) that characterises fibromyalgia (FM). The importance of distinguishing SpA and FM is underlined by the fact that SpA is currently treated with costly drugs such as tumour necrosis factor (TNF) inhibitors, and direct costs are higher in patients with concomitant CWP or FM than in those with FM or SpA alone. Optimal treatment needs to take into account symptoms such as fatigue, mood, sleep, and the overall quality of life, and is based on the use of tricyclic antidepressants or selective serotonin reuptake inhibitors such as fluoxetine, rather than adjustments in the dose of anti-TNF agents or disease-modifying drugs.

Pain in fibromyalgia and related conditions.

Pain is the hallmark symptom of fibromyalgia (FM) and other related syndromes, but quite different from that of other rheumatic diseases, which depends on the degree of damage or inflammation in peripheral tissues. Sufferers are often defined as patients with chronic pain without an underlying mechanistic cause, and these syndromes and their symptoms are most appropriately described as "central pain", "neuropathic pain", "nonnociceptive pain" or "central sensitivity syndromes". The pain is particular, regional or widespread, and mainly relates to the musculoskeletal system; hyperalgesia or allodynia are typical. Its origin is currently considered to be distorted pain or sensory processing, rather than a local or regional abnormality. FM is probably the most important and extensively described central pain syndrome, but the characteristics and features of FM-related pain are similar in other disorders of particular interest for rheumatologists, such as myofascial pain syndromes and temporo-mandibular joint disorders, and there is also an intriguing overlap between FM and benign joint hypermobility syndrome. This suggests that the distinctive aspects of pain in these idiopathic or functional conditions is caused by central nervous system hypersensitivity and abnormalities. Pharmacological and non-pharmacological therapies have been suggested for the treatment of these conditions, but a multidisciplinary approach is required in order to reduce the abnormal cycle of pain amplification and the related maladaptive and self-limiting behaviours.

New parameters for identifying subclinical atherosclerosis in patients with primary Sjögren's syndrome: a pilot study.

OBJECTIVES: We investigated sub-clinical cardiovascular involvement in primary Sjögren's syndrome (pSS) patients by means of ADMA, coronary flow reserve (CFR), intima media thickness (cIMT), pulse wave velocity (PWV) and myocardial deformation. METHODS: The study involved 22 outpatients with pSS (6 males, 16 females; mean age 60.14±7.81 years) and no documentable cardiovascular disease, and 22 age- and gender-matched controls. Dipyridamole transthoracic stress echocardiography was used to evaluate wall motion and CFR. A CFR value of <2.5 was considered a sign of impaired coronary function. We also evaluated cIMT arterial stiffness PWV and plasma ADMA levels, and made a speckle tracking echocardiography (STE) analysis. RESULTS: All of the patients were affected by pSS. Although within the normal range, the patients' CFR was lower than that of the controls (median 2.70; IQR 2.40-2.90 vs. 3.20; IQR 3.06-3.33; p<0.0001), whereas their ADMA levels were significantly higher (median 0.81 µM; IQR 0.79-0.85 µM vs. 0.54 µM; IQR 0.52-0.58 µM; p<0.0001). Both left and right PWV values were significantly higher in the patients than in the controls (median 8.8 m/s right and 8.9 m/s left vs. 6.86 and 6.89 m/s), whereas QIMT was substantially similar in the two groups. CONCLUSIONS: Higher ADMA levels suggest the presence of endothelial dysfunction and sub-clinical atherosclerosis in pSS patients, even in the case of a normal CFR. This finding is supported by the PWV values, which were higher in the pSS patients. ADMA levels and PWV values may be useful markers for identifying early endothelial dysfunction in pSS patients.

Cardiovascular involvement in psoriatic arthritis.

Psoriasis is a chronic, genetically determined and immunomediated inflammatory skin disease that affects 2-3% of the Caucasian population. A considerable proportion of these patients develop a form of inflammatory arthritis known as psoriatic arthritis (PsA), although the prevalence of this has not been well defined. Patients with PsA have a higher mortality rate than the general population and the risk of mortality is related to disease severity at the time of presentation. Endothelial dysfunction and early atherosclerosis have been found in patients with PsA without any cardiovascular disease (CVD) risk factors, and experts believe that CVD is one of the leading causes of death, as it is in patients with rheumatoid arthritis (RA). Various disease-related mechanisms may be involved in the development of premature vascular damage in both cases, including an increased synthesis of proinflammatory mediators (such as cytokines, chemokines and adhesion molecules), autoantibodies against endothelial cell components, perturbations in T-cell subsets, genetic polymorphisms, hyperhomocysteinemia, oxidative stress, abnormal vascular repair, and iatrogenic factors. In a recent study of 22 patients with PsA without any signs of CVD, we found that the plasma concentration of asymmetric dimethylarginine (ADMA) levels were significantly high and coronary flow reserve (CFR) was significantly reduced. Moreover, there was a significant correlation between CFR and plasma ADMA levels in the PsA group. The significant correlation between the reduced CRF and increased ADMA levels suggests that, like patients with early RA, PsA patients suffer from endothelial dysfunction and impaired coronary microcirculation. Active PsA is a risk factor for CVD, and so PsA patients should be screened for subclinical forms of the disease and its risk factors, and an early treatment approach should be adopted.

