Safety management in treatment with antimalarials in rheumatology. Interdisciplinary recommendations on the basis of a systematic literature review.

BACKGROUND: Antimalarial medication (AM) plays an important role in the treatment of rheumatic diseases. OBJECTIVE: Updated evidence-based recommendations on the safety management of rheumatological treatment with AM are presented. METHODS: A systematic literature search in the databases Medline (PubMed) and Cochrane identified 1160 studies on the safety of treatment with AM in rheumatology. In addition, a manual search was carried out and 67 publications considered to be particularly relevant by the authors were analyzed in more detail. These publications served as a basis for consensus-based recommendations. RESULTS: Treatment with AM in rheumatology should be carried out with hydroxychloroquine (HCQ) with a dosage not exceeding 5 mg/kg body weight/day. Patients should undergo a basic ophthalmological examination within the first 6 months of AM treatment. Pre-existing maculopathy, renal insufficiency (glomerular filtration rate, GFR <60 ml/min), tamoxifen comedication, a daily dose of >5 mg/kg HCQ or treatment with chloroquine (CQ) show an increased risk for AM-induced retinopathy. These patients should undergo an annual ophthalmological check from the beginning of the treatment, whereas patients with no risk factors are recommended to start this only after 5 years of taking the medication. The ophthalmological examination should comprise at least both an appropriate subjective and an objective method and these are usually an automated visual field test and optical coherence tomography (OCT). A visual field test revealing a parafoveal sensitivity loss and an OCT showing a parafoveal circumscribed loss of the photoreceptor layer or focal interruptions of the structural line of the outer segment are signs of a possible AM retinopathy. Determination of creatine kinase (CK) and lactate dehydrogenase (LDH) in blood is appropriate to screen for cardiomyopathy and myopathy and should be checked before starting the treatment and then ca. every 3 months. The use of cardiac biomarkers, such as brain natriuretic peptide (BNP) or troponin in serum, electrocardiograph (ECG) or cardiac imaging should be considered depending on the situation. An intake of HCQ is safe during pregnancy and breastfeeding according to the current state of knowledge and is protective for mother and child in patients with systemic lupus erythematosus. CONCLUSION: The updated recommendations on AM treatment in rheumatology in particular include a more rigorous measuring of doses, risk stratification in monitoring and defined ophthalmological examination methods to detect a possible retinopathy.

[Safety management of the treatment with antimalarial drugs in rheumatology. Interdisciplinary recommendations based on a systematic literature search]. / Sicherheitsmanagement der Therapie mit Antimalariamitteln in der Rheumatologie. Interdisziplinäre Empfehlungen auf der Basis einer systematischen Literaturrecherche.

BACKGROUND: Antimalarial medication (AM) plays an important role in the treatment of rheumatic diseases. OBJECTIVE: Updated evidence-based recommendations on the safety management of rheumatological treatment with AM are presented. METHODS: A systematic literature search in the databases Medline (PubMed) and Cochrane identified 1160 studies on the safety of treatment with AM in rheumatology. In addition, a manual search was carried out and 67 publications considered to be particularly relevant by the authors were analyzed in more detail. These publications served as a basis for consensus-based recommendations. RESULTS: Treatment with AM in rheumatology should be carried out with hydroxychloroquine (HCQ) with a dosage not exceeding 5 mg/kg body weight/day. Patients should undergo a basic ophthalmological examination within the first 6 months of AM treatment. Pre-existing maculopathy, renal insufficiency (glomerular filtration rate, GFR <60 ml/min), tamoxifen comedication, a daily dose of >5 mg/kg HCQ or treatment with chloroquine (CQ) show an increased risk for AM-induced retinopathy. These patients should undergo an annual ophthalmological check from the beginning of the treatment, whereas patients with no risk factors are recommended to start this only after 5 years of taking the medication. The ophthalmological examination should comprise at least both an appropriate subjective and an objective method and these are usually an automated visual field test and optical coherence tomography (OCT). A visual field test revealing a parafoveal sensitivity loss and an OCT showing a parafoveal circumscribed loss of the photoreceptor layer or focal interruptions of the structural line of the outer segment are signs of a possible AM retinopathy. Determination of creatine kinase (CK) and lactate dehydrogenase (LDH) in blood is appropriate to screen for cardiomyopathy and myopathy and should be checked before starting the treatment and then ca. every 3 months. The use of cardiac biomarkers, such as brain natriuretic peptide (BNP) or troponin in serum, electrocardiograph (ECG) or cardiac imaging should be considered depending on the situation. An intake of HCQ is safe during pregnancy and breastfeeding according to the current state of knowledge and is protective for mother and child in patients with systemic lupus erythematosus. CONCLUSION: The updated recommendations on AM treatment in rheumatology in particular include a more rigorous measuring of doses, risk stratification in monitoring and defined ophthalmological examination methods to detect a possible retinopathy.

