Arthritis

Rev Rhum Engl Ed 1998 Jun;65(6):372-377

Rheumatic manifestations and immunological abnormalities in patients with chronic hepatitis C. A study in the Middle East.

al-Awadhi A, al-Jarallah K, Hasan F, Olusi S, al-Attiyah R, Sugathan TN, al-Salem I, Attiyah Y, Sedequi H, Ahmed AH Department of Medicine, School of Medicine, Kuwait University, Kuwait.

Hepatitis C virus infection and rheumatic disorders are both common in the Middle East and share many clinical and immunological manifestations, raising diagnostic problems. We compared the prevalence of extrahepatic clinical manifestations and immunological disorders in 40 patients with chronic hepatitis C and in 42 carefully matched healthy controls. Polyarthralgia or polyarthritis was the most common rheumatic manifestation (35%) in the cases, followed by cutaneous vasculitis (15%). Glomerulonephritis and xerophthalmia were uncommon, and none of the cases had systemic vasculitis. Immunological abnormalities included serum rheumatoid factor (47.5%), cryoglobulins (30%), and one or more antitissue antibodies (37.5%). The prevalences of polyarthralgia, cutaneous vasculitis, rheumatoid factor, cryoglobulinemia, and anti-tissue antibodies were significantly higher in the hepatitis C group than in the control group. Our data suggest that patients in the Middle East who present with features of rheumatic or autoimmune diseases should be screened for hepatitis C.

PMID: 9670328, UI: 98334984

Rheumatic syndromes during the course of HCV infection

[Article in Polish]

Olesinska M, Chwalinska-Sadowska H.

Klinika Chorob Tkanki Lacznej Instytutu Reumatologicznego w Warszawie.

The aim of the study was to evaluate clinical features and serological abnormalities in patients(pts) with rheumatological symptoms in the course of HCV infection (5 pts) and interferon-alpha treatment (2 pts). The diagnosis of hepatitis C was based on positive history on jaundice and risk factors of HCV infection, abnormal liver laboratory tests, the presence of anti-HCV and HCV-RNA and on results of liver biopsy. Among the patients with rheumatological features in the course of HCV infection seropositive arthritis in 4 pts, leucocytoclastic vasculitis, clinical and serological manifestations of mixed cryoglobulinemia-in 3 pts were observed. Glomerulonephritis, Raynaud's phenomenon and antinuclear antibodies were found in 2 pts. Sjogren's syndrome with anti-Ro/La antibodies, polyneuropathy and myalgia were observed in single cases. The most frequent therapy were corticosteroids alone or in combination with chlorochine or azathioprine. Arthritis, leucocytoclastic vasculitis and serological abnormalities: antinuclear antibodies, rheumatoid factor and low complement were seen in 2 pts with rheumatological features after the IFN-alpha treatment of HCV infection. Myalgia and xerostomia with anti-Ro antibody were found in one patient; lupus-like disease with anti-dsDNA antibody and autoimmune thyroiditis-in one patient. The therapy of these two cases was to withdraw interferon-alpha.

PMID: 11995247 [PubMed - indexed for MEDLINE]

HCV/RA/Raynauds/Vasculitis

Hi Norm,

This is gonna be rather complicated: With Hep C infection, about 30% of people have cryoglobulinemia. This means they have proteins in the blood that typically settle in joints, the subjective experience is much like any other kind of arthritis. Hands, fingers, wrists, elbows and hips are most commonly affected. Vasculitis (blood vessel inflammation) also can come along with Hep C. This can be very similar to Raynaud's. Where this is very important is in the case of the vessels of the kidney are involved - the patient can lose the kidney. (I believe this is what happened to Freddie Fender) If you can get rid of the Hep C, you get rid of the cryoglobulinemia.

If a patient has an underlying autoimmune disorder like Rheumatoid Arthritis, and they are given interferon (which may be seen as an immune system supercharger), there is a likelihood that it will make the symptoms of the autoimmune disorder worse. The trickiest cases are where the patient has autoimmune hepatitis along with Hep C : to make the Hep C go away, you have to make the autoimmune hep worse.