Osteopenia and osteoporosis in HIV+ patients, untreated or receiving HAART.

In the last few years there are increasing evidences suggesting that osteopenia and osteoporosis are frequent among HIV positive patients. It is still not clear if the bone demineralization is a direct consequence of viral infection or of the antiretroviral drugs. Studies to date therefore give conflicting results. We performed a study to evaluate the prevalence of osteopenia and osteoporosis in HIV positive patients, either untreated or receiving antiretroviral therapy, to asses the frequency of these conditions and the role of antiretroviral drugs.

The role of NSAIDs in psoriatic arthritis: evidence from a controlled study with nimesulide.

OBJECTIVE: To define the optimal dose of nimesulide (NIM) for treating psoriatic arthritis. METHODS: Eighty patients entered a 4-week, double-dummy, randomised, controlled study. Each patient was allocated to one of the following treatment groups: NIM 100 mg/day, NIM 200 mg/day, NIM 400 mg/day, or placebo. Primary end points for arthritis assessment were the scores for tender and swollen joints, and the physician's and patient's global assessment of efficacy. RESULTS: 76/80 patients completed the study. NIM decreased the score for tender and swollen joints from baseline to the end swollen joints from baseline to the end of therapy (p < 0.05). Pain severity on a visual analogue scale (VAS) was reduced by NIM 200 mg (p = 0.03) or NIM 400 mg (p = 0.019) compared to placebo, as was morning stiffness (p = 0.038 and p = 0.008, respectively), but the trends with 100 mg were not statistically significant. The investigators and patients assessed the global efficacy of the NIM 200 and 400 mg/day groups as better than placebo or NIM 100 mg. Side effects were observed in 12 patients (15%) during treatment. They were mostly mild, only one patient withdrew from the study as a result, and the trend for a higher incidence with NIM was not statistically significant. The Psoriasis Area Severity Index (PASI) and the ESR did not show any significant changes. Patients in the placebo group took more paracetamol per day compared with those in the NIM groups (p = 0.007). CONCLUSIONS: Nimesulide 200 and 400 mg/day are effective and safe in psoriatic arthritis.

Diet therapy for rheumatoid arthritis. A controlled double-blind study of two different dietary regimens.

OBJECTIVE: To evaluate the effects of a diet therapy in patients with rheumatoid arthritis (RA). METHODS: Fifty RA patients entered a 24-week double-blind, randomised, controlled-study of two different dietary regimens (an experimental diet high in unsaturated fats, low in saturated fats with hypoallergenic foods vs. a control well-balanced diet). The primary end points of the study were 20% and 50% improvement in disease activity according to composite symptoms (Paulus index) of arthritis. Other end points were the other measures of disease activity at 12 and 24 weeks of diet treatment. RESULTS: The 2 groups were comparable at inclusion. Diet treatment was well tolerated and the rate of drop-outs was low. Percentage of patients with global 20 or 50% response didn't differ between experimental and control group after the 24-week of diet treatment. The experimental diet group did better for all the variables considered but only four variables (Ritchie's index, tender and swollen joints, and ESR) reached a statistical difference by multivariate analysis. Adjusting these data for weight variations, the number of tender joints (p=0.014) and ESR (p=0.025) were still statistically significant. CONCLUSIONS: Dietary manipulation, either by modifying food supplements or by reducing weight, may give some clinical benefit although no significant improvement can be observed assessing the results with a composite index.

Rifamycin SV administered by intra-articular infiltrations shows disease modifying activity in patients with pauci- or polyarticular juvenile rheumatoid arthritis.