[Ocular findings and differential diagnoses in giant cell arteritis (Arteriitis cranialis)]. / Augenbefunde und Differenzialdiagnosen bei Riesenzellarteriitis (Arteriitis cranialis).

A visual impairment occurs in about 50% of patients with giant cell arteritis (GCA), an amaurosis fugax (AF) in about 30%, and diplopia in about 10%. An arteritic anterior ischemic optic neuropathy was found in about 80%-90% of patients with visual loss and an arteritic central retinal artery occlusion in about 10%-20%. Without therapy, involvement of the fellow eye may occur within hours or days in a patient with unilateral blindness. Involvement of the anterior segment of the eye (iris ischemia, episcleritis) is rare. Ocular ischemic syndrome is defined by visual loss with hypotony, ischemia of the iris, and cotton wool spots (CWS). CWS may already occur with AF episodes. In the case of strong suspicion of GCA, immediate therapy with steroids is indicated. Duplex sonography and a gadolinium MRI examination are of diagnostic importance. A biopsy of the temporal artery may be carried out after the initiation of therapy.

Update of the evidence based, interdisciplinary guideline for anti-inflammatory treatment of uveitis associated with juvenile idiopathic arthritis.

BACKGROUND: Uveitis in juvenile idiopathic arthritis (JIAU) is frequently associated with the development of complications and visual loss. Topical corticosteroids are the first line therapy, and disease modifying anti-rheumatic drugs (DMARDs) are commonly used. However, treatment has not been standardized. METHODS: Interdisciplinary guideline were developed with representatives from the German Ophthalmological Society, Society for Paediatric Rheumatology, Professional Association of Ophthalmologists, German Society for Rheumatology, parents' group, moderated by the Association of the Scientific Medical Societies in Germany. A systematic literature analysis in MEDLINE was performed, evidence and recommendations were graded, an algorithm for anti-inflammatory treatment and final statements were discussed in a consensus meeting (Nominal Group Technique), a preliminary draft was fine-tuned and discussed thereafter by all participants (Delphi procedure). RESULTS: Consensus was reached on recommendations, including a standardized treatment strategy according to uveitis severity in the individual patient. Thus, methotrexate shall be introduced for uveitis not responding to low-dose (≤ 2 applications/day) topical corticosteroids, and a TNFalpha antibody (preferably adalimumab) used, if uveitis inactivity is not achieved. In very severe active uveitis with uveitis-related deterioration of vision, systemic corticosteroids should be considered for bridging until DMARDs take effect. If TNFalpha antibodies fail to take effect or lose effect, another biological should be selected (tocilizumab, abatacept or rituximab). De-escalation of DMARDs should be preceded by a period of  ≥ 2 years of uveitis inactivity. CONCLUSIONS: An interdisciplinary, evidence-based treatment guideline for JIAU is presented.

Chronic psychological stress enhances nociceptive processing in the urinary bladder in high-anxiety rats.

This study sought to determine whether acute and/or chronic psychological stress produce changes in urinary bladder nociception. Female Sprague-Dawley (SD; low/moderate anxiety) or Wistar-Kyoto (WK; high-anxiety) rats were exposed to either an acute (1 day) or a chronic (10 days) water avoidance stress paradigm or a sham stress paradigm. Paw withdrawal thresholds to mechanical and thermal stimuli and fecal pellet output, were quantified at baseline and after the final stress or sham stress exposure. Rats were then sedated, and visceromotor responses (VMRs) to urinary bladder distension (UBD) were recorded. While acute stress exposure did not significantly alter bladder nociceptive responses in either strain of rats, WK rats exposed to a chronic stress paradigm exhibited enhanced responses to UBD. These high-anxiety rats also exhibited somatic analgesia following acute, but not chronic, stress. Furthermore, WK rats had greater fecal pellet output than SD rats when stressed. Significant stress-induced changes in nociceptive responses to mechanical stimuli were observed in SD rats. That chronic psychological stress significantly enhanced bladder nociceptive responses only in high-anxiety rats provides further support for a critical role of genetics, stress and anxiety as exacerbating factors in painful urogenital disorders such as interstitial cystitis (IC).