The other thing that happens in combination therapy for hep C is that ribavirin destroys red blood cells, and patients can expect to transiently lose about 2.9 grams of hemoglobin, about 19% of their normal level(some lose much more, some lose none). With the loss of hemoglobin comes a loss of oxygen carrying capacity. When blood vessels realize there is not enough oxygen, they constrict. The subjective experience is much like Raynaud's. It is like putting your hand in a bucket of ice water.

This ribavirin effect is also experienced as shortness of breath and lowered exercise tolerance. Many physicians will do a dose reduction from 1200mg to 800mg per day and many of the leading docs are now giving selected patients Procrit to stimulate the creation of more red blood cells. The idea is to keep the hep C patient on as much of the full dose as possible to preserve the probability of achieving a sustained virological response. Currently, about 86% of people who start combination therapy are able to finish. Recent data also show that, overall about 56% of those completing therapy achieve sustained virologic response and can be considered cured of hep C. If you really dig into the data, the patients who really were fully compliant (took all their doses when they were supposed to) the success rate is higher: about 62% of genotype 1 patients and about 90% of genotype two or three.

If you really want to get into the science of any of the disorders mentioned, go to the National Library of Medicine at: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi and type in whatever you are interested in and it will show you abstracts on it, you are then free to pursue the topic to your heart's content - you can spend days at this site. For more patient-friendly stuff go to www.webMD.com and again, just type in whatever you are interested in.

Physicians can run tests to see if the patient has rheumatoid factors and other autoimmune problems. so, good luck - I hope the patient achieves SVR!

Dave Erickson, Dr.PH
Director of Education
Texas Liver Coalition
St. Luke's Episcopal Hospital
6720 Bertner Ave. MC 1-187
Houston, TX 77030
phone: 800 725 4837

Norm <normseiff@attbi.com> wrote:

I was wondering if you would know or could find out for me;

1) if Raynaud's & Vasculitis can be result of the
Interferon/Peg-Interferon combo with Rivavaron Treatment?

2) or is it a result of HCV and/or RA by itself?

And if you could direct me to documentation on any of above?

Thank You:
Norm Seiff (708) 453-2206      normseiff@attbi.com

Ask the Experts on . . .

Rheumatoid Arthritis and Hepatitis C

Question

What is appropriate treatment for a patient with rheumatoid arthritis (RA) and active hepatitis C?

Raffaele Improta, MD

Response

from Robert Terkeltaub, MD, 04/24/01
The first issue is to be certain of each diagnosis. Rheumatoid arthritis can be associated with false-positive hepatitis C virus (HCV) serology (though this was more common with older generation immunoassays). Mixed cryoglobulinemia and vasculitis associated with HCV can cause joint symptoms and clinically inflamed joints (but without destructive arthritis). In addition, HCV infection can be associated with a symmetric inflammatory polyarthritis; many patients in this situation test positive for rheumatoid factor (RF). Sjögren's syndrome also can be associated with HCV. In addition, treatment of HCV with interferon-alfa has been reported to trigger an inflammatory seronegative rheumatoid-like polyarthritis, and possibly promotes the development of classical RA from latent disease in a few individuals.

Hydroxychloroquine and sulfasalazine are a good foundation for treatment in cases where disease-modifying antirheumatic drugs (DMARDs) are indicated for bona fide RA in a patient with active HCV infection. Methotrexate would be contraindicated. There are not enough data at this point to know whether etanercept and leflunomide adversely impact HCV-related liver disease. But I would not be inclined to use either of these drugs for RA in the setting of a chronic infectious disease.

Comments

6/12/01
Gold salts is a good option but should be used with care in patients with HCV. Liver function is already compromised in this patient and gold salt can cause it to further deteriorate. Moreover, the effect of gold on the immune system is not well known and could make the viremia worse.

Harbhajan S. Parmar, MD
India

5/8/01
Treatment with injectable gold is another option that can be tried. In fact, we have been using it in some patients with good results, and there is no worsening of liver function even after long-term treatment.

