Factors associated with COVID-19-related death in people with rheumatic diseases: results from the COVID-19 Global Rheumatology Alliance physician-reported registry.

OBJECTIVES: To determine factors associated with COVID-19-related death in people with rheumatic diseases. METHODS: Physician-reported registry of adults with rheumatic disease and confirmed or presumptive COVID-19 (from 24 March to 1 July 2020). The primary outcome was COVID-19-related death. Age, sex, smoking status, comorbidities, rheumatic disease diagnosis, disease activity and medications were included as covariates in multivariable logistic regression models. Analyses were further stratified according to rheumatic disease category. RESULTS: Of 3729 patients (mean age 57 years, 68% female), 390 (10.5%) died. Independent factors associated with COVID-19-related death were age (66-75 years: OR 3.00, 95% CI 2.13 to 4.22; >75 years: 6.18, 4.47 to 8.53; both vs ≤65 years), male sex (1.46, 1.11 to 1.91), hypertension combined with cardiovascular disease (1.89, 1.31 to 2.73), chronic lung disease (1.68, 1.26 to 2.25) and prednisolone-equivalent dosage >10 mg/day (1.69, 1.18 to 2.41; vs no glucocorticoid intake). Moderate/high disease activity (vs remission/low disease activity) was associated with higher odds of death (1.87, 1.27 to 2.77). Rituximab (4.04, 2.32 to 7.03), sulfasalazine (3.60, 1.66 to 7.78), immunosuppressants (azathioprine, cyclophosphamide, ciclosporin, mycophenolate or tacrolimus: 2.22, 1.43 to 3.46) and not receiving any disease-modifying anti-rheumatic drug (DMARD) (2.11, 1.48 to 3.01) were associated with higher odds of death, compared with methotrexate monotherapy. Other synthetic/biological DMARDs were not associated with COVID-19-related death. CONCLUSION: Among people with rheumatic disease, COVID-19-related death was associated with known general factors (older age, male sex and specific comorbidities) and disease-specific factors (disease activity and specific medications). The association with moderate/high disease activity highlights the importance of adequate disease control with DMARDs, preferably without increasing glucocorticoid dosages. Caution may be required with rituximab, sulfasalazine and some immunosuppressants.

Association of Race and Ethnicity With COVID-19 Outcomes in Rheumatic Disease: Data From the COVID-19 Global Rheumatology Alliance Physician Registry.

OBJECTIVE: Racial/ethnic minorities experience more severe outcomes of coronavirus disease 2019 (COVID-19) in the general US population. This study was undertaken to examine the association between race/ethnicity and COVID-19 hospitalization, ventilation status, and mortality in people with rheumatic disease. METHODS: US patients with rheumatic disease and COVID-19 were entered into the COVID-19 Global Rheumatology Alliance physician registry between March 24, 2020 and August 26, 2020 were included. Race/ethnicity was defined as White, African American, Latinx, Asian, or other/mixed race. Outcome measures included hospitalization, requirement for ventilatory support, and death. Multivariable regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) adjusted for age, sex, smoking status, rheumatic disease diagnosis, comorbidities, medication use prior to infection, and rheumatic disease activity. RESULTS: A total of 1,324 patients were included, of whom 36% were hospitalized and 6% died; 26% of hospitalized patients required mechanical ventilation. In multivariable models, African American patients (OR 2.74 [95% CI 1.90-3.95]), Latinx patients (OR 1.71 [95% CI 1.18-2.49]), and Asian patients (OR 2.69 [95% CI 1.16-6.24]) had higher odds of hospitalization compared to White patients. Latinx patients also had 3-fold increased odds of requiring ventilatory support (OR 3.25 [95% CI 1.75-6.05]). No differences in mortality based on race/ethnicity were found, though power to detect associations may have been limited. CONCLUSION: Similar to findings in the general US population, racial/ethnic minorities with rheumatic disease and COVID-19 had increased odds of hospitalization and ventilatory support. These results illustrate significant health disparities related to COVID-19 in people with rheumatic diseases. The rheumatology community should proactively address the needs of patients currently experiencing inequitable health outcomes during the pandemic.

COVID-19 and what pediatric rheumatologists should know: a review from a highly affected country.

