Do steroids increase lymphoma risk? A case–control study of lymphoma risk in polymyalgia rheumatica/giant cell arteritis

BACKGROUND: Recent studies indicate increased risks of malignant lymphomas among individuals treated with corticosteroids, but have not taken into account the underlying reasons for steroid use, so the increased risks might be attributable to the underlying disease or concomitant treatments other than steroids. Polymyalgia rheumatica (PMR) and temporal arteritis (giant cell arteritis, GCA) are common inflammatory conditions treated with steroids as single immunosuppressive therapy, but data on lymphoma risk in GCA/PMR are limited. OBJECTIVE: To assess the risk of lymphoma associated with steroid treatment of GCA/PMR. METHODS: The association between GCA/PMR and malignant lymphomas (overall, and separately for non-Hodgkin lymphoma, Hodgkin lymphoma, and chronic lymphatic leukaemia) was examined in a nationwide, population based, case-control study of 42,676 lymphoma cases and 78,487 matched population controls, using prospectively recorded data on lymphomas from the Swedish cancer register 1964-2000 and data on pre-lymphoma hospital admissions for GCA/PMR from the Swedish inpatient register 1964-2000. Odds ratios (OR) associated with a pre-lymphoma hospital admission for GCA/PMR were calculated using conditional logistic regression. RESULTS: 153 lymphoma cases and 345 population controls had a history of GCA/PMR, resulting in an overall OR for malignant lymphomas of 0.81 (95% confidence interval, 0.67 to 0.98). The OR varied little with lymphoma type, sex, age, and calendar period. The OR for GCA was 0.67 (0.48 to 0.98) and for PMR, 0.83 (0.67 to 1.04). CONCLUSIONS: Treated GCA is not associated with increased lymphoma risks, which suggests that even at considerable cumulative doses, steroids may not appreciably increase lymphoma risk.     

Anticardiolipin antibodies in giant cell arteritis and polymyalgia rheumatica: a study of 40 cases

The occurrence and clinical value of anticardiolipin antibodies (aCL) were studied in 33 patients with giant cell arteritis (GCA) and in seven patients with polymyalgia rheumatica (PMR), at onset and during follow-up. aCL were present in 19/40 (47.5%) GCA/PMR cases, most of them of the IgG isotype, whereas all controls (21 subjects) were aCL negative. The presence of aCL was not associated with inflammatory parameters or clinical signs of arteritis; however, they disappeared in a significant percentage (56%) of patients during steroid therapy. No correlation was found between ischaemic events and aCL, suggesting that they are not important for the development of vascular complications in GCA/PMR patients. Moreover, a retrospective evaluation of our data showed a correlation between aCL positivity and anaemia, whose significance remains to be elucidated.      

Management of difficult polymyalgia rheumatica and giant cell arteritis: Updates for clinical practice

Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) represent a family of systemic inflammatory diseases occurring in adults aged 50 years and above. Clinical presentation of PMR/GCA can be variable, making diagnosis at times challenging. There has been an increased appreciation of the role of various large-vessel imaging modalities to help confirm a diagnosis of GCA. Systemic corticosteroids (CS) remain the mainstay of treatment for both PMR and GCA, yet both relapses and CS-related side effects are common. Recent research has demonstrated efficacy of certain biologic agents in these diseases, with particular emphasis on the role of interleukin-6 (IL-6) blockade in GCA. This chapter discusses the latest updates on the diagnosis and treatment of PMR/GCA, with an emphasis on clinical care.     

Intercellular adhesion molecule 1 gene polymorphisms in polymyalgia rheumatica/giant cell arteritis: association with disease risk and severity

