IL-12, TNF-alpha, and hormonal changes during late pregnancy and early postpartum: implications for autoimmune disease activity during these times.

Clinical observations indicate that some autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis, frequently remit during pregnancy but exacerbate, or have their onset, in the postpartum period. The immune basis for these phenomena is poorly understood. Recently, excessive production of IL-12 and TNF-alpha was causally linked to rheumatoid arthritis and multiple sclerosis. We studied 18 women with normal pregnancies in their third trimester and during the early postpartum period. We report that during the third trimester pregnancy, ex vivo monocytic IL-12 production was about 3-fold and TNF-alpha production was approximately 40% lower than postpartum values. At the same time, urinary cortisol and norepinephrine excretion and serum levels of 1,25-dihydroxyvitamin were 2- to 3-fold higher than postpartum values. As shown previously, these hormones can directly suppress IL-12 and TNF-alpha production by monocytes/macrophages in vitro. We suggest that a cortisol-, norepinephrine-, and 1,25-dihydroxyvitamin-induced inhibition and subsequent rebound of IL-12 and TNF-alpha production may represent a major mechanism by which pregnancy and postpartum alter the course of or susceptibility to various autoimmune disorders.

Antinuclear antibody-negative, drug-induced lupus caused by lisinopril.

The clinical symptoms of drug-induced lupus (DIL) are similar to those of idiopathic systemic lupus erythematosus. The literature indicates that in patients with DIL, sera generally contain antinuclear antibodies (ANAs); however, ANA-negative DIL has been reported. The list of medications implicated as etiologic agents in DIL continues to grow. This list includes two different types of angiotensin-converting enzyme inhibitors--captopril and enalapril. We report the first case of DIL caused by lisinopril. Our patient had negative results on ANA testing and had histone antibodies (IgG anti-[H2A-H2B]-DNA) mirroring the disease course. Antibodies to the (H2A-H2B)-DNA complex are seen in more than 90% of patients with active DIL, excluding those with DIL due to hydralazine. Thus, it is important to recognize the clinical significance of IgG anti-(H2A-H2B)-DNA antibodies and that negative ANA test results do not preclude the diagnosis of DIL.

Polymyalgia rheumatica and temporal arteritis with sacroiliitis and osteitis pubis.

Polymyalgia rheumatica (PMR) and temporal arteritis (TA) have been associated with a seronegative polyarthritis that can mimic rheumatoid arthritis. Sacroiliitis and osteitis pubis are most often encountered in the different types of spondyloarthropathy. However, sacroiliitis and osteitis pubis have rarely been described in patients with polymyalgia rheumatica and temporal arteritis. We present two patients, one with temporal arteritis and the other with polymyalgia rheumatica, who also had many features of a spondyloarthropathy, including sacroiliitis and osteitis pubis. In reviewing the literature, we found 30 other patients with a diagnosis of PMR who also had sacroiliitis and/or osteitis pubis. We propose that the inflammatory arthritis associated with polymyalgia rheumatica and temporal arteritis can involve the axial joints, resembling a spondyloarthropathy. It is important for the clinician to recognize that sacroiliitis and osteitis pubis have been associated with PMR and TA so that their radiographic presence does not dissuade the clinician from making the correct diagnosis.

Hormonal alterations in rheumatoid arthritis, including the effects of pregnancy.