On March 11th, 2020 the World Health Organization declared COVID-19 a global pandemic. The infection, transmitted by 2019 novel coronavirus (2019-nCov), was first discovered in December 2019, in Wuhan, Hubei Province, and then rapidly spread worldwide. Italy was early and severely involved, with a critical spread of the infection and a very high number of victims. Person-to-person spread mainly occurs via respiratory droplets and contact. The median incubation period is 5 days. The spectrum of respiratory symptoms may range from mild to severe, strictly depending on the age of the patient and the underlying comorbidities.In children COVID-19 related disease is less frequent and less aggressive. In Italy 1% of positive cases are under 18 years of age, and no deaths have been recorded before 29 years of age. For patients affected by rheumatic disease, despite the concerns related to the imbalance of their immune response and the effect of immunosuppressive treatments, there are still few data to understand the real consequences of this infection. Major scientific societies have issued recommendations to help rheumatologists in caring their patients. Interestingly, some of the drugs mostly used by rheumatologists appear to be promising in critical COVID-19 infected patients, where the hyperinflammation and cytokine storm seem to drive to the multiorgan failure.Pediatric rheumatologists are expected to play a supporting role in this new front of COVID-19 pandemic, both as general pediatricians treating infected children, and as rheumatologists taking care of their rheumatic patients, as well as offering their experience in the possible alternative use of immunomodulatory drugs.

The contribution of HERV-E clone 4-1 and other HERV-E members to the pathogenesis of rheumatic autoimmune diseases.

Human endogenous retroviruses (HERV)-E consist of a family of more than 1300 elements, stably integrated in the human genome. Some of them are full-length proviruses able to synthesize the viral proteins gag, pol and env. The reactivation of HERV-E elements has been associated to placentation, cancer and autoimmunity. In this narrative review, we aimed to report the status of the art concerning the involvement of HERV-E in rheumatic autoimmune diseases. Following a research on PubMed database, a total of 87 articles were selected. The highest amount of evidence derives from studies on systemic lupus erythematosus (SLE), whereas a few to no data are available on other immune-mediated diseases. In SLE, the hyper-expression of HERV-E clone 4-1 in peripheral blood mononuclear cells or differentiated lymphocytes has been associated with disease activity and autoantibody production. It is likely that HERV-E take part to the pathogenesis of rheumatic autoimmune diseases but additional research is needed.

Rheumatological Manifestations Associated with Viral Hepatitis B or C.

INTRODUCTION: Rheumatological findings and rheumatic diseases may be associated with hepatitis virus infection. This study assessed the frequency of these manifestations in a reference unit in Acre, Brazil. METHODS: This was a cross-sectional study with a convenience sample of patients having their first consultation at the rheumatology outpatient clinics of a referral unit in Rio Branco, Acre, from March to November 2017. Sociodemographic, clinical, laboratory, and imaging data registereds using a standardized questionnaire form. RESULTS: Among the 600 patients with rheumatic complaints, 3.0% were newly diagnosed with hepatitis B virus (HBV) or hepatitis C virus (HCV), and 8.7% were previously diagnosed with hepatitis. Among the 70 patients with hepatitis, 54.3% were carriers of HBV and 45.7% of HCV. For patients infected with HBV and HCV, arthralgia was the most prevalent rheumatic manifestation in 97.4% and 90.6%, followed by myalgia in 81.6% and 65.6%, and arthritis in 26.3% and 40.6% of patients, respectively, according to the descriptive analysis performed using the Statistical Package for the Social Sciences software. In comparative analyses using the chi-squared test, despite the fact that fibromyalgia was the most prevalent rheumatic disease only the Rheumatoid Arthritis there were differences in distribution between the carriers of HCV (18.8%) and HBV (2.6%). According to the Fisher's exact test, hypothyroidism was the most frequent comorbidity in patients with HCV (21.9%). CONCLUSIONS: An increased frequency of musculoskeletal manifestations, better than those reported in the medical literature, in patients infected with HBV and HCV was observed.

