Hydroxychloroquine as a potential therapy for ANCA-associated vasculitis
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, ... Abstract
Antimalarial agents have been used to treat various autoimmune rheumatic diseases for over a century. Hydroxychloroquine is a safe, effective and inexpensive antimalarial drug with additional antithrombotic, cardioprotective, antimicrobial, and anti-neoplastic benefits. It has been used extensively in various diseases, especially systemic lupus erythematosus and rheumatoid arthritis; however, it has not been used in anti-neutrophil cytoplasmic antibody associated vasculitides (AAVs). There exists a significant unmet need for safe and inexpensive treatments for non-severe AAV or those with low-grade “grumbling” disease activity who do not warrant significant escalation of therapy but who remain at risk of disease flares and damage accumulation. Hydroxychloroquine may be an option to help fill this void. Although the mechanisms of action of Hydroxychloroquine are not fully understood, it interacts with various inflammatory mediators involved in the pathogenesis of AAV. Based on these benefits, along with the unmet need in AAV, we present evidence to support the use of Hydroxychloroquine as a potential therapy for AAV.
Keywords
INTRODUCTION
The anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) are a group of small vessel vasculitides characterized by necrotizing inflammation of blood vessels and often positive autoantibodies to neutrophil proteins - leukocyte proteinase 3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA)[1,2]. They comprise three distinct conditions - Granulomatosis with Polyangiitis (GPA, previously known as Wegener’s Granulomatosis), Eosinophilic Granulomatosis with Polyangiitis (EGPA, previously known as Churg-Strauss syndrome), and Microscopic Polyangiitis (MPA)[2]. They usually present with severe life- or organ-threatening disease; however, less severe and limited disease also occurs[1]. Treatment usually involves remission induction (with high dose Glucocorticoids (GCs) + either Rituximab or Cyclophosphamide) followed by maintenance therapy (with either low dose GCs, Azathioprine, Methotrexate, Mycophenolate Mofetil, Rituximab or Avacopan)[3].
Despite significant advances in diagnoses and management, patients with AAV continue to have significant morbidity and mortality, reduced survival rates, poor quality of life, and increased socio-economic burden compared to the general population[4-7]. This is due to a combination of the disease itself, treatment adverse effects, poor physical health (mostly from fatigue), psychological factors (mainly anxiety), decreased social participation (due to lifestyle changes related to disease and social perceptions of vasculitis), and decreased employment (due to functional impairment)[8]. Despite adequate treatment, 20%-30% of patients have refractory disease[9], and relapse rates remain high (up to 50% at 5 years)[10].
There remain several unmet needs in AAV. Better and less toxic glucocorticoid-sparing therapies are required to reduce treatment-related adverse events. Avacopan is an exciting new therapy in the AAV armamentarium[11]. It is an orally administered small molecule complement C5a receptor blocker that inhibits neutrophil chemoattraction and activation (terminal C5a production is a component of AAV pathogenesis)[11]. There is also an unmet need for safe and inexpensive treatments for non-severe AAV or those with low-grade “grumbling” disease activity[12] who do not warrant significant escalation of therapy but who remain at risk of disease flares and damage accumulation. Trimethoprim/Sulfamethoxazole (TMP/SMX) is an option for this patient group; however, previous results have been variable[13-15].
Antimalarial agents have been used to treat various autoimmune rheumatic diseases for over a century. Hydroxychloroquine (HCQ) is a safe and effective antimalarial drug that was approved by the United States Food and Drug Administration in 1955 for the treatment of discoid lupus, systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA). It has since become the cornerstone background therapy in SLE patients; however, it has not been used for AAV. HCQ has additional antithrombotic, cardioprotective, antimicrobial, and anti-neoplastic benefits, which would be immensely valuable in patients with AAV who are at risk of infections, malignancy, and thrombosis, owing to the disease itself and background immunosuppression.
Based on these benefits, along with the unmet need for safe and inexpensive treatments for non-severe/low-grade “grumbling” AAV, we suggest that HCQ may help fill this void. Through this review, we hope to present evidence to support the use of HCQ as a potential therapy for AAV.
HISTORY OF ANTIMALARIALS
The history of antimalarials is an interesting one, based on a mixture of facts and legends, and subsequently researched by several authors. The bark of the Cinchona tree (then called “fever tree”) appears to have been first used by the Andean population to combat shivering, fevers (although it was not included in the Inca pharmacopeia)[16]. Since then, the medicine became known by several names such as Cortex peruanus, Peruvian bark, or Jesuit’s powder (since it was imported into Europe from Latin America by Jesuit missionaries). It is documented that in 1638, the Viceroy of Peru (Countess Cinchona) was treated by an Incan herbalist with the bark of a “fever tree” (subsequently named after her, the Cinchona tree), with dramatic improvement[17]. The Schedula Romana, published in 1649, is an early example of an efficient antimalarial recipe, assumed to have been designed by the Spanish cardinal Juan de Lugo, based on trial and error and recipes proposed by Roman apothecaries[16]. Oliver Cromwell, Lord Protector of England, died of a fever illness (later thought to be malaria) as he refused the Jesuit powder cure.
By the 18th and 19th centuries, Cinchona bark was in widespread use for treating intermittent fevers; however, it was not until 1820 that Quinine was discovered as the active ingredient[18]. It became one of the first drugs produced and sold by a global pharmaceutical industry, and factories in Europe, North America and later Asia dominated manufacturing. Initially, the raw material (the Cinchona bark) came from South America; however between 1890 and 1940, Cinchona plantations on Java (Netherlands East Indies) supplied 90% of the bark for the quinine pharmaceutical business (other sources were Latin America and British India)[19].
Subsequently Chloroquine (CQ) was synthesized in 1934 and used extensively as an antimalarial drug. However, due to its significant toxicity, a modification of Chloroquine (via hydroxylation) was required and led to the development of Hydroxychloroquine in 1945, which was less toxic[17,18].
The first documented use of antimalarials for rheumatic disease was in a postgraduate lecture by Joseph Frank Payne at St. Thomas’ Hospital, London, where he described using Quinine for treating cutaneous lupus[20]. The subsequent discovered benefit of antimalarials for inflammatory arthritis and rashes was serendipitous - during the Second World War, millions of soldiers taking antimalarial prophylaxis noted significant improvement in their joint pains and rashes[17]. This led to the first trial (in 1951) showing the benefit of antimalarials (Mepacrine) in 18 SLE patients, many of whom had failed quinine[21]. Since then, antimalarials have been used for a wide variety of autoimmune rheumatic diseases. The first use of HCQ in rheumatic diseases was in 1956 for treating cutaneous and mild (benign) systemic lupus[22-24].