OBJECTIVE: Intercellular adhesion molecule 1 (ICAM-1) is widely distributed in shoulder synovial membrane of active polymyalgia rheumatica (PMR) and strongly expressed in granulomatous inflammatory infiltrate of the temporal artery in giant cell arteritis (GCA). ICAM-1 genes may contribute to the inflammatory PMR/GCA processes. We examined potential associations of ICAM-1 gene polymorphisms with PMR/GCA susceptibility and severity. METHODS: We enrolled 121 consecutive patients with "pure" PMR and 56 patients with biopsy positive GCA residing in Reggio Emilia, Italy. Among patients with PMR, 91 had a followup duration of at least one year. Selected as control subjects were 228 healthy blood donors, 75 patients with nonarteritic central retinal artery occlusion, and 116 cataract surgery patients from the same geographic area. All PMR/GCA patients and controls were genotyped by polymerase chain reaction and allele-specific oligonucleotide techniques for ICAM-1 polymorphism at codon 241 (exon 4) and codon 469 (exon 6). RESULTS: The frequency of R241 was significantly higher in PMR/GCA patients [p = 0.00001, odds ratio (OR) 5.0 (95% confidence intervals, CI 2.6-9.6) ], in pure PMR patients [p = 0.00001, OR 5.0 (95% CI 2.5-10.0)], and in GCA patients [p = 0.00005; OR 5.0 (95% CI 2.2-11.5)] compared to the healthy controls. The frequency of R241 was significantly higher in total PMR/GCA patients compared to patients with nonarteritic central retinal artery occlusion [p = 0.0007; OR 5.3 (95% CI 1.8-15.5)] and cataract surgery patients [p = 0.0003; OR 4.1 (95% CI 1.8-9.0)]. The distribution of E/K 469 genotype was similar in PMR/GCA patients and in the 3 control groups. Cox proportional hazards modeling identified 2 variables that independently increased the risk of PMR relapse/recurrence: erythrocyte sedimentation rate at diagnosis > 72 mm/h [relative risk 1.6 (95% CI 1.1-2.3)] and the presence of R241 allele [relative risk 1.6 (95% CI 1.1-2.4)]. CONCLUSION: Our findings show that G/R 241 polymorphism of ICAM-1 is associated with PMR/GCA susceptibility and confers an increased risk of relapse/recurrence in PMR.     

The ESR in the diagnosis and management of the polymyalgia rheumatica/giant cell arteritis syndrome.

A review of 80 patients with the polymyalgia rheumatica/giant cell arteritis (PMR/GCA) syndrome has revealed that the erythrocyte sedimentation rate (ESR) is normal in 22.5% of cases at presentation. Too much reliance on the ESR as a screening test led to delay in diagnosis in 10 patients. Serious complications occurred in 4 patients with a normal or minimally raised ESR. Analysis of follow-up data at 4 weeks showed no significant correlation between change in the ESR and change in symptoms, and at subsequent clinical attendances symptoms did not consistently parallel the ESR. Our results cast serious doubts on the use of the ESR as an entirely reliable diagnostic and therapeutic aid in the PMR/GCA syndrome.     

Steroid-reversible parkinsonism as presentation of polymyalgia rheumatica

Polymyalgia rheumatica (PMR) is an inflammatory disorder typically affecting elderly people, characterized by pain and stiffness in the neck and in the shoulder and pelvic girdless with prompt clinical response to low doses of corticosteroids. PMR is closely related to giant cell arteritis (GCA), likely sustained by a “subclinical vasculitis”. Whereas in GCA both the central and peripheral nervous systems may be involved, only a PMR case of global, steroid-reversible dementia has been hitherto described. We report two elderly patients who abruptly developed, as PMR presenting symptom, an akinetic-rigid parkinsonian syndrome that promptly and completely resolved after corticosteroid treatment.     

Low serum levels of DHEAS in untreated polymyalgia rheumatica/giant cell arteritis

OBJECTIVE: To address a controversy regarding the existence of a relative adrenal hypofunction in patients with untreated polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) we evaluated baseline serum levels of ACTH, cortisol, and DHEAS in a cohort of patients with recent onset PMR/GCA not previously treated with glucocorticoids, in comparison with healthy controls. Possible correlations between baseline DHEAS levels and laboratory measures of disease activity were also explored. METHODS: Basal serum levels of these hormones were prospectively investigated in 25 patients with active untreated disease and compared with those of 25 age- and sex-matched control subjects. RESULTS: Of the 25 patients, 19 had isolated PMR and 6 had biopsy-proven GCA + PMR. Basal levels of cortisol and ACTH in PMR/GCA patients did not differ from control subjects; in relation to inflammatory status, lower than expected basal production of cortisol was observed in active untreated PMR/GCA. Baseline serum DHEAS levels were significantly lower in all patients compared with controls. In these patients, a significant correlation was found between baseline DHEAS values and laboratory measures of disease activity. The percentage of DHEAS reduction and the severity of inflammatory response were higher in women than in men. CONCLUSION: Patients with PMR/GCA with new-onset active disease before steroid treatment have inappropriately normal cortisol levels regarding the ongoing inflammation, and significantly lower levels of DHEAS compared to the age- and sex-matched healthy control subjects. These data support the existence of a relative adrenal hypofunction in PMR and GCA.     