Rheumatological manifestations associated with viral Hepatitis B or C

Abstract INTRODUCTION Rheumatological findings and rheumatic diseases may be associated with hepatitis virus infection. This study assessed the frequency of these manifestations in a reference unit in Acre, Brazil. METHODS This was a cross-sectional study with a convenience sample of patients having their first consultation at the rheumatology outpatient clinics of a referral unit in Rio Branco, Acre, from March to November 2017. Sociodemographic, clinical, laboratory, and imaging data registereds using a standardized questionnaire form. RESULTS Among the 600 patients with rheumatic complaints, 3.0% were newly diagnosed with hepatitis B virus (HBV) or hepatitis C virus (HCV), and 8.7% were previously diagnosed with hepatitis. Among the 70 patients with hepatitis, 54.3% were carriers of HBV and 45.7% of HCV. For patients infected with HBV and HCV, arthralgia was the most prevalent rheumatic manifestation in 97.4% and 90.6%, followed by myalgia in 81.6% and 65.6%, and arthritis in 26.3% and 40.6% of patients, respectively, according to the descriptive analysis performed using the Statistical Package for the Social Sciences software. In comparative analyses using the chi-squared test, despite the fact that fibromyalgia was the most prevalent rheumatic disease only the Rheumatoid Arthritis there were differences in distribution between the carriers of HCV (18.8%) and HBV (2.6%). According to the Fisher's exact test, hypothyroidism was the most frequent comorbidity in patients with HCV (21.9%). CONCLUSIONS An increased frequency of musculoskeletal manifestations, better than those reported in the medical literature, in patients infected with HBV and HCV was observed.

Risk of human papillomavirus infection in women with rheumatic disease: cervical cancer screening and prevention.

Human Papillomavirus (HPV) is the most common sexually transmitted infection in the USA, with over 14 million people acquiring HPV each year. HPV is also the cause of most anogenital cancers. About 90% of HPV infections spontaneously resolve over 3 years. However, about 10% remain as persistent infection defined as repeatedly detected in cervical samples. As HPV is controlled by local and systemic immune responses, individuals with immunosuppression are at risk for cervical cancer. It is hypothesized that immunosuppressed individuals are more likely to have HPV persistence, which is necessary for malignant transformation. Accordingly, women with rheumatic diseases such as SLE and RA are likely vulnerable to HPV infection and the progression of cervical disease. The HPV vaccine, given as a series of vaccinations, is safe and effective that can prevent HPV infection and cervical cancer. There is no contraindication to HPV vaccination for women to age 26 with rheumatic disease, as it is not live. As in the general population, timing is key for the efficacy of the HPV vaccine as the goal is to vaccinate prior to sexual debut and exposure to HPV. There are no formal recommendations for cervical cancer screening in women with rheumatic disease but recommendations for the HIV-positive population can be adopted, meaning to screen with a Pap test annually for three consecutive years and if all normal, to extend the interval to every 3 years with the option of co-testing with HPV at 30 years and older.

Rheumatism and chronic fatigue, the two facets of post-chikungunya disease: the TELECHIK cohort study on Reunion island.

Prolonged fatigue is increasingly reported among chikungunya virus (CHIKV)-infected populations. We investigated the relationships between CHIKV exposure, long-lasting rheumatic musculoskeletal pain (LRMSP) and chronic fatigue. 1094 participants (512 CHIKV seropositive and 582 seronegative) of the TELECHIK population-based cohort were analysed considering the duration of the manifestations throughout an average 2-year follow-up. Weighted prevalence rates and prevalence ratios for LRMSP, idiopathic chronic fatigue (ICF), and chronic fatigue syndrome (CFS)-like illness, both latter syndromes adapted from Centers for Disease Control (CDC)-1994/Fukuda criteria, were compared. Population attributable fractions (PAF) were estimated to assess the contribution of CHIKV infection to each of the three phenotypes. Among 362 adult subjects who had reported either rheumatic pain or fatigue at the onset of the infection, weighted prevalence rates of LRMSP, ICF and CFS-like illness were respectively of 32.9%, 38.7% and 23.9%, and of 8.7%, 8.5% and 7.4% among initially asymptomatic peers (P < 0.01, respectively). Each of the three outcomes was highly attributable to chikungunya (PAF of 43.2%, 36.2% and 41.0%, respectively). In the sub-cohort of CHIKV-infected subjects, LRMSP, ICF and CFS-like illness, which overlapped in 70%, accounted for 53% of the chronic manifestations. In addition to rheumatic disease, chronic fatigue could be considered in caring for patients with chronic chikungunya disease.

Rheumatic manifestations of hepatitis C virus chronic infection: Indications for a correct diagnosis.