Influence of corticosteroid treatment on MRI findings in giant cell arteritis.

Giant cell arteritis (GCA) remains a diagnostic challenge. With the use of a high-resolution MRI protocol, visualization of the superficial cranial arteries is feasible and mural inflammation can be assessed noninvasively. Until today, it is not known how soon inflammatory signals in diagnostic MR imaging vanish after initiation of treatment. Here, we report sequential MR imaging findings during the initial weeks of corticosteroid treatment in a 79-year-old female patient with histologically proven GCA. Mural inflammatory changes decreased within the first 2 weeks and have almost entirely vanished after 2 1/2 months of continued treatment. Moreover, MR angiography revealed sequential stenoses of the subclavian artery, which improved in variable extent with some residuals despite high dose steroid medication. This report underlines the value of high-resolution MRI in diagnosis and follow-up of GCA and illustrates the potential of MRI to detect and monitor intra- and extra-cranial involvement patterns of GCA in high detail.

[Endogenous endophthalmitis]. / Endogene endophthalmitis.

Endogenous endophthalmitis is a severe and potentially blinding complication of hematogenous spread of microorganisms. Predisposing factors are intravenous drug abuse, immunosuppression, and prolonged intensive care. Intraocular material needs to be cultured or subjected to PCR to detect the causative microorganisms. In contrast to PCR, culture has the advantage of providing additional information about the resistance of the microorganism. Fungi and bacteria cause endogenous endophthalmitis with the same frequency. Treatment consists in a combination of local and systemic antibiotics or antimycotics, systemic and local corticosteroids, and vitrectomy. The prognosis depends mainly on the initial visual acuity and the pathogen concerned.

[Lues - Ocular syphilis]. / Lues ­ Okuläre Syphilis.

Ocular syphilis is not a new issue but due to increasing rates of new cases is now a contemporary issue. The clinical features are unspecific and can be manifested as all forms of ocular inflammation. Unspecific anterior uveitis is the most frequent ocular involvement; however, typical distinctive patterns are superficial white preretinal precipitates within a panuveitis and acute syphilitic posterior placoid chorioretinitis. The diagnosis should be confirmed by serological tests. Treatment is based on parenteral administration of penicillin.

[Temporal arteritis (giant cell arteritis). Clinical picture, histology, and treatment]. / Arteriitis temporalis (Riesenzellarteriitis). Klinik, Histologie und Therapie.

Giant cell arteritis (arteritis temporalis) is the most common form of systemic vasculitis in the elderly. A series of symptoms such as new-onset headache, jaw claudication, proximal myalgia, weight loss, and fever may lead to the diagnosis. However, there is also a silent or occult presentation with minor or no systemic symptoms, especially no headache. A number of laboratory values (erythrocyte sedimentation rate, CRP, fibrinogen, thrombocytes, and cardiolipin antibodies) indicate giant cell arteritis, but none of this proves the diagnosis. Temporal artery biopsy is the gold standard for diagnosis of giant cell arteritis. Due to skip lesions, a negative result does not exclude the diagnosis. The most important complication of giant cell arteritis is visual loss in one or both eyes due to AION or retinal artery occlusion. Usually, visual loss is irreversible even with therapy. Corticosteroids are the drug of choice to treat giant cell arteritis. Therapy is required for a long time, monitored by parameters of inflammation (ESR, CRP).

[Adverse ocular effects of vaccinations]. / Impfschäden am Auge.

Vaccinations are very effective measures for prevention of infections but are also associated with a long list of possible side effects. Adverse ocular effects following vaccination have been rarely reported or considered to be related to vaccinations. Conjunctivitis is a frequent sequel of various vaccinations. Oculorespiratory syndrome and serum sickness syndrome are considered to be related to influenza vaccinations. The risk of reactivation or initiation of autoimmune diseases (e. g. uveitis) cannot be excluded but has not yet been proven. Overall the benefit of vaccination outweighs the possible but very low risk of ocular side effects.