The therapeutic activity of rifamycin SV administered by the intra-articular route was evaluated in 52 children with juvenile rheumatoid arthritis (oligopolyarthritis). Each active joint was injected once a week for 10 weeks; thereafter patients were followed for 3-48 months. The number of active joints and joints with limitation of motion, the erythrocyte sedimentation rate (ESR) and C-reactive protein improved significantly at the end of the treatment cycle, with progressive improvement during the subsequent period of observation. At 48-month of follow-up, 78% of joints did not present signs of inflammation; and 66% of joints showed no functional limitations. Joints without radiological lesions at baseline and large joints responded best to the rifamycin treatment. Persistent knee effusions were reabsorbed completely in most cases during the treatment and within the first 6 months of follow-up. Recurrences of synovitis were observed in 7% of joints. De novo radiological lesions in initially undamaged joints occurred during the second year of follow-up in only 10% of patients. At 24 months, 62% of patients with oligoarthritis and 24% with polyarthritis showed complete remission in all affected joints and recovered movement in all those joints which had shown limitations at baseline. There was also a normalization of inflammatory indexes (ESR, C-reactive protein) and regression of general features of disease. Further long term studies are now required to confirm these promising preliminary results.

A double-blind crossover study of two cyclobenzaprine regimens in primary fibromyalgia syndrome.

In a double-blind crossover study, the efficacy and tolerability of oral cyclobenzaprine administered in two different regimens were compared in 40 patients affected by primary fibromyalgia syndrome. The patients were randomly divided into two groups. Each group of 20 patients was treated for 15 days with either a single dose of 10 mg/day cyclobenzaprine at bedtime or 30 mg/day cyclobenzaprine in three equal doses daily. Following treatment there was a 15-day washout period before the groups were crossed over to the other treatment. Both regimens resulted in a significant decline in the number of tender points; significant improvements were also reported in the quality of sleep, anxiety, fatigue, irritable bowel syndrome and stiffness. There was no significant difference in efficacy between the two therapeutic regimens at any stage during the trial. The frequency of reported side-effects was significantly greater (P < 0.001) when patients received 30 mg/day cyclobenzaprine (26 patients, 84%) than when they received 10 mg/day (10 patients, 27%). A dose of 10 mg cyclobenzaprine at bedtime significantly improved the symptomatology of patients affected by primary fibromyalgia syndrome. The higher dose did not further reduce these symptoms but did result in a higher incidence of side-effects.

Multiple intra-articular treatment of rheumatoid arthritis: a randomized prospective study comparing rifamycin SV with pefloxacin.

In a randomized, prospective study the efficacy and tolerability of extensive multiple intra-articular administrations of two antibiotics, rifamycin SV and pefloxacin, were evaluated in 40 patients with classical or definite rheumatoid arthritis. Total weekly doses of 525 mg rifamycin or 560 mg pefloxacin were given for 10 weeks, and 12 months after treatment all clinical indices, erythrocyte sedimentation rate and C-reactive protein improved significantly in the rifamycin group. Some of the treatment indices (morning stiffness, severity of pain by visual analogue scale, grip strength and Ritchie's index) were already improved when the treatment ended, whereas others (erythrocyte sedimentation rate, C-reactive protein, number of painful and swollen joints) improved progressively during the follow-up. In the pefloxacin treatment group all indices except C-reactive protein and severity of pain determined using a visual analogue scale were significantly improved 12 months after treatment. Comparison of the two treatments showed a significant difference in erythrocyte sedimentation rate (P less than 0.047), Ritchie's index (P less than 0.036) and C-reactive protein (P less than 0.028) in favour of rifamycin.

Prevention of appearance of radiological lesions in early rheumatoid arthritis: a randomized, single-blind study comparing intra-articular rifamycin with auranofin.

In a prospective, randomized, single-blind study of 116 patients with early rheumatoid arthritis (mean disease duration 7 months), therapeutic activity of intra-articular rifamycin SV (525 mg/week) infiltration into each peripheral joint over 10 weeks was compared with that of 3 mg auranofin given orally twice daily. The incidence of side-effects was lower in rifamycin-treated patients. At the end of follow-up, the clinical variables and erythrocyte sedimentation rate showed a significant and persistent improvement both in 16 patients who continued the auranofin treatment regularly and in 55 treated with rifamycin who had completed the therapeutic cycle 62.5 months before; the latex test decreased only in the rifamycin group. In patients treated with auranofin or who changed to other commonly used antirheumatic agents, 57% of those with an initially negative radiological picture developed new radiological lesions in at least one of the small joints compared with 9% in the rifamycin group. Although the number of patients treated with rifamycin was small and the follow-up relatively short, the results of the study indicated that treatment with intra-articular rifamycin SV may prevent the appearance of radiological lesions in patients with early rheumatoid arthritis and normal radiographs initially.

Clinical, laboratory and radiographic features in early rheumatoid arthritis.