Hepatitis C virus (HCV) is a hepato- and lymphotropic agent that is able to induce several autoimmune rheumatic disorders: vasculitis, sicca syndrome, arthralgias/arthritis and fibromyalgia. The severity of clinical manifestations is variable and sometimes life-threatening. HCV infection can mimic many primitive rheumatic diseases, therefore, it is mandatory to distinguish HCV-related manifestations from primitive ones because the prognosis and therapeutic strategies can be fairly dissimilar. The new direct-acting antivirals drugs can help to avoid the well-known risks of worsening or new onset of autoimmune diseases during the traditional interferon-based therapies.

The hepatitis C virus infection as a systemic disease.

Hepatitis C Virus (HCV) is a major health problem, infecting about 3 % of people worldwide and leading to liver as well as extrahepatic diseases. This justifies the definition of HCV infection as a systemic disease. Based on available data, the link between the virus and some of these extrahepatic disorders is certain, whereas for some others needs further confirmation. HCV-related lymphoproliferative disorders, ranging from benign, but pre-lymphomatous conditions, like mixed cryoglobulinemia, to frank lymphomas, represent the extrahepatic manifestations most closely related to HCV. The primary involvement of the liver and lymphatic system corresponds to the double viral tropism, being HCV able to infect both hepatic and lymphatic cells. Other HCV-associated disorders include renal, endocrine, dermatological, cardiovascular, rheumatologic and central nervous system diseases. On the whole, the HCV disease appears a very important, mainly hidden, public health problem leading to heavy direct and indirect costs. The possibility that HCV may be eradicated following antiviral therapy is important for both the therapeutic and preventive points of view, making the HCV disease an ideal model for pathogenetic studies.

Usefulness of routine hepatitis C and hepatitis B serology in the diagnosis of recent-onset arthritis. Systematic prospective screening in all patients seen by the rheumatologists of a defined area--brief report.

OBJECTIVE: Previous studies evaluating the usefulness of systematic screening for hepatitis B and C in patients with recent-onset arthritis suffered from a major bias since they were conducted in hospitals. The objective of the present study was to evaluate the relevance of such screening, performed by hospital and office-based rheumatologists of a defined area, in the diagnosis of arthritis or inflammatory polyarthralgia of less than 1 year duration. METHODS: The CRRRI is a network which includes most hospital and office-based rheumatologists of an area with a population of 506,755 inhabitants. All patients seen by the CRRRI participants in their usual practice between March 2008 and December 2010 for inflammatory polyarthralgia, mono-, oligo-, or polyarthritis of less than 1 year duration were included. Patients' serum samples were screened for the presence of anti-hepatitis C virus (HCV) antibodies, with positive samples further evaluated for HCV-RNA with a reverse transcriptase-polymerase chain reaction, and for the presence of hepatitis B virus (HBV) infection. RESULTS: Two hundred and thirty-three patients were included (162 women, 71 men; mean age of 50.6±15.8 years). Patients were evaluated for inflammatory polyarthralgia (n=51), monoarthritis (n=21), oligoarthritis (n=35) or polyarthritis (n=126) lasting for a mean 19.8±29.8 weeks. No new HCV or HBV infection diagnosis was done. CONCLUSION: In this study not suffering from a hospital-selection bias, screening for hepatitis C and B infection was not helpful in the diagnosis process of recent-onset arthritis. KEY MESSAGES: Systematic hepatitis B and C serology is not relevant in patients with recent-onset (<1 year) arthritis.

Safety of tumor necrosis factor alpha blockers in hepatitis B virus occult carriers (hepatitis B surface antigen negative/anti-hepatitis B core antigen positive) with rheumatic diseases.