Mannose-binding lectin variant alleles and HLA-DR4 alleles are associated with giant cell arteritis

OBJECTIVE: To determine whether variant alleles of the mannose-binding lectin (MBL) gene causing low serum concentrations of MBL and/or polymorphisms of HLA-DRB1 are associated with increased susceptibility to polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) or particular clinical phenotypes of PMR/GCA. METHODS: MBL and HLA-DRB1 alleles were determined by polymerase chain reaction in 102 Danish patients with PMR (n = 37) or GCA (n = 65). Two hundred fifty and 193 healthy individuals served as controls for MBL and HLA genotyping, respectively. RESULTS: The prevalence of MBL variant alleles in controls, patients with PMR only, and patients with GCA was 37, 32, and 53% (p = 0.01), respectively. HLA-DRB1*04 was found in 47% of patients with PMR only and in 54% of patients with GCA, which differed significantly from the 35% found in controls (p = 0.01). HLA-DR4 alleles were not associated with any clinical phenotypes of PMR/GCA, whereas MBL variant alleles were associated with cranial arteritis, high erythrocyte sedimentation rate, and low B-hemoglobin. CONCLUSION: We found MBL variant alleles and HLA-DR4 alleles to be weak susceptibility markers for GCA. In patients with PMR/GCA, MBL variant alleles were associated with signs of increased inflammatory activity and clinical signs of arteritic manifestations. This was not found for HLA-DR4 alleles. These findings indicate that HLA-DR4 and MBL are contributing to the pathophysiology of GCA at different levels in the disease process.     

Interleukin-6 promoter polymorphism at position -174 in giant cell arteritis

OBJECTIVE: To investigate potential associations between the -174 G/C interleukin-6 (IL-6) promoter polymorphism and susceptibility to and clinical features of giant cell arteritis (GCA), particularly in patients with or without polymyalgia rheumatica (PMR) and with or without ischemic complications. METHODS: One hundred and twenty-six patients with biopsy-proven GCA who were residents in Reggio Emilia, Italy, and 112 population-based controls from the same geographic area were genotyped for IL-6 polymorphism at position -174 by molecular methods. Patients were divided in subgroups according to presence or absence of PMR and ischemic complications (visual loss, jaw claudication, cerebrovascular accidents, aortic arch syndrome). RESULTS: Distribution of the G/C 174 genotype was similar in patients with GCA and controls. No significant associations with the IL-6 promoter polymorphism at position -174 were found when GCA patients with or without PMR or with or without ischemic complications were compared. Further, IL-6 genotypes did not significantly affect levels of C-reactive protein or other inflammatory markers at diagnosis. CONCLUSION: Our findings show that the 174 G/C promoter IL-6 polymorphism does not seem to be implicated in susceptibility to and clinical expression of GCA.     

A new serological reaction in patients with polymyalgia rheumatica and/or giant cell (temporal) arteritis: deposition of complement C4 and C3 components on rat kidney structures detected by indirect immunofluorescence

Summary Using indirect immunofluorescence deposition of complement C4 and C3 components to rat kidney medullary structures was demonstrated. This serological reaction (C4/C3-IFT) is regularly obtained with fresh sera of patients suffering from active polymyalgia rheumatica (PMR) and/or giant cell (temporal) arteritis (GCA). Sera of normal controls and of steroid-treated PMR and/or GCA patients in clinical remission have a negative C4/C3-IFT reaction. A positive conversion of the test in steroidtreated patients indicates enhanced disease activity. Because of its technical simplicity, C4/C3-IFT can be routinely used first, as a reliable serological marker in the primary diagnosis of PMR and/or GCA and second, as a sensitive criterion of disease activity in these patients. C4/C3-IFT reactivity is, however, not specific for GCA and/or PMR. Various systemic inflammatory diseases may have a positive reaction as well (e.g., certain viral and bacterial infections, malignant tumors, vasculitides, inflammatory joint diseases of different etiology). Recent experimental findings suggest that C-reactive protein (CRP) in patients' sera mediates an activation of the classical complement pathway resulting in a deposition of C4 and C3 complement components to certain rat kidney structures.     

Rheumatic polymyalgia

Polymyalgia rheumatica (PMR) is a common clinical syndrome that is characterized by pain and stiffness in neck, shoulder girdle and pelvic girdle. The aetiology is unknown. However, recent studies have documented an association with HLA antigens and infectious agents. It occurs mostly after the age of 50 years and is often accompanied by systemic features such as fever, asthenia, hyporexia and weight loss. An erythrocyte sedimentation rate (ESR) of at least 40 mm/hour has been considered diagnostic criterion. Nevertheless, a normal ESR accounted for up to 20% of cases of PMR. A dramatic and prompt response to corticosteroid treatment is characteristic. Giant cell arteritis/temporal arteritis (GCA) has been found in 0-80% of cases of PMR. Temporal biopsy could initially be deferred in patients with PMR younger than 70 years with no cranial symptoms, in which the risk of GCA is very low.     