Halim Siddiqui, MD
Kuwait

Musculoskeletal manifestations and autoantibody profile in 90 hepatitis C virus infected Israeli patients.

Semin Arthritis Rheum 1998 Oct;28(2):107-13 Buskila D, Shnaider A, Neumann L, Lorber M, Zilberman D, Hilzenrat N, Kuperman OJ, Sikuler E Department of Medicine B, Soroka Medical Center, Beer Sheeva, Israel.

OBJECTIVES: Recent interest has been expressed in rheumatic manifestations in hepatitis C virus (HCV)-infected populations. The aim of this study was to determine the prevalence and characteristics of the musculoskeletal manifestations and serological markers of autoimmunity in HCV-infected patients in Israel.

METHODS: Ninety anti-HCV-positive patients were consecutively interviewed and examined. The prevalence of autoantibodies and their association with rheumatologic symptoms were also determined.

RESULTS: Rheumatic manifestations were found in 28 subjects (31%), and included arthralgias (9%), arthritis (4%), cryoglobulinemia (11%), sicca symptoms (8%), cutaneous vasculitis (2%), polymyositis (1%), and antiphospholipid syndrome (1%).

Rheumatic complications were not associated with liver disease severity, or subjects' gender. In addition, myalgia was reported by 22 patients (24%), and fibromyalgia was diagnosed in 14 (16%). Sixty-nine percent of the patients had at least one autoantibody detected in their serum, the most prevalent being rheumatoid factor (RF), 44%; antinuclear antibody (ANA), 38%; and IgM and IgG anticardiolipin antibodies (ac1), 28% and 22%, respectively.

The frequency of autoantibodies was not associated with liver disease severity or rheumatic disorders.

CONCLUSIONS: Musculoskeletal manifestations and autoimmune markers are common in HCV infection.

An investigation of risk factors for HCV infection is pertinent in a patient presenting new rheumatic manifestations and should be included in the history of present illness.

Future studies of these disorders may uncover the full spectrum of these associations and provide new insights into their operating mechanisms.

VA Research being done in the US: Contact H. Ralph Schumacher, MD Professor of Medicine
VA Medical Center, Arthritis Clinic
University & Woodland Avenues
Philadelphia, PA 19104 http://www.med.upenn.edu/rheum/schumacher.html

HUP Clinic: 8 Penn Tower
34th & Civic Center Boulevard
Philadelphia, PA 19104 Office: 215-823-5979
Fax: 215-823-6032

Rheumatic manifestations and immunological abnormalities in patients with chronic hepatitis C. A study in the Middle East.

AUTHOR: al-Awadhi A, al-Jarallah K, Hasan F, Olusi S, al-Attiyah R, Sugathan TN, al-Salem I, Attiyah Y, Sedequi H,Ahmed AH, Department of Medicine, School of Medicine, Kuwait University, Kuwait.
SOURCE: Rev Rhum Engl Ed 1998 Jun;65(6):372-377

Hepatitis C virus infection and rheumatic disorders are both common in the Middle East and share many clinical and immunological manifestations, raising diagnostic problems. We compared the prevalence of extrahepatic clinical manifestations and immunological disorders in 40 patients with chronic hepatitis C and in 42 carefully matched healthy controls. Polyarthralgia or polyarthritis was the most common rheumatic manifestation (35%) in the cases, followed by cutaneous vasculitis (15%). Glomerulonephritis and xerophthalmia were uncommon, and none of the cases had systemic vasculitis. Immunological abnormalities included serum rheumatoid factor (47.5%), cryoglobulins (30%), and one or more antitissue antibodies (37.5%). The prevalences of polyarthralgia, cutaneous vasculitis, rheumatoid factor, cryoglobulinemia, and anti-tissue antibodies were significantly higher in the hepatitis C group than in the control group. Our data suggest that patients in the Middle East who present with features of rheumatic or autoimmune diseases should be screened for hepatitis C.

Hepatitis C Infection Presenting with Rheumatic Manifestations/ A Mimic of Rheumatoid Arthritis."

August 2, 1996AUTHORS: Lovy, M.R.; Starkebaum, G.; Uberoi, S.
SOURCE: Journal of Rheumatology, June 1996;23(6):979-983.