OBJECTIVE: To assess the safety of anti-tumor necrosis factor alpha (anti-TNFalpha) therapy on the course of hepatitis B virus (HBV) infection in carriers of antibodies to hepatitis B core antigen (anti-HBc) affected by chronic inflammatory arthropathies. METHODS: From January 2001 to December 2008, HBV markers were determined before the first administration of anti-TNFalpha agents in all 732 patients affected by inflammatory arthropathies treated with anti-TNFalpha at 2 outpatient rheumatologic clinics in Northern Italy. Anti-HBc-positive patients were prospectively evaluated and HBV markers and HBV DNA were assessed every 6 months, in case of aminotransferase elevation, and at the end of the study. RESULTS: At the time of recruitment, 72 patients were anti-HBc carriers, 5 of whom were positive for hepatitis B surface antigen (HBsAg) and not included in the study. The ratio of men:women was 26:41 and the mean +/- SD followup was 42.52 +/- 21.33 months. Of the patients, 25 were treated with infliximab, 23 with etanercept, and 19 with adalimumab. Fifty-one patients were treated also with methotrexate, 52 with nonsteroidal antiinflammatory drugs, and 43 with prednisone (3 with a dosage >7.5 mg/day). All anti-HBc patients were HBV DNA negative at the first observation. During followup, no patient presented HBV reactivation with viral load increase and no patient became HBsAg positive. CONCLUSION: Anti-HBc positivity in HBsAg-negative patients is a sign of previous HBV infection and does not indicate chronic hepatitis. In these patients, anti-TNFalpha therapy appears to be quite safe, as no HBV reactivation was found in our study. Nevertheless, careful monitoring is necessary.

Rheumatic manifestations of hepatitis B and C and their association with viral load and fibrosis of the liver.

The objective of this study is to investigate rheumatologic manifestations of hepatitis B and C and their relation with viral load and degree of hepatic fibrosis. Thirty-six HBV and 36 HBV patients were included. Liver biopsy was performed for all participants. We detected arthralgia 53-50%, myalgia 58-61% and fatigue 64-81% in HBV and HCV groups in order. All manifestations did not differ between groups significantly. Pain intensity was higher in HCV group (P = 0.023). Arthralgia is associated with viral load of the patients in both groups (P = 0.000 and P = 0.001). Viral load and fatigue are correlated in both groups (P = 0.000 and P = 0.001). There is a considerable relation between inflammation and arthralgia (P = 0.000) and myalgia (P = 0.033). We conclude that rheumatologic manifestations are common both in HBV and HCV and related with viral load and fibrosis.

Use of tumor necrosis factor-alpha-blocking agents in hepatitis B virus-positive patients: reports of 3 cases and review of the literature.

OBJECTIVE: To evaluate the development of hepatitis B virus (HBV) infection in patients receiving tumor necrosis factor-alpha-blocking agents (TNFBA), and to evaluate whether lamivudine (LAM) prophylaxis can reduce the risk of viral reactivation in inactive HBsAg carriers. METHODS: Local experience and published reports were reviewed. Patients with HBV infection were classified as having chronic HBV hepatitis, or being inactive HBsAg carriers or occult carriers. RESULTS: Three patients in our series and 24 patients in the literature were identified: 2 had active HBV-associated disease, 23 were inactive HBsAg carriers, and 2 occult carriers. When exposed to TNFBA, HBsAg-inactive carriers pretreated with LAM had lower risk of having detectable HBV-DNA (p=0.02) or viral reactivation (p=0.046) than those without LAM prophylaxis. In 3 patients who discontinued TNFBA, LAM prophylaxis was also discontinued 10-12 months thereafter without hepatitis flares. Two cases of reactivation in occult carriers (HBsAg-negative, anti-HBs+, anti-HBc+) were described in the literature. CONCLUSION: TNFBA should be avoided in patients with active HBV replication and should be used with caution in inactive HBsAg carriers. In these patients, the risk of viral reactivation seems to be high, but it might be reduced by prophylactic LAM, which should probably be given for a long time when TNFBA are discontinued (e.g., 12 mo). Potential occult carriers might carry a low, but not negligible, risk of viral reactivation. They should therefore be monitored with particular care.

The emergence of progressive multifocal leukoencephalopathy (PML) in rheumatic diseases.

Progressive multifocal leukoencephalopathy (PML) is a rare and devastating neurological disease with areas of demyelination in the central nervous system classically associated with profound imunosuppression. PML is caused by reactivation of latent JC virus, leading to the death of myelin-producing oligodendrocytes typically with a rapidly fatal outcome. Once seen primarily in severely immunosuppressed states including lymphoma, solid organ malignancies, and organ transplant recipients, PML became an AIDS-defining illness in the 1980s. PML has now emerged as a catastrophic illness in multiple sclerosis with biologic drug therapy (natalizumab) and reported in rheumatic diseases with and without biologic therapeutic agents. With current and future treatments that suppress and manipulate the immune system, there is risk for severe acute infections and reactivation of latent infections, such as JC virus reactivation leading to PML. It is critical, therefore, to proceed cautiously when immune system modification strategies are being evaluated for fear of unleashing undesirable or even fatal diseases. Fortunately this complication remains a rare event.