Polymyalgia rheumatica: myalgic syndrome or occult vasculitis?

Polymyalgia rheumatica (PMR) is a chronic inflammatory disorder of unknown etiology which typically presents with symmetric myalgias in the shoulder and pelvic girdles. Other clinical signs include the rapid onset of symptoms and the almost exclusive manifestation in the elderly population. In around 20% of cases, PMR is associated with giant cell arteritis (GCA). However, new imaging techniques suggest that the prevalence of subclinical GCA (e. g. aortitis) in PMR is probably higher. Acute phase reactants like erythrocyte sedimentation rate and c-reactive protein are usually elevated. Myalgias are accompanied by synovitis and bursitis of the large proximal joints and can be visualized by ultrasound or magnetic resonance imaging. While the diagnosis of GCA can be verified by temporal artery biopsy, pathognomonic findings for PMR like specific autoantibodies are lacking. Typical for PMR is the rapid response to corticosteroids. Usually the therapy needs to be continued for at least 2 years. Due to adverse events in many cases a corticosteroid saving therapy like methotrexate is needed.     

Antiphospholipid antibody syndrome and polymyalgia rheumatica/giant cell arteritis

SIR, By 1988 many authors described antiphospholipid antibodies(aPL), such as anticardiolipin (aCL) and/or anti-ß₂-glycoproteinI (anti-ß₂-GPI) antibodies, in patients with polymyalgiarheumatica (PMR) and/or giant cell arteritis (GCA), with positivityrates between 7.5 and 63.6% of cases [1–12]. Nonetheless,as far as we have been able to ascertain, aPL syndrome (APS)has been reported in only one patient affected with GCA [13]. Evident clinical and serological signs in keeping with the diagnosisof APS were found in three of 248 (1.20%) patients seen in ourhospitals [187 females and 61 males, with mean age 73.53 yr± 7.77 standard deviation (S.D.) and range 50–92yr], 212 affected with PMR, five with GCA, and 31 with PMR andGCA. PMR was diagnosed as the presence of typical clinical features,including pain in     

Polymyalgia rheumatica

Polymyalgia rheumatica (PMR) is a chronic inflammatory disorder of unknown etiology which typically presents with symmetric myalgias in the shoulder and pelvic girdles. Other clinical signs include the rapid onset of symptoms and the almost exclusive manifestation in the elderly population. In around 20% of cases, PMR is associated with giant cell arteritis (GCA). However, new imaging techniques suggest that the prevalence of subclinical GCA (e. g. aortitis) in PMR is probably higher. Acute phase reactants like erythrocyte sedimentation rate and c-reactive protein are usually elevated. Myalgias are accompanied by synovitis and bursitis of the large proximal joints and can be visualized by ultrasound or magnetic resonance imaging. While the diagnosis of GCA can be verified by temporal artery biopsy, pathognomonic findings for PMR like specific autoantibodies are lacking. Typical for PMR is the rapid response to corticosteroids. Usually the therapy needs to be continued for at least 2 years. Due to adverse events in many cases a corticosteroid saving therapy like methotrexate is needed.     

Corticotropin releasing hormone promoter polymorphisms in giant cell arteritis and polymyalgia rheumatica

OBJECTIVE: Giant cell (temporal) arteritis (GCA) and polymyalgia rheumatica (PMR) are different but overlapping diseases of unknown etiology affecting the elderly. Corticotropin-releasing hormone (CRH) helps to regulate the immune response and maintain homeostasis during inflammatory stress. CRH promoter region polymorphisms in the 5'regulatory region of the CRH gene have been described. To investigate the possible implications of the CRH promoter polymorphisms in PMR and GCA susceptibility we have examined a series of patients with these conditions. METHODS: Sixty-two patients with biopsy-proven GCA, 86 patients with isolated PMR and 147 ethnically matched controls from the Lugo region of Northwest Spain were included in this study. Patients and controls were genotyped for CRH polymorphism in the 5' regulatory region of the gene at position 1273 (alleles A1 andA2) and at position 225 (alleles B1 and B2) by PCR-restriction fragment length polymorphism. Allele frequencies and genotype distribution were evaluated by the chi-square test. RESULTS: When GCA and PMR patients were examined for alleles and genotypes for each CRH polymorphism no significant differences in frequency were found compared with controls. A higher CRH-A2 allele frequency was observed in GCA patients with visual complications (21.4%) compared with controls (9.2%) and GCA cases without eye involvement [6.3%; p= 0.017, Pcorr = 0.034, O.R: 4.1 (95% CI 1.2- 13.9)], although this was based on a small sample of patients with ischemic visual complications (n = 14) and should be interpreted with caution. No differences in CRH allele or genotype frequencies were observed in isolated PMR patients stratified by relapses and recurrence of disease symptoms. CONCLUSION: Polymorphisms in the CRH gene regulatory region do not appear to be associated with increased susceptibility to PMR or GCA. The CRH-A2 allele may encode risk for the development of visual complications in GCA, although further studies to confirm this will be required.     