OBJECTIVE:
To describe the clinical features of a group of patients presenting with rheumatic manifestations who were subsequently determined to have hepatitis C infection.

METHODS:
A case study of 19 consecutive patients referred to private practitioners in Tacoma and Federal Way, Washington, because of polyarthritis, polyarthralgia, or positive rheumatoid factor (RF) who were subsequently found to have hepatitis C. Patients were tested for hepatitis C when they met the following screening criteria: abnormal liver biochemical studies or history of transfusion, jaundice, or hepatitis.

RESULTS:
Risk factors for hepatitis C infection were present in 14 patients, including transfusions (8) or intravenous drug use (6). Eight patients gave a history of previous jaundice or hepatitis predating their articular complaints by intervals ranging from 3 mos to 23 yrs. Liver biochemical tests were normal in 6 patients. Serologic evidence of hepatitis B or human T lymphotrophic virus type II was present in 3 of 19 and 2 of 14 patients, respectively. Carpal tunnel syndrome (8 patients), palmar tenosynovitis (7 patients), fibromyalgia (6 patients), and nonerosive, nonprogressive arthritis typified the articular manifestations. Fifteen patients fulfilled diagnostic criteria for rheumatoid arthritis (RA). Three patients had small vessel skin vasculitis. The arthritis responded well to treatment with low dose prednisone and hydroxychloroquine.

CONCLUSION:
Hepatitis C infection can present with rheumatic manifestations indistinguishable from RA. The predominant clinical findings include palmar tenosynovitis: small joint synovitis, and carpal tunnel syndrome. Risk factors such as transfusions and IV drug abuse or a history of hepatitis or jaundice should be included in the history of present illness of any patient with acute or chronic polyarthritis or unexplained positive RF. In such patients, gammaglutamyl aminotransferase, serologic studies for hepatitis C, and other tests appropriate for chronic liver disease should be performed."

The corresponding author for this study is: MR Lovy, 2420 South Union 150, Tacoma, WA 98405 USA.
For subscription information for this journal contact the publisher: J Rheumatol Publ Co, 920 Yonge St, Suite 115, Toronto on M4W 3C7, Canada.

Arthritis and Rheumatism

January 2003 (Volume 48, Number 1)

Increased Salivary Gland Tissue Expression of Fas, Fas Ligand, Cytotoxic T Lymphocyte-Associated Antigen 4, and Programmed Cell Death 1 in Primary Sjogren's Syndrome

Bolstad AI, Eiken HG, Rosenlund B, Alarcon-Riquelme ME, Jonsson R
Arthritis and Rheumatism. 2003;48(1):174-185

Bolstad and coworkers examined salivary gland tissues obtained from patients with primary Sjögren's syndrome (SS) for the gene expression profile of the candidate genes involved in apoptosis, including FAS (TNFRSF6), Fas ligand (TNFSF6, FasL), and genes involved in modulating response to apoptotic signals such as cytotoxic T lymphocyte-associated antigen 4 (CTLA4), programmed cell death 1 (PDCD1, PD-1), and orosomucoid 2 (ORM2). Quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR) was used to examine the expression of messenger RNA (mRNA), and tissue localization of the expressed proteins was determined using immunohistochemistry. The study researchers found increased levels of expression of mRNA for Fas (5.1-fold), FasL (8.8-fold), cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) (11.2-fold), programmed cell death 1 (PD-1) (15.2-fold), and orosomucoid 2 (ORM2) (4.4-fold) in patients compared with controls, when GAPDH was used as the endogenous standard. The study demonstrates a substantial increase in expression of the apoptotic signal molecules Fas and FasL in patients with primary SS compared with controls. However, a significant increase in negative regulators of apoptosis such as CTLA-4, PD-1, and ORM2 (discussed below) was also detected in the salivary gland cells as well as in the mononuclear cells. This study is important for rheumatologists because it presents an example of how disease results from delicate imbalance of cytokine signals. The complex balance of pro- and antiapoptotic signals also points out the difficulty in designing therapies for autoimmune disorders characterized by organ-specific immunity.