The use of anti-tumour necrosis factor therapy in HIV-positive individuals with rheumatic disease.

OBJECTIVE: The purpose of this study was to examine the safety and efficacy of anti-tumour necrosis factor (TNF) agents (etanercept, infliximab and adalimumab) in HIV-positive patients with rheumatic diseases refractory to standard therapy. METHODS: Patients were treated with anti-TNF blocker with rheumatic diseases refractory to disease modifying antirheumatic drugs who had a CD4 count of >200 mm3 and an HIV viral load of <60 000 copies/mm3 and no active concurrent infections. Changes in CD4 counts, HIV viral loads, or other adverse effects while on anti-TNF agents and clinical response were monitored for 28.1 (SD 20.9) months (range 2.5-55). RESULTS: Eight HIV-positive patients were treated with anti-TNF blockers (two patients with rheumatoid arthritis, three with psoriatic arthritis, one with undifferentiated spondyloarthritis, one with reactive arthritis and one with ankylosing spondylitis). No significant clinical adverse effect was attributed to this treatment in any patient. CD4 counts and HIV viral load levels remained stable in all patients. Three patients on etanercept therapy and two patients on infliximab had sustained clinical improvement in their rheumatic diseases. CONCLUSIONS: This retrospective series of eight patients suggests that treatment with anti-TNF-alpha therapy is a viable alternative in HIV patients without advanced disease with associated rheumatic diseases refractory to standard therapy.

Risks of immunosuppressive therapies including biologic agents in patients with rheumatic diseases and co-existing chronic viral infections.

PURPOSE OF REVIEW: A number of chronic viral infections could be reactivated by immunosuppressive agents used in rheumatic diseases. In this review, we will focus on the complex effect of immunosuppressive agents, including biologic agents, on the natural course of chronic viral infections as well as an approach to the prevention and management of therapy-induced viral reactivation. RECENT FINDINGS: Chronic viral infections that are affected by immunosuppression in the setting of an underlying rheumatic disease include those due to hepatitis B virus, hepatitis C virus, or human immunodeficiency virus, and latent infections from Epstein-Barr virus, JC virus, or varicella zoster virus. The most recent data of the effects of immunosuppressive agents are reviewed, with special emphasis on the effects of biologic therapies (anti-tumor necrosis factor, anti-B cell), on these viral agents. SUMMARY: Clinicians should be aware of the risk for viral reactivation of an underlying chronic viral infection during immunosuppressive therapy. Despite the existence of such risk, the presence of chronic viral infection is not a contraindication to immunosuppressive therapy, given that appropriate pretherapy screening and close monitoring is applied.

Rheumatologic manifestations of chronic hepatitis C infection.

The many rheumatologic manifestations associated with chronic hepatitis C virus (HCV) infection include arthralgia, myalgia, arthritis, vasculitis, and sicca syndrome. Arthralgia is the most common extrahepatic manifestation and may indicate mixed cryoglobulinemia or an adverse reaction to interferon therapy. HCV arthritis unrelated to cryoglobulinemia is far less common but constitutes an independent entity. The picture may mimic rheumatoid arthritis (RA), particularly as rheumatoid factor is present in 50-80% of cases. Tests are usually negative for antibodies to cyclic citrullinated peptides (anti-CCP), which may help to differentiate the two conditions. The management of HCV arthritis is empirical and poorly standardized. Although low-dose glucocorticoid therapy, hydroxychloroquine, and methotrexate have been used successfully in several patients, little is known about their hepatic safety profile. Arthritis associated with cryoglobulinemia usually responds to antiviral treatment. Sicca syndrome is common in patients with chronic HCV infection and shares similarities with primary Sjögren syndrome, suggesting that HCV infection may deserve to be included among the causes of secondary Sjögren syndrome. HCV-associated vasculitis is usually related to cryoglobulinemia, although a few cases of polyarteritis nodosa-like disease affecting the medium-sized vessels have been reported. Other conditions reported in patients with chronic HCV infection include fibromyalgia, systemic lupus erythematosus (SLE), antiphospholipid syndrome, and osteosclerosis.