Epidemiologic and immunogenetic aspects of polymyalgia rheumatica and giant cell arteritis in northern Italy

We studied the epidemiology of giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) in a Mediterranean population. Ninety-nine patients with PMR and/or GCA were identified over a 9-year period (1980-1988) in Reggio Emilia, Italy. The average annual incidence of PMR and GCA was 12.7/100,000 and 6.9/100,000, respectively, in a population aged 50 years or older. Frequencies of HLA antigens were determined in 49 patients with PMR and/or GCA who were followed by staff at our rheumatology unit during the 1980-1988 period. When compared with HLA findings in 242 healthy controls, DR4 was not found to be significantly associated with PMR (24% in PMR patients versus 14% in controls). Patients with GCA also showed an increased frequency of DR4 compared with controls (36% versus 14%), but this difference was also not statistically significant. The immunogenetic features of PMR and GCA and the relationship between the immunogenetic and epidemiologic patterns in different populations are discussed.     

Is there a role for Pneumocystis jiroveci pneumonia prophylaxis in giant cell arteritis or polymyalgia rheumatica?

BackgroundPneumocystis jiroveci pneumonia (PJP) is an opportunistic fungal infection that affects immunocompromised patients. The objective of this study was to describe the incidence of PJP among patients with giant cell arteritis (GCA) or polymyalgia rheumatica (PMR).MethodsA retrospective cohort study of incident cases of GCA and PMR was conducted using claims data from the TriNetX database to describe the incidence of PJP during the first 6 months of therapy. Additionally, a systematic review was performed to identify other publications describing PJP among patients with GCA or PMR.ResultsDuring 547 patient-years of follow-up time, no cases of PJP were identified among 1,168 cases of GCA (incident rate 0 per 1,000 person-years); during 7,446 patient-years of follow up time, one case of PJP was identified out of 15,575 cases of PMR (incident rate 0.07 cases per 1,000 patient-years). This patient was alive at last follow up. Our systematic review identified 1 case-control study, 4 cohort studies, and 18 case series / case reports of PJP among patients with GCA or PMR. The incident rate of PJP was reported from one additional study for GCA and was estimated at 0.08 cases per 1,000 person years; no additional cohort studies were identified for patients with PMR. Over the entirety of the published literature, the total number of cases identified among case series and case reports was 33, from which 4 total deaths were identified.ConclusionsPatients with newly diagnosed GCA or PMR rarely develop PJP. Existing data does not support routine prescribing of PJP prophylaxis for either group of patients.     

'ASIA' - Autoimmune/inflammatory syndrome induced by adjuvants: even and odd

Recently, Shoenfeld and Agmon-Levin described a potential new syndrome, namely ASIA - autoimmune/inflammatory syndrome induced by adjuvants, that comprises four medical conditions: siliconosis, the Gulf war syndrome, the macrophagic myofasciitis syndrome and post-vaccination phenomena, characterized by hyperactive immune responses accompanied by a similar complex of signs and symptoms. Most relevantly, these conditions share a linkage represented by adjuvants. This common soil may possibly induce autoimmune or auto-inflammatory diseases in humans as it was demonstrated in different animal models. Reconsidering under a unified umbrella this apparently detached condition is not only intriguing, but also provocative, and may help in unraveling novel pathogenetic mechanisms, preventive measures, and therapeutic targets.     

Secondary amyloidosis associated with giant cell arteritis/polymyalgia rheumatica

Although giant cell arteritis (GCA) is characterized by chronic inflammation, secondary (AA) amyloidosis appears to be an exceptionally rare complication of this disorder. We describe an 84-year-old man with biopsy proven GCA and polymyalgia rheumatica (PMR) who was found at autopsy to have AA amyloid deposition in numerous organs, 9 years after his diagnosis of GCA. Persistent musculoskeletal symptoms, attributed to refractory PMR during the patient's life, were likely due to AA amyloidosis. This unrecognized complication of GCA/PMR confounded his therapy, leading to excessive treatment with corticosteroids and methotrexate. This case shows that the occurrence of AA amyloidosis should be considered in patients with "refractory PMR" developing after a period of treatment, and that autopsies play a vital role in enigmatic cases.