Visceral nociceptive input to the area of the medullary lateral reticular nucleus ascends in the lateral spinal cord.

In halothane-anesthetized rats, neurons stereotaxically located in the region of the medullary lateral reticular nucleus (LRN) and responsive to urinary bladder distension (UBD) were characterized using extracellular electrodes. Most neurons excited by UBD were also excited by noxious stimuli applied to bilateral receptive fields comprising at least half of the body surface. These bilateral nociceptive specific (bNS) neurons exhibited graded responses to graded intensities of UBD. Neuronal responses to noxious UBD were highly positively correlated with responses to noxious colorectal distension, suggesting a convergence of visceral sensory information in the area of LRN. Bilateral lateral mid-cervical spinal cord lesions virtually abolished activity of bNS neurons evoked by noxious UBD, while dorsal midline lesions had no significant effect. These data support a role for neurons in the region of the LRN in visceral nociception and implicate traditional lateral spinal cord pain pathways in the transmission of visceral information to caudal ventrolateral medullary structures.

Effects of smoking on neuropathic pain in two people with spinal cord injury.

BACKGROUND/OBJECTIVE: To describe an apparent relationship between smoking and the neuropathic pain experience in people with spinal cord injury (SCI). METHOD: Case Reports. PARTICIPANTS/METHODS: Two individuals treated at a rehabilitation center. The first was a 38-year-old white man with a T1 2 SCI, American Spinal Injury Association (ASIA) impairment scale (AIS) A, secondary to motor vehicle crash. Duration of injury was 14 years. He reported burning pain in his legs, and has smoked 1/2 pack per day for the last 15 years. The second was a 55-year-old African American man with a T6 SCI, AIS A, secondary to gunshot wound. Duration of injury was 22 years. He was a 40-year 1/2 to 1 pack per day smoker, who, after injury, consistently experienced burning, radicular pain, rated 7/10, around the level of the injury. SUMMARY: The first subject rated his pain as 4/10 when not smoking and 7/10 when smoking. The pain subsided 30 minutes after smoking was discontinued. He noted an immediate increase in neuropathic pain when smoking. The second subject quit smoking for 1 month and immediately noted that the pain disappeared, rating it 0/10. After he resumed smoking, his radicular pain was 8.5/10 in the morning and 5/10 in afternoon. CONCLUSIONS: No similar reports have been published, based on a MEDLINE search. Nicotinic receptors have been implicated in pain perception. It is unclear to what extent these 2 cases generalize to the SCI population. We plan to explore this via survey and experimental research. Smoking cessation may have a dual benefit of increased health and decreased neuropathic pain.

Sex-related hormonal influences on pain and analgesic responses.

Considerable evidence indicates sex-related differences in pain responses and in the effectiveness of various analgesic agents. Specifically, females are at greater risk for experiencing many forms of clinical pain and are more sensitive to experimentally induced pain relative to males. Regarding analgesic responses, nonhuman animal studies indicate greater opioid analgesia for males, while a limited human literature suggests the opposite. Though the mechanisms underlying these effects remain unclear, the influence of gonadal hormones on nociceptive processing represents one plausible pathway whereby such sex differences could emerge. The present article reviews the complex literature concerning sex steroid effects on pain responses and analgesia. First, nonhuman animal research related to hormonal effects on nociceptive sensitivity and analgesic responses is presented. Next, human studies regarding gonadal hormonal influences on experimental pain responses are reviewed. Several potential mechanisms underlying hormonal effects on nociceptive processing are discussed, including hormonal effects to both peripheral and central nervous system pathways involved in pain transmission. Finally, based on these findings we draw several conclusions and make specific recommendations that will guide future research as it attempts to elucidate the magnitude and importance of sex-related hormonal effects on the experience of pain.

Evidence for ascending visceral nociceptive information in the dorsal midline and lateral spinal cord.