A number of hormonal abnormalities are present in RA patients. A major theme of these abnormalities seems to be that deficiencies in the production or action of gonadal (estrogens and androgens) and adrenal (corticosteroids and DHEA) hormones may be involved in regulating the onset, severity, and progression of RA. Differences in RA incidence and activity in the pregnant and postpartum periods provide the strongest support for this view. Hormonal changes during these periods clearly have the potential to exert profound effects on RA incidence and activity. The effect of pregnancy on RA activity is actually greater than the effect of some of the newer therapeutic agents. The striking increase in corticosteroids, estrogen, and progesterone during pregnancy may suppress RA onset or activity through the regulation of production or action of cytokines such as TNF alpha, IL-1, IL-6, IL-12, and IL-10. The relative adrenal- and gonadal-deficient environment of the postpartum period further supports the view that hormonal deficiencies predispose to the development or increased activity of RA. These observations justify the search for hormonal abnormalities in RA patients outside the pregnancy and postpartum periods. In particular, further studies on the period before the onset of disease are needed. Additional evidence does exist that a functional abnormality in the adrenal glands in RA patients results in dysregulation of corticosteroid and DHEA production. These abnormalities seem to be linked to aging and disease activity. It is still not established whether these abnormalities are primary or secondary, although data indicating adrenal hypofunction before the development of RA or within the first year of disease activity suggest a primary abnormality. Several hormonal abnormalities seem to be restricted by gender and age, particularly around perimenopause and menopause. These age- and gender-influenced effects may be the cause of some of the contradictory data reviewed here. Studies in the future should make greater efforts to segregate study populations by age, gender, and reproductive status. The identification of the specific hormonal abnormalities and patient populations that are at risk is important, because these factors may allow new therapeutic approaches that are less toxic than current regimens.

Adrenocorticotropin, glucocorticoid, and androgen secretion in patients with new onset synovitis/rheumatoid arthritis: relations with indices of inflammation.

To determine whether alterations in adrenocortical function occur early in the development of inflammatory joint disease, we examined patients with new onset synovitis (<1 yr) prior to treatment with corticosteroids or other disease-modifying antirheumatic drugs. Thirty-two patients with new onset synovitis, including 15 fitting criteria for rheumatoid arthritis (RA), taking no medications, were referred for study by local rheumatologists; 32 age- and sex-matched healthy individuals were recruited as controls. Patients and controls had blood drawn under identical conditions between 0900 and 1100 h. Plasma ACTH, cortisol, dehydroepiandrosterone (DHEA), DHEA sulfate, free and total testosterone, erythrocyte sedimentation rate, C-reactive protein, and rheumatoid factor were measured. Compared with controls, patients had higher inflammatory indices (erythrocyte sedimentation rate, C-reactive protein) and lower basal morning levels of free testosterone (lower in males age > or =45 yr), but similar levels of ACTH, cortisol, DHEA, DHEA sulfate, and total testosterone. In addition, the positive correlations between ACTH-cortisol, ACTH-DHEA, and cortisol-DHEA, observed in the normal controls, were weakened or abolished in the patients (both total and RA subset). No positive relations between inflammatory indices and ACTH or cortisol were noted, yet an inverse correlation between these indices and DHEA and testosterone was observed. Moreover, a steeper age-associated decline in DHEA was observed in our cross-sectional sample of patients with new onset synovitis. We conclude that patients with synovitis (including those fitting criteria for RA) have adrenocortical hormone alterations within a year of disease onset. Paradoxically, these patients have no positive relation between indices of inflammation and ACTH or cortisol, but rather serum androgen levels are inversely correlated with these indices. In addition, the relations between ACTH, the classic stimulus of cortisol and adrenal androgens, and these hormones are weakened or abolished, whereas the negative relation between age and zona reticularis function is steeper than that of controls.

Neck mass in a rheumatoid arthritis patient taking etanercept.

A 60-year-old Caucasian woman with a history of rheumatoid arthritis and a remote history of a post-traumatic splenectomy developed a serious head and neck infection 11 weeks after beginning therapy with etanercept. The patient required incision and drainage of a neck abscess and 2 weeks of i.v. antibiotics to achieve complete recovery. Her etanercept was also discontinued. The causative organism was Streptococcus constellatus, which is a member of the group of encapsulated organisms known as S. intermedius. A normal functioning spleen as well as tumor necrosis factor are both necessary to ward off encapsulated bacteria. Patients who have had a splenectomy and are then started with etanercept may be especially prone to infections with encapsulated organisms, such as streptococcus.