PHARMACOKINETICS AND PHARMACODYNAMICS
Hydroxychloroquine belongs to the antimalarial drug class 4-aminoquinolines[25]. It has a large volume of distribution and long half-life (around 50 days), which is responsible for its delayed onset of action and prolonged effect after drug discontinuation[26]. It is a weak base and hence accumulates in acidic compartments such as lysosomes and inflamed (acidic) tissues - this is thought to be crucial for its action[27]. HCQ also strongly binds to melanin and can deposit in melanin containing tissues such as the skin and eyes, which might explain its benefit in cutaneous disease and its adverse effects of retinopathy and skin pigmentation after prolonged use[27]. It is taken orally as Hydroxychloroquine Sulphate in doses between 100-400 mg, rapidly absorbed in the upper intestines, metabolized by the liver, and excreted by the kidneys with an oral bioavailability between 60%-90%[28]. It reaches peak concentration 2-4 h after an oral dose[28]. Caution must be taken regarding dosage in patients with kidney disease, as reduced creatinine clearance leads to increased bioavailability and subsequent toxicity of HCQ[28]. Despite the fact that HCQ crosses the placenta and previous concerns regarding drug-related pigmentation in foetal tissue, HCQ is considered safe to use in pregnancy and breastfeeding[29,30].
CURRENT INDICATIONS FOR HYDROXYCHLOROQUINE
Apart from malaria, HCQ has been used in the treatment of various rheumatic and non-rheumatic diseases [Table 1]; however, its use in systemic vasculitis has been very limited [Table 2]. The best-known use of HCQ has been in SLE and RA.
Previous use of hydroxychloroquine in other diseases
| Disease condition | Hydroxychloroquine use | Evidence base for hydroxychloroquine |
| 1. Autoimmune rheumatic diseases: | ||
| (a) Sjögren’s syndrome (SS) | HCQ not routinely used Based on its benefits for SLE, a 12-month therapeutic trial is recommended in patients with mild systemic disease (rash, arthralgia/arthritis, fatigue). If there is no response at 12 months, advice is to stop[176,177] | • Previous studies - benefits on sicca symptoms (ocular/oral dryness), arthralgia, fatigue[178,179], immunoglobulin levels, and ESR*[180,181] • Subsequent trials and meta-analyses - no significant benefit[182-184] |
| (b) Antiphospholipid syndrome (APS) | HCQ may be used as an add-on therapy in patients with APS and recurrent thrombotic/pregnancy complications despite combination treatment with low-dose aspirin and prophylactic dose heparin[185] | • No RCT’s** • Previous multicentre RCT of HCQ for primary thrombosis prevention in primary APS patients - terminated early due to poor recruitment[186] • Main evidence comes from SLE patients - HCQ shown to reduce the risk of both arterial and venous thrombosis[42,43] • Small European multicentre study - reduction in pregnancy losses from 81% to 19% (P < 0.05) in APS patients treated with HCQ during pregnancy[142] • Other studies, systematic reviews - similar benefits[187,188] • In vitro experiments - HCQ reduces antiphospholipid antibody mediated thrombosis in mouse models[189] |
| (c) Sarcoidosis | HCQ may be used as a second-line steroid sparing in patients with pulmonary and/or extrapulmonary sarcoidosis[190,191] | • No RCT’s • Several trials and publications - benefit in pulmonary and extrapulmonary manifestations (musculoskeletal, cutaneous, osseous, and neurological)[192-195] |
| (d) Hand osteoarthritis | HCQ not used as treatment | • 2 RCT’s - no significant benefit of HCQ in pain relief compared to placebo[196,197] |
| (e) Other autoimmune diseases | Variable success in: • Eosinophilic fasciitis[198] • Dermatomyositis (including clinically amyopathic and childhood-onset dermatomyositis)[199-201] • Kikuchi-Fujimoto disease[202,203] • Adult-onset Still’s disease[204] • Juvenile idiopathic arthritis[204] • Chronic Chikungunya (viral) related arthritis[205] • Immune thrombocytopenia[206,207] • IgA nephropathy[208-210] | |
| 2. Infections | ||
| (a) Malaria | HCQ primarily developed as antimalarial drug. Due to widespread drug resistance, no longer recommended for the treatment of P. falciparum malaria | • WHO guideline[211] - CQ or HCQ are indicated for the treatment of uncomplicated malaria due to Plasmodium vivax, P. malariae, P. ovale and P. knowlesi |
| (b) COVID-19 infection | Although several trials showed no benefit in COVID-19 infection, HCQ was used in several countries as an inexpensive treatment with variable response | • HCQ initially thought to be a promising prospect based on previous benefits on SARS-COV1, 2 viruses[212] • Several RCT’s including RECOVERY and REMAP-CAP trials - no benefit of HCQ vs. placebo[212,213] • Some trials, meta-analysis showing worse outcomes including cardiac complications and death[214-216] |
| (c) Other infections (variable benefit) | • Bacterial infections (e.g., Coxiella burnetti infections[217,218], Whipple’s disease[219]) • Fungal infections (e.g., cryptococcal[220,221], Aspergillus[222], Paracoccidioides infections[223]) • Viral infections (HIV[224], Zika virus infection[225], Chikungunya virus infection[205], etc.) | |
| 3. Graft versus host disease (GVHD) | HCQ not routinely used[226]; however may be beneficial as an adjuvant therapy | • Phase II clinical trials - some benefit of HCQ in treatment of chronic GVHD[227,228] • Phase III clinical trials - no benefit[229,230] |
| 4. Malignancies | HCQ not routinely used | • HCQ shown to have possible benefit in chronic lymphocytic leukaemia (CLL)[231,232] and breast cancer[233,234] |
| 5. Porphyria cutanea tarda (PCT) | Current recommended treatments for PCT are repeated phlebotomy or low dose HCQ (100 mg bd)[235] | • Previous trials, studies - HCQ in an effective therapy for PCT and is better than phlebotomy or desferrioxamine[236-238] • Large RCT’s lacking |
| 6. Other diseases | HCQ has shown some benefit in miscellaneous other diseases: • Polymorphous light eruptions[239] • Granuloma annulare[240] • Lichen planus[241,242] • Chronic ulcerative stomatitis[243] • Hidradenitis suppurativa[244] • Chronic urticaria[245,246] • Multiple sclerosis[247] • Alport syndrome[248] There are several on-going clinical trials of HCQ in immunological, infectious, neurological, and neoplastic disorders[249] and the indications of use for this “wonder drug” are ever-growing | |
Previous use of hydroxychloroquine in systemic vasculitis
| Disease condition | Hydroxychloroquine use | Evidence base for hydroxychloroquine |
| [A] Large vessel vasculitis: | ||
| 1. Giant cell arteritis (GCA) | HCQ not routinely used | • Previous retrospective study - steroid-sparing benefit of HCQ in GCA[250] • Subsequent double-blind RCT (only published in abstract form) - no benefit of adjunctive HCQ vs glucocorticoids (GC’s) alone as a steroid sparing agent or on relapse rates[251] • No further RCT’s done |
| 2. Takayasu arteritis (TA) | HCQ not routinely used | • No RCT’s • Longitudinal observational retrospective study by Rongyi et al. - HCQ enhanced anti-inflammatory effect, greater reduction in inflammatory markers (ESR, CRP), alleviated angiographic progression[252] • Case report - HCQ associated with improvement in arthralgia, reduced risk of relapse[253] |