We evaluated disease status in relation to age, sex and disease duration using some short term indices of disease activity, laboratory tests, and radiological features in 315 patients with rheumatoid arthritis of duration varying from 3 to 36 months (mean 12 months). No differences were observed among various age groups in disease duration, female/male ratio, incidence of radiologic lesions and other indices of disease process. Some clinical markers of the disease process such as involvement of the flexor tendons of the hands and Ritchie's index (score greater than 9) were significantly more frequent in the women (p less than 0.0013 and p less than 0.04, respectively). In the patients with disease of recent onset women were slightly more numerous (56%) than men; however, in those with disease duration of 36 months there were significantly more women (72%) (p less than 0.039), suggesting a greater tendency to chronic disease in this sex. Radiological lesions of the small joints of the hands, feet, and/or wrists were found in 37% of the cases with disease duration of up to 4 months and in 91% at 36 months (p less than 0.0001). The lesions were associated significantly more frequently with Ritchie index (p less than 0.02) and with laboratory indices of inflammatory activity (erythrocyte sedimentation rate greater than or equal to 25 mm/h) (p less than 0.001) and immune response (latex test greater than or equal to 80) (p less than 0.0001). Logistic regression analysis showed that the duration of illness is the most important factor correlating with radiologic lesions.

A comparison of dothiepin versus placebo in the treatment of pain in rheumatoid arthritis and the association of pain with depression.

The effectiveness of dothiepin (a tricyclic anti-depressant) at a dose of 75 mg given orally at night was compared with placebo for 4 weeks in alleviating pain in 60 patients with classical or definite active rheumatoid arthritis. Patients were classified as either 'depressed' or 'not depressed'. The week before, during and 2 weeks after the study, 600 mg ibuprofen was given orally three times daily to all patients. Compared with placebo, dothiepin produced a significant reduction in daytime pain by the end of the treatment period. The Hamilton rating scale in 'depressed' patients was significantly improved in patients given dothiepin. The Cassano-Castrogiovanni self-evaluation rating scale in both 'depressed' and 'not depressed' patients showed a tendency (not significant) to be improved following dothiepin treatment compared with placebo. These results suggest that patients with rheumatoid arthritis may experience an increase in pain symptoms due to an alteration of mood. Therapy with tricyclic anti-depressants, such as dothiepin, therefore, may determine an improvement of pain indexes besides having an anti-depressant effect.

Double-blind study of dothiepin versus placebo in the treatment of primary fibromyalgia syndrome.

A double-blind study comparing the efficacy and tolerability of dothiepin with that of placebo in the treatment of primary fibromyalgia syndrome was carried out. Dothiepin was shown to improve significantly the condition of patients with primary fibromyalgia syndrome and there was a significant difference between dothiepin and placebo in all the clinical variables measured. Only mild and transient side-effects were reported. Further controlled studies are required to define the effects of dothiepin on fibromyalgia.

Absence of antinuclear antibodies in cryoprecipitates of patients with essential mixed or secondary non-lupoid cryoglobulinemia.

A panel of autoantibodies has been tested in serum samples and cryoprecipitates of 14 patients affected by essential mixed cryoglobulinemia (EMC) as well as in 12 subjects with secondary non-lupoid cryoglobulinemia (SC). Three out of 14 patients affected by EMC were ANA-positive (2 at 1:40 dilution and one at 1:80 dilution). Two out of 12 patients with SC were ANA-positive (both at 1:40 dilution). No autoantibodies were found in the cryoprecipitates. These data seem to confirm some previous observations and do not indicate a role of autoantibodies in the cryoprecipitate formation.

Timegadine: long-term open study in rheumatoid arthritis.

The efficacy and tolerability of Timegadine, a new antirheumatic agent, administered at a dose of 250 mg twice daily was evaluated in an open trial of 24 weeks' duration in 31 patients with active rheumatoid arthritis. The subjective and objective clinical parameters improved significantly from the 2nd to 6th week of treatment. For some of the parameters further improvement was observed during the continuation of the treatment. At 6 weeks the ESR was significantly decreased, and a further reduction of the ESR was seen with the continuation of the treatment. At the end of the treatment period other humoral parameters of the disease were significantly modified. Moreover, in 65% of the patients with seropositive rheumatoid arthritis a reduction of the rheumatoid factor titre by at least two dilutions was observed. Five of the 31 patients were withdrawn from treatment due to the appearance of side effects. Although the study was open and the number of patients relatively small, the observed changes in the laboratory parameters of disease activity encourage further investigations to assess the potential of Timegadine as a remissive drug.