Mycobacterium avium/Mycobacterium intracellulare Complex-Associated Arthritis Masquerading as a Seronegative Rheumatoid Arthritis.

Mycobacterium avium/Mycobacterium intracellulare[cf1] complex (MAC) is a rare cause of tenosynovitis. We describe a case in which a previously healthy patient developed bilaterally symmetric synovitis and was treated with disease modifying anti rheumatic drugs (DMARDs); the synovitis progressed into a bilaterally symmetric chronic granulomatous tenosynovitis that was uncontrollable despite a synovectomy and DMARD therapy. Three years after developing symptoms, and 2 1/2 years after her diagnosis of rheumatoid arthritis, MAC was cultured from synovial fluid. All DMARDS were stopped, and the patient received a total of 24 months of triple antibiotic therapy. All swelling and stiffness resolved after 7 months of therapy. The patient remains asymptomatic two months after completion of antibiotic therapy. Rheumatologists and other arthritis specialists need to include MAC in their differential diagnosis of seronegative symmetrical inflammatory arthritis.

V2 regions of 16S ribosomal RNA used as a molecular marker for the species identification of streptococci in peripheral blood and synovial fluid from patients with psoriatic arthritis.

OBJECTIVE: To detect the 16S ribosomal RNA (rRNA) of 3 streptococcal species in the peripheral blood and synovial fluid of patients with psoriatic arthritis (PsA). METHODS: Reverse transcription-polymerase chain reaction (RT-PCR) detection targets bacterial 16S rRNA, which is present in bacteria at high copy numbers. The 3 species-specific primers for group A streptococci (GAS; Streptococcus pyogenes), group B streptococci (GBS; Streptococcus agalactiae), and Streptococcus pneumoniae were designed from the fragments of highly variable V2 regions of 16S rRNA. Total RNA was prepared from whole peripheral blood and joint fluid obtained from patients with PsA and rheumatoid arthritis (RA). All positive PCR reactions were then sequenced with a Pharmacia ALF DNA sequencing system. RESULTS: Our data in 19 PsA patients showed that 7 peripheral blood samples were positive for GAS (P = 0.006 versus GAS-positive RA patients [n = 0], by Fisher's exact test), and 2 were also positive for GBS. One synovial fluid sample from a PsA patient was positive for GAS. S pneumoniae was absent from all specimens. Seventeen patients with RA were PCR negative for the 3 streptococcal species. Peripheral blood from a patient with inflammatory bowel disease was positive for GAS. CONCLUSION: The presence of GAS 16S rRNA in the peripheral blood and synovial fluid of patients with PsA supports the concept that PsA is a reactive arthritis to certain streptococci.

Distinct patterns of cytokine secretion characterize new onset synovitis versus chronic rheumatoid arthritis.

OBJECTIVE: To compare patterns of cytokine secretion in patients with new onset synovitis (< 1 yr duration, n = 14), chronic rheumatoid arthritis (RA) (n = 16), and healthy controls (n = 17). METHODS: ELIspot assays were used to detect mononuclear cells in the peripheral blood (PMBC) and synovial fluid (SFMC) secretion the type 1 cytokines interleukin 2 (IL-2) and interferon-gamma (IFN-gamma), the type 2 cytokines IL-4, IL-6 and IL-10, and the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha). Results were correlated with measures of disease activity. RESULTS: Patients with new onset synovitis had increased (p < 0.05) numbers of PBMC secreting IL-2. The number of PBMC secreting IFN-gamma correlated with the joint score in the new onset synovitis population (p = 0.006). By comparison, patients with chronic RA had significantly increased numbers of PBMC secreting IL-6, IL-10, and TNF-alpha (p < 0.05). The production of these cytokines correlated with joint score in chronic RA (p = 0.008, 0.06, 0.001, respectively). CONCLUSION: Patients with new onset synovitis have increased numbers of PBMC secreting IL-2 and IFN-gamma, while patients with chronic RA have increased numbers of PBMC secreting IL-6, IL-10, and TNF-alpha. Correlations between joint score and number of PBMC secreting cytokines suggest the number of PBMC secreting IFN-gamma is most relevant in new onset synovitis, while the number of PBMC secreting IL-6, IL-10, and TNF-alpha is of greater relevance in chronic RA.