| [B] Medium vessel vasculitis: | ||
| 3. Polyarteritis Nodosa (PAN) | HCQ has been used as an adjunctive therapy along with GC’s[254] | • No RCT’s • Case series - HCQ used as an adjunctive therapy along with GCs in cutaneous PAN[254] |
| 4. Kawasaki disease (KD) | HCQ not routinely used | • No literature found • HCQ was empirically used in COVID-19 with multi-system inflammatory syndrome in children (MIS-C) which presents similar to Kawasaki disease; however, subsequent trials and meta-analyses found this not to be beneficial[255] |
| [C] Small vessel vasculitis: | ||
| 5. Urticarial vasculitis (UV) | HCQ is included in the recommendations for treatment of cutaneous UV[256] | • No RCT’s • Several case reports and series - benefit of HCQ in hypo/normocomplementemic urticarial vasculitis with improvement in symptoms, anti-C1q antibody levels[257,258], associated retinal vasculitis[259], C1-esterase inhibitor concentration and activity[260] • Largest study from the French Vasculitis Study Group (n = 5) - HCQ was as effective as GC’s for hypocomplementemic urticarial vasculitis[261] |
| 6. IgA vasculitis (IgAV)/Henoch Schonlein purpura (HSP) | HCQ not routinely used | • No RCT’s • Limited case reports - improvements in arthralgia, rash, fatigue, gastrointestinal symptoms, reduction in flare rates, steroid dose[253], reduction in proteinuria in IgA nephropathy patients[208-210] |
| 7. Anti-GBM*** disease/Goodpasture syndrome | HCQ not routinely used | • No relevant literature found • Single case report - mentioned use of HCQ as maintenance therapy in a patient with Goodpasture syndrome and hemophagocytic lymphohistiocytosis (HLH). Patient relapsed after 2 months[262] |
| 8. ANCA-associated vasculitis (AAV) | HCQ not routinely used | • No RCT’s • Case reports - improvements in arthralgia, reduction in flare rates and dose of steroids with HCQ[253,263] |
Systemic lupus erythematosus
HCQ has become the recommended background therapy in all SLE patients and is a part of all major guidelines[31-34]. HCQ has been shown to improve disease activity in mild to moderate disease[35], improve long-term outcomes/survival[36], and reduce disease flares[37,38], steroid burden[38], damage accrual[39,40], hospitalisations[41], and mortality[36]. It has also been shown to improve cardiovascular risk (by lowering lipids, glucose, and atherosclerosis risk), reduce VTE risk[42,43], improve bone mineral density[44] and protect against osteonecrosis[45] and malignancies[46]. It was previously also suggested that HCQ use in antinuclear antibody (ANA) positive individuals may delay the progression to SLE[47] or onset of renal disease[48].
Apart from systemic lupus, HCQ has shown benefit in cutaneous lupus erythematous (including discoid lupus, lupus panniculitis and refractory disease)[49-51] and as an adjuvant therapy for lupus nephritis[52,53]. It is also considered safe for use in in pregnancy and improves disease activity[54,55], reduces risk of flare[55,56], protects against complications (preeclampsia[57,58], intrauterine growth restriction/prematurity[59]) and reduces the risk of developing neonatal lupus and congenital heart block in Ro positive patients[60].
Rheumatoid arthritis
HCQ is an established treatment for Rheumatoid arthritis (RA) and is a part of all major national and international guidelines[61-63]. It can be used as monotherapy in early mild disease (without poor prognostic factors) or palindromic rheumatism but is most commonly used as combination therapy with either Methotrexate and/or Sulfasalazine. Apart from improving disease activity[64,65], slowing the rate of disease progression[65], and enhancing Methotrexate exposure[66], HCQ also improves the lipid profile, blood sugar levels and cardiovascular profile in patients with RA, leading to an overall reduction in cardiovascular events[67,68]. HCQ has previously also been shown to have some benefit in rheumatoid vasculitis[69,70]. A recent large observational cohort study by Wu et al. showed that RA patients on HCQ also have a significantly lower (36%) incidence of chronic kidney disease compared to those not on HCQ (HR 0.64,
PROPOSED MECHANISMS FOR HYDROXYCHLOROQUINE IN ANCA ASSOCIATED VASCULITIS
The exact mechanisms by which HCQ benefits in autoimmune rheumatic diseases are still not fully understood; however, HCQ interacts with various inflammatory mediators involved in the pathogenesis of ANCA-associated vasculitis and hence might be effective in treatment of this disease[72]:
1. HCQ is a weak diprotic base. At neutral pH (e.g., in serum), it remains uncharged and can easily diffuse across the lipid cell membrane of lysosomes. Once inside, the drug becomes protonated causing an increase in intracellular pH, which in turn causes disruption of proteins (cytokines, immune receptors) and impaired proteolysis, chemotaxis, and protein degradation (via endocytosis, phagocytosis, or autophagy). This in turn inhibits MHC (major histocompatibility complex) Class II auto-antigen processing and presentation to
2. Recently it has been shown that the NLRP3 inflammasome may play an important role in the pathogenesis of several autoimmune and vascular disorders including vasculitis through inflammatory cytokines IL (interleukin)-1β and IL-18[74,75]. Inflammasome mediated IL-1β has also been shown to play a role in ANCA vasculitis associated renal involvement[76,77]. HCQ has been shown to inhibit NLRP3 inflammasome activation and IL-1β secretion without affecting inflammasome priming steps[78,79]. This might be an exciting and novel mechanism through which HCQ, and other drugs may be beneficial in AAV[75].
3. B-cell activating factor (BAFF) is a pro-survival factor for autoreactive memory B-cells[80]. BAFF has been shown to be elevated in patients with AAV[81,82]. HCQ has been shown to reduce BAFF levels in the serum of patients with Sjögren’s syndrome, SLE and Rheumatoid arthritis[83-85], as well as in salivary and tear fluid in patients with Sjögren’s syndrome[83].
4. There is increasing evidence to suggest that Toll-like receptors (TLR), especially TLR2, TLR4 and TLR9, are critically involved in the immune response in AAV[86-88]. These can be triggered by infections and microbial peptides (such as bacterial CpG oligodeoxynucleotide), leading to neutrophil activation[89] and ANCA formation[90-92]. TLR9 single nucleotide polymorphisms (SNPs) have been identified to be genetically associated with Granulomatosis with Polyangiitis (GPA), Microscopic Polyangiitis (MPA) and ANCA positive disease in genome wide disease association studies[93]. HCQ has been shown to inhibit TLR signalling and cell activation by altering the pH of endosomes, preventing TLR7 and TLR9 from binding to ligands and inhibiting the activity of nucleic acid sensor cyclic GMP-AMP synthase (cyclic guanosine monophosphate-adenosine monophosphate synthase)[27,94,95]. This in turn inhibits the production of pro-inflammatory cytokines. TLR inhibition has also been suggested as a potential target for several other autoimmune diseases[96,97] and this may apply to AAV as well.