The effect of acute, mid-cervical spinal cord lesions on neuronal and reflex activity evoked by the noxious visceral stimulus, colorectal distension (CRD; 80 mmHg, 20 s), was determined in halothane-anesthetized rats. Extracellular recordings were performed of neurons stereotaxically located within the ventrobasal group of the thalamus and in the region of the medullary lateral reticular nucleus. CRD-evoked activity of thalamic neurons was attenuated by lesions of the dorsal midline, but minimally affected by lateral lesions of the spinal cord. In contrast, CRD-evoked activity of medullary neurons was attenuated by lateral lesions ipsilateral to the recording site, but minimally affected by contralateral lateral lesions or dorsal midline lesions. Pseudo-affective visceromotor/cardiovascular responses were vigorous in rats with dorsal midline lesions and absent/attenuated in rats with bilateral lateral spinal lesions. This study presents evidence that visceral nociceptive information ascends in the spinal cord by both dorsal midline and lateral spinal pathways.

Visceral pain: a review of experimental studies.

This paper reviews clinical and basic science research reports and is directed toward an understanding of visceral pain, with emphasis on studies related to spinal processing. Four main types of visceral stimuli have been employed in experimental studies of visceral nociception: (1) electrical, (2) mechanical, (3) ischemic, and (4) chemical. Studies of visceral pain are discussed in relation to the use and 'adequacy' of these stimuli and the responses produced (e.g., behavioral, pseudoaffective, neuronal, etc.). We propose a definition of an adequate noxious visceral stimulus and speculate on spinal mechanisms of visceral pain.

A psychophysiological study in humans using phasic colonic distension as a noxious visceral stimulus.

Psychophysiological experiments were performed in 9 humans using constant-pressure, phasic, graded distention (30 sec, 20-70 mm Hg) of the sigmoid colon as a visceral stimulus. Reliable cardiovascular (pressor), respiratory and visceromotor responses in addition to reports of pressure/pain sensations were evoked by colonic distension in 8 of the 9 subjects. The pressure/pain sensations were referred to the lower abdomen, lower back and perineum and their intensity quantified using a visual analogue scale. Responses to colonic distension were graded and increased with repeated distensions at the same intensity (60 mm Hg). The area of referral as indicated by subject drawings increased with repeated distensions as did the intensity of the subjects' sensory and affective descriptors of the sensation. Five of the subjects differentiated between 'pressure' and 'pain' sensations evoked by colonic distension; the intensity of the 'pain' sensation accelerated during the distending stimulus whereas the 'pressure' sensation was typically stable or adapting during the distending stimulus.

Low intensity vagal nerve stimulation lowers human thermal pain thresholds.

The effect of vagal nerve stimulation (VNS) on thermal pain sensation was studied in eight subjects who had vagal nerve stimulators surgically implanted for purposes of seizure control. Prior to their involvement in the study, all subjects had the intensity of their VNS (30 Hz, 0.5 ms, 1.0-2.75 mA) adjusted upwards until achieving their desired clinical effect of reduced seizures. Thermal pain thresholds were determined using a Medoc TSA-2001 with a thermode applied to the skin of the forearm. During VNS at settings 100% of those used clinically to control their seizures, subjects showed a statistically significant decrease in their thermal pain threshold of 1.1+/-0.4 degrees C. Acute effects of graded VNS on thermal pain thresholds were determined in seven of the subjects after cessation of chronic VNS. Two thermal threshold measurements were obtained while the subject received sham stimulation (0 mA intensity), during tactile control stimulation and during 30 s of VNS at intensities approximately 33, 66 and 100% of the settings utilized to control their seizures. Tactile control stimulation was provided by electrical stimulation of the skin of the ankle with the intensity adjusted by the patient to match the intensity of any sensations felt in the neck during VNS. Subjects were not aware of the settings employed. Their stimulator was adjusted with each trial and an ascending/descending ordering of intensity was utilized with an inter-trial interval of 2 min. Thermal pain thresholds were significantly decreased in relation to tactile control stimulation at all intensities of VNS tested with the greatest effect occurring at the 66% level. Subjects were also monitored non-invasively and hemodynamic responses to VNS were determined. No significant alterations in hemodynamic variables were observed. The findings of this human study are consistent with experiments in non-human animals which demonstrate a pro-nociceptive effect of low intensity VNS.

A psychophysical study of discomfort produced by repeated filling of the urinary bladder.