In the past, we used to have a simple paradigm for SS, namely that lymphocytes would migrate into the gland and kill all of the glandular cells by Fas/Fas-L-mediated mechanisms and then the patients would complain of dryness. Our analogy was the pancreatic glandular destruction in type 1 diabetes. Everything was explained by a simple autoimmune attack on autoantigens such as SS-A or SS-B that were generated by apoptosis and then expressed on the glandular cell surface in "blebs" where they "broke tolerance." However, we now find that the SS in humans is different from the murine models and that the majority of salivary gland cells are not killed, even though Fas/Fas-L genes are upregulated.

This study extends a previous study by Jonsson and colleagues^[1] that demonstrated that cell death by apoptosis, as measured by the TUNEL method, appears to be low in the salivary glands of patients with primary SS. Similar to animal models of SS, both Fas and Fas-L are upregulated in the human SS biopsies, but apoptotic cells are low in number in the human biopsies.^[1] To explain this apparent paradox, Bolstad and colleagues now demonstrate that salivary gland biopsies express antiapoptotic proteins PD-1 and ORM2(discussed below), which work to prevent apoptosis in addition to antiapoptotic molecules of the bcl2/bax family.^[2]

There are several implications of these findings. First, the "persistence" of mononuclear cells in the glands is not a result of the genetic defect in the cells to respond to apoptotic signals, as was found in murine SS. Other factors must be considered to explain the persistence of lymphoid infiltrates in the glands. It now appears that proteins antagonizing apoptosis appear responsible for the characteristic histopathology noted on biopsy.

Second, the glandular cells also express Fas/Fas-L but are not undergoing apoptosis, again probably due to the upregulation of the antiapoptotic proteins. This raises the more interesting question concerning the mechanism(s) responsible for glandular dysfunction, which leads to the clinical symptoms of dry eyes and dry mouth. It seems that stimulation of Fas/Fas-L receptors can cause second signals that interfere with glandular function such as response to cholinergic stimuli and aquaporin translocation.^[3] Thus, an outcome of Fas/Fas-L receptor stimulation may also be dysfunction without death. This type of glandular dysfunction may impair the gland in addition to the inhibitory effect on cholinergic nerves of proinflammatory cytokines.^[4]

As noted above, rheumatologists have received confusing messages about the mechanisms of apoptosis and the role of the rapidly growing number of cytokines that may be targets for therapies. All of these cytokines and mechanisms of apoptosis were interesting but "theoretical," until the introduction of biologic therapies that inhibited cytokines and their receptors. Thus, a re-evaluation of how we look at autoimmunity is required. It is clear that an important role exists for both the "acquired" immune system and the "innate" immune system. Although these immune pathways share common pathways, they also have distinct characteristics that may be therapeutically approached.

In an excellent recent editorial, Giapl and coworkers^[5] point out that the balance between stimulatory and inhibitory signaling is important for maintaining immune tolerance, and that breakdown of self-tolerance is involved in the pathogenesis of autoimmune diseases. Initially, the wave of enthusiasm was focused on genetic defects in Fas and Fas ligand as the generation of human autoimmunity, based on lupus-like diseases in animals with mutations in these genes.^[5] Subsequent studies in human SLE and SS patients did not find such mutations in the Fas or Fas ligand sequences and the complexity of the immune system became more apparent.

The next important step in understanding pathogenesis was the largely unexpected, dramatic effect of TNF inhibitors in RA that could not be explained using the older models of arthritis that derived from T-cell activation by MHC-bearing, antigen-presenting cells. Examination of the regulation of TNF and its receptors led to recognition of the key role for the "innate" immune system. For rheumatologists, the concepts of the innate immune system and its mediators are critical since they are the basis for current anticytokine therapies such as TNF inhibition and, perhaps, for their untoward side effects.^[6]