5. Several cytokines are implicated in the pathogenesis of AAV, especially IL-6, IL-8, IL-10, IL-17 and
6. T-cells play an important role in immunopathogenesis of AAV. Abnormalities in peripheral T-cell subset numbers and function have been varyingly identified in patients, consistent with the heterogeneity of disease phenotypes encompassed within AAV. Transcriptional changes in peripheral CD4 and CD8 T-cell subsets, including naïve and memory T-cell subsets are indicative of persistent activation and bear hallmarks of toll-like receptor activation and exposure to microbial infection[101-105]. Furthermore, increased levels of circulating CD4+CD25+ cells have been identified in AAV patients, including CD4+CD25lo T-effector cells and CD4+CD25hi T-regulatory (Treg) cells, which are vital cells in controlling the immune response to quell inflammation[102]. Despite the increased Treg levels, these cells were shown to be defective in their suppression of Teff proliferation in vitro[106]. In contrast, other studies noted reduced levels of circulating Tregs and increased follicular T-helper (TFH) cells in GPA patients, with no defect in suppressive function of Tregs[107]. The reasons for these differing observations remain unclear and may in part be due to clinical heterogeneity within AAV patients. Future studies exploring functional Treg subpopulations in blood and granulomatous tissue by deep sequencing technologies, will shed light on any functional defects in this population between different groups of AAV patients.
Interestingly, we have observed that HCQ treatment can inhibit the expression of the T-cell activation marker CD25 on unactivated CD4 T-cells from healthy donors, in plasma co-culture experiments using ex-vivo plasma from patients, or by addition of HCQ in in-vitro cultures. In contrast, HCQ has no effect on unactivated peripheral blood mononuclear cells (PBMCs) cultured with healthy control donor plasma
Figure 1. Effect of HCQ on CD25 activation on ex-vivo and in-vitro CD4 T cells from GPA patients. (A) Peripheral blood mononuclear cells (PBMCs) from healthy control (HC) donors were co-cultured with 10% plasma from HCQ-treated GPA patients (n = 4), HCQ-untreated GPA patients (n = 5) or HC plasma (n = 5) for 5 days. PBMCs from HC were co-cultured with (B) HCQ-untreated GPA plasma or (C) HC plasma samples with or without 3 µM HCQ treatment. Following co-culture for 5 days, PBMCs were stained with antibodies for CD4, CD8, CD19, and CD25 and evaluated by flow cytometry to identify lymphocyte subsets expressing CD25. Statistical significance was calculated by (A) Mann-Whitney test and (B) and (C) two-way ANOVA grouped analysis. *P < 0.05, **P < 0.01.
Figure 2. HCQ inhibits T cell activation in vitro. PBMC from 6 healthy control donors were incubated with 50 µM HCQ for 24 h, then left unstimulated or stimulated with plate-bound anti-CD3 (10 mg/mL UCHT1, Ancell) and anti-CD28 (1 mg/ml, ANC28.1/5D10, Ancell) for 18 h, and analysed by flow cytometry to identify CD3+CD4+ and CD3+CD8+ T cell subsets expressing activation markers CD69 and CD25. Statistical significance was assessed by the Mann-Whitney test. **P < 0.01.
7. High mobility group box 1 (HMGB1) is among the most important chromatin proteins in humans and is encoded by the HMGB1 gene. In the nucleus, it helps to organize DNA and regulate transcription; however, outside the nucleus, it is also a crucial cytokine that mediates response to infection, injury, inflammation, and cancer[112]. HMGB1 is thought to play a role in a wide range of diseases including but not limited to cancers[113], inflammatory disorders[114-116], and vascular disorders[117] and might be a potential target for drug therapy[118]. Patients with AAV have higher levels of HMGB1[119,120] and this is associated with disease activity[120-122], presence of renal disease[119] and vascular inflammation[123]. Antimalarials such as CQ and HCQ have been shown to inhibit HMGB1 inflammatory signalling[124,125].
8. Matrix metalloproteinases (MMP) are a group of proteinases that degrade both matrix and non-matrix proteins in the extracellular space. They play an important role in wound healing, tissue repair and remodelling in response to injury[126]. Tissue inhibitors of matrix metalloproteinases (TIMP) are a family of proteins that function to inhibit MMPs[127]. Altered levels of MMP and TIMP have been implicated in several human diseases[128].
TIMP-1, TIMP-2, MMP-2, MMP-3, and MMP-7 levels are promising biomarkers in AAV and help to distinguish between active disease, remission, and renal disease. TIMP-1, MMP-3 and MMP-7 levels are elevated in active disease, whereas MMP-2 and TIMP-2 levels are elevated in remission. Elevated TIMP-1, MMP-3 and MMP-7 are associated with worsening renal function[129-132]. HCQ has been shown to modulate the levels of TIMP-1, MMP-2 and MMP-9[133,134] and this might be of use in AAV.
OTHER BENEFITS OF HYDROXYCHLOROQUINE
Hydroxychloroquine has been shown to have antithrombotic, cardioprotective, anti-infective and antineoplastic benefits. These benefits have been mainly described in patients with altered risk secondary to underlying autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus and antiphospholipid syndrome. Patients with AAV are at higher risk of comorbidities such as thromboembolism, cardiovascular events, infections, and malignancies due to active disease and side effects of systemic immunosuppression (especially steroids).
It remains unclear whether these benefits are as a direct result of HCQ itself, or an indirect consequence of the interacting mechanism outlined earlier, and whether these benefits may translate to a different autoimmune milieu as seen in AAV; however, this may provide an additional avenue of benefit of HCQ in AAV patients.
Antithrombotic effect
Patients with AAV have a 2-3 times higher risk of venous and arterial thromboembolism (VTE, ATE) compared to the general population[135,136]. This risk is higher earlier in the disease course (when disease activity is higher); however, the increased risk persists despite remission[137]. Apart from classical risk factors for VTE (e.g., older age, higher BMI, immobilization, major surgery, malignancy, etc.), AAV specific risk factors include higher disease activity, myeloperoxidase-ANCA (MPO-ANCA) positivity, and hypoalbuminemia[138,139]. Proteinase 3 ANCA (PR3-ANCA) positivity was previously thought to be a risk factor[139]; however, a recent meta-analysis showed an inverse relationship between PR3-ANCA positivity and VTE risk[138].
The earliest documented trials using HCQ for thromboprophylaxis were in the 1970’s and 80’s for reducing peri-operative VTE’s in orthopaedic (joint replacement) and non-orthopaedic surgeries[140,141]. Since then, the antithrombotic benefits of HCQ have been well documented, especially in patients with SLE[42,43] and antiphospholipid syndrome (APS)[142,143].