Psychophysical studies were performed in 10 healthy, female volunteers using urinary bladder distension (UBD) as a visceral stimulus. Stimulus methodology was similar to that used clinically for obtaining cystometrograms with a fixed-rate (100 cc/min normal saline) filling of the urinary bladder, occasional pauses and simultaneous measure of bladder pressure using a catheter-transducer assembly. During bladder filling, subjects were asked to report sensations by verbal report and by using an electronic, hand-held, visual-analog-scale device. Sensations evoked by UBD were generally localized to the suprapubic region. UBD produced cardiovascular responses which increased with repeated trials. Sensation intensity increased with repeated UBDs as indicated by global pain ratings. Intravesical pressure and volume correlated with sensation intensity. The volume of distending fluid needed to produce a report of discomfort was highly variable from trial to trial and did not change significantly with repeated UBDs. The intravesical pressure which produced a report of discomfort was less variable and significantly decreased with repeated UBDs. The change in intravesical pressure and volume needed to produce discomfort was inversely correlated with initial intravesical pressure measures. Similar to findings in other organ systems, these findings demonstrate that repeated presentations of a visceral stimulus may lead to an increase in physiological and perceptual responses to pain.

Evidence for two populations of rat spinal dorsal horn neurons excited by urinary bladder distension.

Spinal L6-S2 dorsal horn neurons of cervical spinal cord-transected, decerebrate female rats were characterized using urinary bladder distension (UBD) as a visceral stimulus. Constant pressure, phasic, graded (20-80 mm Hg, 20 s) air UBD was delivered via a transurethral catether and extracellular single-unit recordings obtained from all neurons excited by UBD. Responses to graded UBD and noxious/non-noxious cutaneous stimuli were determined in 258 neurons which could be stratified into two groups based on their effect of a counterirritation stimulus: Type I neurons (n=112) were inhibited by noxious pinch presented in a non-segmental field; Type II neurons (n=146) were not similarly inhibited. Both Types of neurons were identified in both superficial and deep recording sites and demonstrated graded responses to graded UBD. All UBD-excited neurons had convergent cutaneous receptive fields (RFs) excited by non-noxious and/or noxious stimuli. As a group, Type I neurons had a period of decreased activity following termination of the distending stimulus whereas Type II neurons typically had a sustained afterdischarge. UBD-evoked activity in Type II neurons was inhibited more than similar activity in Type I neurons by both intravenous morphine and lidocaine. These results support the assertion that at least two different populations of spinal dorsal horn neurons exist which encode for a stimulus of urinary bladder distension. These populations are an analogue to previously characterized, similar neuronal populations excited by colorectal distension and suggest that they are representative of the overall phenomenon of visceral sensory processing, a component of which is nociception.

Characterization of superficial T13-L2 dorsal horn neurons encoding for colorectal distension in the rat: comparison with neurons in deep laminae.

Fifty-five neurons responsive to colorectal distension located in the superficial spinal dorsal horn (0.0-0.3 mm ventral to the cord dorsum) of the T13-L2 spinal segments of pentobarbital-anesthetized, physiologically intact or spinalized (C1 transection), decerebrate rats were characterized. These neurons could be separated into three groups based upon their response to an 80 mm Hg, 20 s colorectal distension: (1) short latency-abrupt (SL-A) neurons (n = 22) that were excited by colorectal distension at a short latency (less than 1 s) and abruptly terminated responses following the termination of the distending stimulus; (2) short latency-sustained (SL-S) neurons (n = 26) that were excited by colorectal distension at a short latency (less than 1 s) and demonstrated sustained responses (greater than 4 s) following termination of the distending stimulus; and (3) INHIB neurons (n = 7) that were spontaneously active and were inhibited by colorectal distension. All 55 neurons had convergent cutaneous receptive fields (i.e. were 'viscerosomatic'), exhibiting excitatory responses to noxious (pinch/heat) and/or non-noxious (brush) stimuli. Neurons excited by colorectal distension also demonstrated monotonic, accelerating responses to graded colorectal distension, were excited by the intraarterial administration of bradykinin, could be antidromically activated by electrical stimulation in the caudal ventrolateral medulla and were subject to tonic descending inhibitory modulation as evidenced by more vigorous responses to distension when rats were reversibly spinalized using a cold block.(ABSTRACT TRUNCATED AT 250 WORDS)