An important aspect of the study by Bolstad and associates is that it reveals the production of negative signaling functions that inhibit Fas/Fas-L-driven apoptosis in both the lymphocytes and the acinar/ductal glandular cells. Among these inhibitory proteins, the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) appear to be very important.^[7,8] Recently, PD-1 was shown to be involved in the autoimmunity of C57BL/6 and BALB/c mice that developed glomerulonephritis and/or arthritis and dilated cardiomyopathy, respectively.^[9] Expression of CTLA-4 (combined with its ligand CTLA-4-B7) and PD-1 (combined with its ligand PD-L) leads to downregulation of T-cell activity.^[7,8,10] The CTLA-4 knockout mouse exhibits a profound spontaneous autoimmune disease.^[11-14] Following T-cell activation, expression of PD-1 and CTLA-4 is induced, and engagement with their respective ligands prevents excessive T cell activation.

There is accumulating evidence suggesting a genetic contribution of the CTLA-4 locus to a number of autoimmune diseases.^[11] CTLA-4 is expressed on activated CD4+ and CD8+ T cells and binds the same ligands (B7-1 and B7-2) that are bound by CD28, but with a 20- to 50-fold higher affinity.^[11] CTLA-4 is also expressed constitutively on the cell surface and intracellularly by human monocytes.^[15-17] Human ORM is an acute-phase protein synthesized by the liver in response to injuries and inflammation.^[18,19] It is also constitutively expressed in salivary glands.^[20]

In addition to the relationship between lymphocytes and glandular cells, an important relationship between lymphocytes and stromal cells is becoming apparent. PD-1 and CTLA-4 may be produced by stromal cells during chronic inflammatory responses in conditions such as rheumatoid arthritis as is currently suggested in the present study in SS. Pilling and colleagues^[21-23] proposed that IFN beta acts as the principal mediator of stromal cell-mediated T-cell rescue from apoptosis by promoting reversion of T cells into a resting stage, which is necessary for maintaining immunologic memory. These investigators showed that this mechanism may play a fundamental role in the persistence of T cells at sites of chronic inflammation, and proposed that chronic inflammation is an aberrant consequence of immunologic memory. PD-1 can bind to PD-L on parenchymal cells of the heart, lung, and kidney. Consequently, it is conceivable that these molecules could operate in the peripheral interstitium and still influence the fate of the infiltrates.

In conclusion, Bolstad and associates examined gene expression patterns of candidate genes in salivary glands of patients with primary SS in order to obtain more knowledge of the pathogenesis of the inflammation. They observed a convincingly increased expression of Fas, FasL, CTLA-4, and PD-1 mRNA in primary SS compared with what was observed in normal salivary glands. However, it is still not clear whether this expression of apoptosis-regulating molecules is a primary event, or whether it is a secondary event attributable to the presence of chronic inflammation.

No Link Found Between Rheumatoid Arthritis and Hepatitis C

A large study has found no association between rheumatoid arthritis
and the hepatitis C virus (HCV), according to a report in the March
issue of the Journal of Rheumatology.

Although the subject has not been well studied, some experts have
believed that infectious organisms such as HCV can trigger
rheumatoid arthritis in susceptible individuals.

Smaller clinical-based studies appeared to have turned up a positive
association between rheumatoid arthritis and hepatitis C virus
infection.

Using data from a large population-based study, researchers at the
VA Puget Sound Health Care System set out to determine just how
many participants aged 60 and over had signs of hepatitis C and
were also suffering from rheumatoid arthritis.

Out of 4,769 study participants, the researchers found that 196
subjects or 4.1 percent met the their criteria for having
rheumatoid arthritis, while 63 or 1.3 percent tested positive for
anti-HCV antibodies and 35 or 0.7 percent were HCV RNA positive.

Only two participants had both HCV antibodies and rheumatoid
arthritis, while one subject was both HCV RNA positive and had
rheumatoid arthritis.

"HCV antibody positivity was not associated with rheumatoid
arthritis," concluded the researchers. "Similarly, HCV positivity
by polymerase chain reaction was not associated with rheumatoid
arthritis. These results argue against a potential role for HCV in
the etiology of rheumatoid arthritis in the U.S. population aged
60 years and over."
SOURCE:Journal of Rheumatology (2003;30:455-8)