The main mechanisms, although incompletely understood, are thought to be related to reduction in disease activity, platelet activation[144], atherosclerotic plaque formation[145], antiphospholipid antibody (aPL) levels[146], aPL related thrombus formation[145,147], aPL mediated disruption of the potent anticoagulant Annexin A5[148,149], and improvement in vascular endothelial function[150,151].
Antineoplastic effect
As with most other autoimmune diseases, patients with AAV have an increased risk of malignancy, particularly bladder cancer, leukaemia, and non-melanoma skin cancers[152-154]. This is thought to be due to impaired immunosurveillance, chronic immune stimulation and immunosuppressive medications (particularly Cyclophosphamide and Azathioprine). Reassuringly, with the increased use of Rituximab, the rates of cancer are declining[155].
The antineoplastic benefits of antimalarials were first observed when Chloroquine (CQ) was used for a malaria prophylaxis programme in Tanzania and was associated with a reduction in the incidence of Burkitt lymphoma[156]. Since then, CQ and HCQ have shown benefit in several malignancies (see Table 1). Antimalarials have also been shown to reduce the risk of malignancy in patients with SLE[46], Sjögren’s Syndrome[157], and RA[158,159].
Improved cardiovascular risk
Patients with AAV have greater than three-fold risk of cardiovascular (CV) events compared to the general population[160,161]. This is thought to be due to a combination of endothelial dysfunction related to active vasculitis[162,163], accelerated atherosclerosis in systemic vasculitis[164,165], and comorbidities, i.e., diabetes mellitus, hypertension etc. related to steroids.
HCQ has previously been shown to have a beneficial effect in lowering blood sugars[166-168], improving lipid profiles[167,168], and reducing atherosclerosis/improving vascular elasticity[150,151] all of which improve CV risk profiles[169].
Reduced infection risk
Patients with AAV are at an increased risk of infections especially within the first year of diagnosis[170,171]. This is due to a combination of immune dysfunction due to the disease itself and concomitant immunosuppression. Infections are the most common cause of mortality within the first year[171].
HCQ is well known for its antimicrobial properties and is used in the treatment of various infections (see Table 1). HCQ has also been shown to reduce infection rates in other autoimmune diseases like SLE and RA[172,173].
SIDE EFFECTS OF HYDROXYCHLOROQUINE
Overall HCQ is considered safe and well tolerated; however, as with all medications, it may be associated with certain adverse effects. In contrast to other immunosuppressive medications, HCQ is not associated with an increased risk of infections or malignancy. The most common side effects are gastrointestinal (nausea, vomiting, diarrhoea, abdominal discomfort) and cutaneous (pruritis, rashes, urticaria). With chronic long-term use, patients may develop blue-grey hyperpigmentation (particularly over gums, palate, face and shins)[18,27].
The most well studied and worrying adverse effect of HCQ remains retinopathy (known as bull’s eye maculopathy), which is often symptomatic in the early stages and may cause permanent visual loss. The most common risk factors for HCQ-related retinopathy include long duration of treatment, cumulative dose, chronic kidney disease and pre-existing retinal disease. As a result, annual ophthalmic screening with OCT (optical coherence tomography) is mandatory for patients on HCQ based on local guidelines[18,27,174].
Apart from these, other rare but serious side effects may include cardiovascular (conduction defects, cardiomyopathy), dermatological (toxic epidermal necrolysis, Steven-Johnson syndrome, exacerbation of psoriasis), haematological (bone marrow toxicity, neutropenia), neuromuscular (myositis, toxic myopathy), neuropsychiatric (confusion, disorientation, hallucination) and others (ototoxicity, tinnitus, fulminant hepatic failure)[18,27].
HAVEN TRIAL
In order to study the hypothesis that HCQ has disease modifying activity in AAV, the HAVEN trial was launched in 2018. HAVEN (Hydroxychloroquine in ANCA Vasculitis Evaluation) is a United Kingdom (UK) multicentre, randomized, double-blind, placebo-controlled trial of HCQ in ANCA vasculitis. Seventy-six patients with AAV and a Birmingham Vasculitis Activity Score (BVAS) > 3 will be randomised 1:1 to HCQ or placebo over 52 weeks. The primary outcome measure is the ability of HCQ to control disease activity measured by the BVAS[175].
CONCLUSION
HCQ has the potential to be an effective, safe, well tolerated, and inexpensive disease modifying anti-rheumatic drug (DMARD) for AAV patients with low-grade “grumbling” disease activity. It already has efficacy in several other autoimmune diseases, especially SLE and RA. Apart from its potential mechanisms of action in AAV, HCQ has antithrombotic, cardioprotective, antimicrobial and antineoplastic effects, which would make it an excellent option in this disease. Similar to SLE, HCQ may have the potential to improve disease activity, reduce steroid use, reduce flares, and improve outcomes in patients with AAV. If the HAVEN trial is positive, this could lead to a change in the management of patients with AAV.
DECLARATIONS
Authors’ contributions
Researched the literature and contributed to writing the manuscript: Jain S, John S
Generated the data for the figures under the supervision of John S: Kim S
Conceived the design, supervised the whole project, and critically reviewed the finalized manuscript: D’Cruz D, John S, Sangle SR
All authors approve the final version and take full responsibility for all its parts.
Availability of data and materials
Not applicable.
Financial support and sponsorship
GSTT Wegener’s Trust Charity provided financial support for research work by Kim S. The grant code is SPF375.
Conflicts of interest
D’Cruz D has provided consultancy services to CSL Vifor and GSK. All other authors declare that there are no conflicts of interest.
Ethical approval and consent for participation
This study involving patients [Figures 1 and 2] was approved by the U.K. Research Ethics Committee (REC no. 11/LO/1433). All patients and healthy individuals who donated blood provided fully informed written consent.
Consent for publication
Not applicable.
Copyright
© The Author(s) 2024.
REFERENCES
1. Kitching AR, Anders HJ, Basu N, et al. ANCA-associated vasculitis. Nat Rev Dis Primers 2020;6:71.
2. Jennette JC, Falk RJ, Bacon PA, et al. 2012 revised international Chapel Hill consensus conference nomenclature of vasculitides. Arthritis Rheum 2013;65:1-11.
3. Hellmich B, Sanchez-Alamo B, Schirmer JH, et al. EULAR recommendations for the management of ANCA-associated vasculitis: 2022 update. Ann Rheum Dis 2024;83:30-47.
4. Tan JA, Dehghan N, Chen W, Xie H, Esdaile JM, Avina-Zubieta JA. Mortality in ANCA-associated vasculitis: ameta-analysis of observational studies. Ann Rheum Dis 2017;76:1566-74.
5. Robson J, Doll H, Suppiah R, et al. Damage in the anca-associated vasculitides: long-term data from the European vasculitis study group (EUVAS) therapeutic trials. Ann Rheum Dis 2015;74:177-84.
6. Basu N, McClean A, Harper L, et al. The characterisation and determinants of quality of life in ANCA associated vasculitis. Ann Rheum Dis 2014;73:207-11.