Does methotrexate increase the risk of infection or malignancy?

Most patients do not exhibit overt signs of immunosuppression. Studies cited in this article support a modest increase in the rate of bacterial respiratory and skin infections. Opportunistic infections occur rarely, however, and may be life threatening. The case for MTX carcinogenicity is less clear. The risk for malignancy other than lymphoproliferative disorders does not seem to be elevated, although multiple sporadic malignancies have been reported in treated patients. MTX is a superb agent for the therapy of a large group of immune-mediated diseases. Although an increased risk for infection and possible malignancy exists, the risk is small compared with the potential clinical benefit.

In vivo gene expression of type 1 and type 2 cytokines in synovial tissues from patients in early stages of rheumatoid, reactive, and undifferentiated arthritis.

It has been reported that the mRNA of the type 1 cytokine, interferon-gamma (IFN-gamma)--but not the type 2 cytokine interleukin-4 (IL-4)--is detected in synovial tissues of rheumatoid arthritis (RA) patients, whereas both IFN-gamma and IL-4 mRNA are detected in reactive arthritis (ReA). To evaluate such data more extensively, we obtained 208 synovial specimens in a prospective study of 52 early synovitis patients (13 RA, 11 ReA, 28 undifferentiated oligoarthropathy) and analyzed type 1 and type 2 cytokine mRNA expression in specimens containing sufficient mRNA. Using a nested reverse transcriptase polymerase chain reaction technique, we measured the relative mRNA levels of 10 cytokines and CD3 delta chain. We detected IL-10, IL-15, and CD3 delta chain mRNA in all RA and ReA patients and frequently detected tumor necrosis factor-alpha, IL-1 beta, and IFN-gamma mRNA. IL-6 and IL-12 p40 mRNA were detected in approximately one-half of the patients. We also detected greater amounts of IL-2 and IFN-gamma mRNA in ReA than were detected in RA. However, we rarely detected IL-4 or IL-13 mRNA. Similar cytokine profiles were observed in undifferentiated oligoarthropathy. The amounts of cytokine mRNAs, except for IL-10, in specimens from the patients taking prednisone or second-line antirheumatic drugs tended to be less than in specimens from the patients taking neither prednisone nor second-line antirheumatic drugs. These results suggest that cytokine mRNA profiles in patients with RA, ReA, and undifferentiated arthritis in their early stages are skewed toward proinflammatory macrophage-derived and type 1 cytokines. IL-10--not IL-4 or IL-13--mRNA appears to be the major antiinflammatory cytokine mRNA. Drug therapy is associated with depressed proinflammatory and type 1 cytokine mRNA production. The differences in the expression of IL-2 and IFN-gamma mRNA between RA and ReA may reflect unique etiological or host factors associated with the early stages of these diseases.

Circadian relationships between interleukin (IL)-6 and hypothalamic-pituitary-adrenal axis hormones: failure of IL-6 to cause sustained hypercortisolism in patients with early untreated rheumatoid arthritis.