7. Raimundo K, Farr AM, Kim G, Duna G. Clinical and economic burden of antineutrophil cytoplasmic antibody-associated vasculitis in the United States. J Rheumatol 2015;42:2383-91.
8. Gill N, Tervaert JWC, Yacyshyn E. Vasculitis patient journey: a scoping review of patient experiences with vasculitis. Clin Rheumatol 2021;40:1697-708.
9. Jones RB, Tervaert JW, Hauser T, et al. European Vasculitis Study Group. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med 2010;363:211-20.
10. Walsh M, Flossmann O, Berden A, et al. European Vasculitis Study Group. Risk factors for relapse of antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum 2012;64:542-8.
11. Jayne DRW, Merkel PA, Schall TJ, Bekker P. ADVOCATE Study Group. Avacopan for the treatment of ANCA-associated vasculitis. N Engl J Med 2021;384:599-609.
12. Hellmich B, Flossmann O, Gross WL, et al. EULAR recommendations for conducting clinical studies and/or clinical trials in systemic vasculitis: focus on anti-neutrophil cytoplasm antibody-associated vasculitis. Ann Rheum Dis 2007;66:605-17.
13. Sangle S, Karim MY, Hughes GR, D'Cruz DP. Sulphamethoxazole-trimethoprim in the treatment of limited paranasal Wegener's granulomatosis. Rheumatology 2002;41:589-90.
14. Tervaert JW. Trimethoprim-sulfamethoxazole and antineutrophil cytoplasmic antibodies-associated vasculitis. Curr Opin Rheumatol 2018;30:388-94.
15. Monti S, Delvino P, Riboli M, et al. The role of trimethoprim/sulfametoxazole in reducing relapses and risk of infections in ANCA-associated vasculitis: a meta-analysis. Rheumatology 2021;60:3553-64.
16. Gachelin G, Garner P, Ferroni E, Tröhler U, Chalmers I. Evaluating Cinchona bark and quinine for treating and preventing malaria. J R Soc Med 2017;110:31-40.
17. Ben-Zvi I, Kivity S, Langevitz P, Shoenfeld Y. Hydroxychloroquine: from malaria to autoimmunity. Clin Rev Allergy Immunol 2012;42:145-53.
18. Dima A, Jurcut C, Chasset F, Felten R, Arnaud L. Hydroxychloroquine in systemic lupus erythematosus: overview of current knowledge. Ther Adv Musculoskelet Dis 2022;14:1759720X211073001.
19. Goss A. Building the world's supply of quinine: dutch colonialism and the origins of a global pharmaceutical industry. Endeavour 2014;38:8-18.
20. Payne JF. A postgraduate lecture on lupus erythematosus. J Clin Med 1894;4:223-9.
23. Lewis HM, Frumess GM. Plaquenil in the treatment of discoid lupus erythematosus; a preliminary report. AMA Arch Derm 1956;73:576-81.
24. Mullins JF, Watts FL, Wilson CJ. Plaquenil in the treatment of lupus erythematosus. J Am Med Assoc 1956;161:879-81.
25. Manohar S, Tripathi M, Rawat DS. 4-aminoquinoline based molecular hybrids as antimalarials: an overview. Curr Top Med Chem 2014;14:1706-33.
26. Rainsford KD, Parke AL, Clifford-Rashotte M, Kean WF. Therapy and pharmacological properties of hydroxychloroquine and chloroquine in treatment of systemic lupus erythematosus, rheumatoid arthritis and related diseases. Inflammopharmacology 2015;23:231-69.
27. Schrezenmeier E, Dörner T. Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nat Rev Rheumatol 2020;16:155-66.
28. Tett SE, Cutler DJ, Day RO, Brown KF. Bioavailability of hydroxychloroquine tablets in healthy volunteers. Br J Clin Pharmacol 1989;27:771-9.
29. Costedoat-Chalumeau N, Amoura Z, Huong DL, Lechat P, Piette JC. Safety of hydroxychloroquine in pregnant patients with connective tissue diseases. Review of the literature. Autoimmun Rev 2005;4:111-5.
30. Russell MD, Dey M, Flint J, et al. BSR Standards; Audit and Guidelines Working Group. British society for rheumatology guideline on prescribing drugs in pregnancy and breastfeeding: immunomodulatory anti-rheumatic drugs and corticosteroids. Rheumatology 2023;62:e48-88.
31. Fanouriakis A, Kostopoulou M, Alunno A, et al. 2019 update of the EULAR recommendations for the management of systemic lupus erythematosus. Ann Rheum Dis 2019;78:736-45.
32. Gordon C, Amissah-Arthur MB, Gayed M, et al. British Society for Rheumatology Standards; Audit and Guidelines Working Group. The British society for rheumatology guideline for the management of systemic lupus erythematosus in adults. Rheumatology 2018;57:e1-45.
33. Hahn BH, McMahon MA, Wilkinson A, et al. American College of Rheumatology. American college of rheumatology guidelines for screening, treatment, and management of lupus nephritis. Arthritis Care Res 2012;64:797-808.
34. Pons-Estel BA, Bonfa E, Soriano ER, et al. Grupo Latino Americano de Estudio del Lupus (GLADEL) and Pan-American League of Associations of Rheumatology (PANLAR). First Latin American clinical practice guidelines for the treatment of systemic lupus erythematosus: Latin American group for the study of lupus (GLADEL, Grupo Latino Americano de Estudio del Lupus)-Pan-American league of associations of rheumatology (PANLAR). Ann Rheum Dis 2018;77:1549-57.
35. Willis R, Seif AM, McGwin G Jr, et al. Effect of hydroxychloroquine treatment on pro-inflammatory cytokines and disease activity in SLE patients: data from LUMINA (LXXV), a multiethnic US cohort. Lupus 2012;21:830-5.
36. Alarcón GS, McGwin G, Bertoli AM, et al. LUMINA Study Group. Effect of hydroxychloroquine on the survival of patients with systemic lupus erythematosus: data from LUMINA, a multiethnic US cohort (LUMINA L). Ann Rheum Dis 2007;66:1168-72.
37. Costedoat-Chalumeau N, Galicier L, Aumaître O, et al. Group PLUS. Hydroxychloroquine in systemic lupus erythematosus: results of a French multicentre controlled trial (PLUS Study). Ann Rheum Dis 2013;72:1786-92.
38. Miyagawa I, Nakano K, Nakayamada S, et al. The additive effects of hydroxychloroquine to maintenance therapy with standard of care in patients with systemic lupus erythematosus. Int J Rheum Dis 2020;23:549-58.
39. Petri M, Purvey S, Fang H, Magder LS. Predictors of organ damage in systemic lupus erythematosus: the Hopkins lupus cohort. Arthritis Rheum 2012;64:4021-8.
40. Pons-Estel GJ, Alarcón GS, González LA, et al. Lumina Study Group. Possible protective effect of hydroxychloroquine on delaying the occurrence of integument damage in lupus: LXXI, data from a multiethnic cohort. Arthritis Care Res 2010;62:393-400.
41. Rosa GPD, Ortega MF, Teixeira A, Espinosa G, Cervera R. Causes and factors related to hospitalizations in patients with systemic lupus erythematosus: analysis of a 20-year period (1995-2015) from a single referral centre in Catalonia. Lupus 2019;28:1158-66.
42. Petri M. Use of hydroxychloroquine to prevent thrombosis in systemic lupus erythematosus and in antiphospholipid antibody-positive patients. Curr Rheumatol Rep 2011;13:77-80.
43. Ruiz-Irastorza G, Egurbide MV, Pijoan JI, et al. Effect of antimalarials on thrombosis and survival in patients with systemic lupus erythematosus. Lupus 2006;15:577-83.
44. Lakshminarayanan S, Walsh S, Mohanraj M, Rothfield N. Factors associated with low bone mineral density in female patients with systemic lupus erythematosus. J Rheumatol 2001;28:102-8.
45. Calvo-Alén J, McGwin G, Toloza S, et al. LUMINA Study Group. Systemic lupus erythematosus in a multiethnic US cohort (LUMINA): XXIV. Cytotoxic treatment is an additional risk factor for the development of symptomatic osteonecrosis in lupus patients: results of a nested matched case-control study. Ann Rheum Dis 2006;65:785-90.
46. Li XB, Cao NW, Chu XJ, et al. Antimalarials may reduce cancer risk in patients with systemic lupus erythematosus: a systematic review and meta-analysis of prospective studies. Ann Med 2021;53:1687-95.
47. James JA, Kim-Howard XR, Bruner BF, et al. Hydroxychloroquine sulfate treatment is associated with later onset of systemic lupus erythematosus. Lupus 2007;16:401-9.
48. Pons-Estel GJ, Alarcón GS, Hachuel L, et al. GLADEL. Anti-malarials exert a protective effect while Mestizo patients are at increased risk of developing SLE renal disease: data from a Latin-American cohort. Rheumatology 2012;51:1293-8.
49. Yokogawa N, Eto H, Tanikawa A, et al. Effects of hydroxychloroquine in patients with cutaneous lupus erythematosus: a multicenter, double-blind, randomized, parallel-group trial. Arthritis Rheumatol 2017;69:791-9.
50. Chasset F, Arnaud L, Costedoat-Chalumeau N, Zahr N, Bessis D, Francès C. The effect of increasing the dose of hydroxychloroquine (HCQ) in patients with refractory cutaneous lupus erythematosus (CLE): an open-label prospective pilot study. J Am Acad Dermatol 2016;74:693-9.e3.
51. Chung HS, Hann SK. Lupus panniculitis treated by a combination therapy of hydroxychloroquine and quinacrine. J Dermatol 1997;24:569-72.
52. Pons-Estel GJ, Alarcón GS, McGwin G Jr, et al. Lumina Study Group. Protective effect of hydroxychloroquine on renal damage in patients with lupus nephritis: LXV, data from a multiethnic US cohort. Arthritis Rheum 2009;61:830-9.
53. Lee JS, Oh JS, Kim YG, Lee CK, Yoo B, Hong S. Recovery of renal function in patients with lupus nephritis and reduced renal function: the beneficial effect of hydroxychloroquine. Lupus 2020;29:52-7.
54. Clowse ME, Magder L, Witter F, Petri M. Hydroxychloroquine in lupus pregnancy. Arthritis Rheum 2006;54:3640-7.
55. Cortés-Hernández J, Ordi-Ros J, Paredes F, Casellas M, Castillo F, Vilardell-Tarres M. Clinical predictors of fetal and maternal outcome in systemic lupus erythematosus: a prospective study of 103 pregnancies. Rheumatology 2002;41:643-50.
56. Koh JH, Ko HS, Kwok SK, Ju JH, Park SH. Hydroxychloroquine and pregnancy on lupus flares in Korean patients with systemic lupus erythematosus. Lupus 2015;24:210-7.
57. Saavedra MÁ, Miranda-Hernández D, Lara-Mejía A, et al. Use of antimalarial drugs is associated with a lower risk of preeclampsia in lupus pregnancy: a prospective cohort study. Int J Rheum Dis 2020;23:633-40.
58. Seo MR, Chae J, Kim YM, et al. Hydroxychloroquine treatment during pregnancy in lupus patients is associated with lower risk of preeclampsia. Lupus 2019;28:722-30.
59. Balevic SJ, Cohen-Wolkowiez M, Eudy AM, Green TP, Schanberg LE, Clowse MEB. Hydroxychloroquine levels throughout pregnancies complicated by rheumatic disease: implications for maternal and neonatal outcomes. J Rheumatol 2019;46:57-63.
60. Izmirly PM, Costedoat-Chalumeau N, Pisoni CN, et al. Maternal use of hydroxychloroquine is associated with a reduced risk of recurrent anti-SSA/Ro-antibody-associated cardiac manifestations of neonatal lupus. Circulation 2012;126:76-82.
61. Rheumatoid arthritis in adults: management. NICE guidelines. Available from: https://www.nice.org.uk/guidance/ng100 [Last accessed on 27 Feb 2024].
62. Smolen JS, Landewé RBM, Bergstra SA, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update. Ann Rheum Dis 2023;82:3-18.
63. Fraenkel L, Bathon JM, England BR, et al. 2021 American college of rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol 2021;73:1108-23.
64. Schapink L, van den Ende CHM, Gevers LAHA, van Ede AE, den Broeder AA. The effects of methotrexate and hydroxychloroquine combination therapy vs methotrexate monotherapy in early rheumatoid arthritis patients. Rheumatology 2019;58:131-4.
65. Klarenbeek NB, Güler-Yüksel M, van der Kooij SM, et al. The impact of four dynamic, goal-steered treatment strategies on the 5-year outcomes of rheumatoid arthritis patients in the BeSt study. Ann Rheum Dis 2011;70:1039-46.
66. Carmichael SJ, Beal J, Day RO, Tett SE. Combination therapy with methotrexate and hydroxychloroquine for rheumatoid arthritis increases exposure to methotrexate. J Rheumatol 2002;29:2077-83.
67. Rempenault C, Combe B, Barnetche T, et al. Metabolic and cardiovascular benefits of hydroxychloroquine in patients with rheumatoid arthritis: a systematic review and meta-analysis. Ann Rheum Dis 2018;77:98-103.
68. Nazir AM, Koganti B, Gupta K, et al. Evaluating the use of hydroxychloroquine in treating patients with rheumatoid arthritis. Cureus 2021;13:e19308.
69. Makol A, Crowson CS, Wetter DA, Sokumbi O, Matteson EL, Warrington KJ. Vasculitis associated with rheumatoid arthritis: a case-control study. Rheumatology 2014;53:890-9.
70. Makol A, Matteson EL, Warrington KJ. Rheumatoid vasculitis: an update. Curr Opin Rheumatol 2015;27:63-70.
71. Wu CL, Chang CC, Kor CT, et al. Hydroxychloroquine use and risk of CKD in patients with rheumatoid arthritis. Clin J Am Soc Nephrol 2018;13:702-9.