Systemic symptoms in rheumatoid arthritis (RA) are mediated, at least in part, by elevated levels of circulating interleukin (IL)-6, and this cytokine is also a potent stimulus of the hypothalamic-pituitary-adrenal axis. To evaluate the 24-h circadian secretory dynamics of ACTH, cortisol, and IL-6 and their interactions in patients with early untreated RA, we recruited and studied five newly diagnosed, untreated RA patients early in the course of their disease and five age-, gender-, and race-matched control subjects. We collected serial blood samples over 24 h and measured plasma ACTH and cortisol every 30 min and IL-6 every hour. The 24-h collection was followed by administration of ovine CRH (oCRH) and post-oCRH serial blood samples over 2 h. We analyzed the 24-h overall levels of these hormones and their circadian variations and performed time-lagged cross-correlation analyses among them. The untreated RA patients had 24 h time-integrated plasma ACTH, plasma cortisol levels, and urinary free cortisol excretion that were not significantly different from control subjects, in spite of their disease activity. However, an earlier morning surge of plasma ACTH and cortisol in the patients was suggested. Plasma ACTH and cortisol responses to oCRH were similar in RA patients and controls. IL-6 levels were significantly increased in the RA patients compared with control subjects during the early morning hours (P < 0.05). There was pronounced circadian variation of plasma Il-6 levels. In the RA patients, we detected a positive temporal correlation between plasma levels of IL-6 and ACTH/cortisol, with elevated levels of IL-6 before the elevations of ACTH and cortisol by 1 and 2 h, respectively. In the same patients, we detected a negative effect of cortisol upon IL-6 exerted with a delay of 5 h. The data presented here suggest that although endogenous IL-6 may stimulate secretion of ACTH and cortisol, overall activity of the hypothalamic-pituitary-adrenal axis remains normal and apparently is insufficient to inhibit ongoing inflammation in early untreated RA patients.

Polymyalgia rheumatica with a low erythrocyte sedimentation rate: comparison of 10 cases with 10 cases with high erythrocyte sedimentation rate.

Polymyalgia rheumatica (PMR) is an inflammatory disorder characterized by severe proximal myalgias associated with an elevated erythrocyte sedimentation rate (ESR). In this report 10 otherwise typical PMR patients with an ESR <35 mm/hr, and 10 PMR patients with an ESR > 35 mm/hr were examined and prospectively followed. We report the initial laboratory response to steroids in both groups as well as follow-up (average32.6 months in the low ESR group). The average follow-up for this study is the longest reported for low ESR PMR. The most significant difference noted was a longer duration before diagnosis and therapy for the low ESR group. Both groups showed similar clinical and laboratory response to therapy and similar post-treatment disease duration.The absence of an elevated ESR does not exclude the diagnosis of PMR. Clinical response to steroids and a drop in the ESR after therapy are proposed as useful to confirm the diagnosis.

Failure of low-dose intravenous immunoglobulin therapy to suppress disease activity in patients with treatment-refractory rheumatoid arthritis.

OBJECTIVE: Treatment with high-dose (400 mg/kg/day) intravenous immunoglobulin (IVIg) shows benefit in many autoimmune diseases but is very expensive. Low-dose IVIg has also been shown to be effective in inhibiting adjuvant arthritis in the rat. This pilot, randomized, double-blind, placebo-controlled trial was conducted to assess the use of low-dose IVIg in patients with treatment-refractory rheumatoid arthritis (RA). METHODS: Twenty patients with active RA were recruited. Ten patients received IVIg and 10 received albumin. Study subjects were given 6 courses of either IVIg (5 mg/kg) or albumin (5 mg/kg), once every 3 weeks. Baseline medications were continued and not changed throughout the study. RESULTS: There were no complications. Five patients dropped out before the 18-week followup visit. No significant differences between treatment groups were noted during the 18-week trial in terms of global activity indices (patient or physician assessment), joint swelling, joint pain or tenderness, erythrocyte sedimentation rate, C-reactive protein level, or rheumatoid factor. The protocol was terminated prematurely because of reported contamination of IVIg by hepatitis C virus. None of the patients showed evidence of hepatitis C infection by serologic analysis or by polymerase chain reaction. CONCLUSION: Low-dose IVIg, as administered in this trial, does not show a therapeutic effect in patients with refractory RA.