72. Casian A, Sangle SR, D'Cruz DP. New use for an old treatment: hydroxychloroquine as a potential treatment for systemic vasculitis. Autoimmun Rev 2018;17:660-4.
73. Fox R. Anti-malarial drugs: possible mechanisms of action in autoimmune disease and prospects for drug development. Lupus 1996;5 Suppl 1:S4-10.
74. So A, Ives A, Joosten LAB, Busso N. Targeting inflammasomes in rheumatic diseases. Nat Rev Rheumatol 2013;9:391-9.
75. Hamzaoui K, Hamzaoui A. Vasculitis and the NLRP3 inflammasome. Curr Opin Rheumatol 2024;36:9-15.
76. Tashiro M, Sasatomi Y, Watanabe R, et al. IL-1β promotes tubulointerstitial injury in MPO-ANCA-associated glomerulonephritis. Clin Nephrol 2016;86:190-9.
77. Wang LY, Sun XJ, Chen M, Zhao MH. The expression of NOD2, NLRP3 and NLRC5 and renal injury in anti-neutrophil cytoplasmic antibody-associated vasculitis. J Transl Med 2019;17:197.
78. Fujita Y, Matsuoka N, Temmoku J, et al. Hydroxychloroquine inhibits IL-1β production from amyloid-stimulated human neutrophils. Arthritis Res Ther 2019;21:250.
79. Lucchesi A, Silimbani P, Musuraca G, et al. Clinical and biological data on the use of hydroxychloroquine against SARS-CoV-2 could support the role of the NLRP3 inflammasome in the pathogenesis of respiratory disease. J Med Virol 2021;93:124-6.
80. Smulski CR, Eibel H. BAFF and BAFF-receptor in B cell selection and survival. Front Immunol 2018;9:2285.
81. Krumbholz M, Specks U, Wick M, Kalled SL, Jenne D, Meinl E. BAFF is elevated in serum of patients with Wegener's granulomatosis. J Autoimmun 2005;25:298-302.
82. Nagai M, Hirayama K, Ebihara I, Shimohata H, Kobayashi M, Koyama A. Serum levels of BAFF and APRIL in myeloperoxidase anti-neutrophil cytoplasmic autoantibody-associated renal vasculitis: association with disease activity. Nephron Clin Pract 2011;118:c339-45.
83. Mumcu G, Biçakçigil M, Yilmaz N, et al. Salivary and serum B-cell activating factor (BAFF) levels after hydroxychloroquine treatment in primary Sjögren's syndrome. Oral Health Prev Dent 2013;11:229-34.
84. Lambers WM, Westra J, Bootsma H, de Leeuw K. Hydroxychloroquine suppresses interferon-inducible genes and B cell activating factor in patients with incomplete and new-onset systemic lupus erythematosus. J Rheumatol 2021;48:847-51.
85. Mahdy AA, Raafat HA, El-fishawy HS, Gheita TA. Therapeutic potential of hydroxychloroquine on serum B-cell activating factor belonging to the tumor necrosis factor family (BAFF) in rheumatoid arthritis patients. Bull Fac Pharm Cairo Univ 2014;52:37-43.
86. Lepse N, Land J, Rutgers A, et al. Toll-like receptor 9 activation enhances B cell activating factor and interleukin-21 induced anti-proteinase 3 autoantibody production in vitro. Rheumatology 2016;55:162-72.
87. O'Sullivan KM, Ford SL, Longano A, Kitching AR, Holdsworth SR. Intrarenal Toll-like receptor 4 and Toll-like receptor 2 expression correlates with injury in antineutrophil cytoplasmic antibody-associated vasculitis. Am J Physiol Renal Physiol 2018;315:F1283-94.
88. Wang H, Gou SJ, Zhao MH, Chen M. The expression of Toll-like receptors 2, 4 and 9 in kidneys of patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Clin Exp Immunol 2014;177:603-10.
89. Holle JU, Windmöller M, Lange C, Gross WL, Herlyn K, Csernok E. Toll-like receptor TLR2 and TLR9 ligation triggers neutrophil activation in granulomatosis with polyangiitis. Rheumatology 2013;52:1183-9.
90. Tadema H, Abdulahad WH, Lepse N, Stegeman CA, Kallenberg CG, Heeringa P. Bacterial DNA motifs trigger ANCA production in ANCA-associated vasculitis in remission. Rheumatology 2011;50:689-96.
91. Hurtado PR, Jeffs L, Nitschke J, et al. CpG oligodeoxynucleotide stimulates production of anti-neutrophil cytoplasmic antibodies in ANCA associated vasculitis. BMC Immunol 2008;9:34.
92. Konstantinov KN, Ulff-Møller CJ, Tzamaloukas AH. Infections and antineutrophil cytoplasmic antibodies: triggering mechanisms. Autoimmun Rev 2015;14:201-3.
93. Husmann CA, Holle JU, Moosig F, et al. Genetics of toll like receptor 9 in ANCA associated vasculitides. Ann Rheum Dis 2014;73:890-6.
94. Torigoe M, Sakata K, Ishii A, Iwata S, Nakayamada S, Tanaka Y. Hydroxychloroquine efficiently suppresses inflammatory responses of human class-switched memory B cells via Toll-like receptor 9 inhibition. Clin Immunol 2018;195:1-7.
95. Cenac C, Ducatez MF, Guéry JC. Hydroxychloroquine inhibits proteolytic processing of endogenous TLR7 protein in human primary plasmacytoid dendritic cells. Eur J Immunol 2022;52:54-61.
96. Hennessy EJ, Parker AE, O'Neill LA. Targeting Toll-like receptors: emerging therapeutics? Nat Rev Drug Discov 2010;9:293-307.
97. Gao W, Xiong Y, Li Q, Yang H. Inhibition of Toll-like receptor signaling as a promising therapy for inflammatory diseases: a journey from molecular to nano therapeutics. Front Physiol 2017;8:508.
98. Hoffmann JC, Patschan D, Dihazi H, et al. Cytokine profiling in anti neutrophil cytoplasmic antibody-associated vasculitis: a cross-sectional cohort study. Rheumatol Int 2019;39:1907-17.
99. van den Borne BE, Dijkmans BA, de Rooij HH, le Cessie S, Verweij CL. Chloroquine and hydroxychloroquine equally affect tumor necrosis factor-alpha, interleukin 6, and interferon-gamma production by peripheral blood mononuclear cells. J Rheumatol 1997;24:55-60.
100. Wakiya R, Ueeda K, Nakashima S, et al. Effect of add-on hydroxychloroquine therapy on serum proinflammatory cytokine levels in patients with systemic lupus erythematosus. Sci Rep 2022;12:10175.
101. Abdulahad WH, Lamprecht P, Kallenberg CG. T-helper cells as new players in ANCA-associated vasculitides. Arthritis Res Ther 2011;13:236.
102. Abdulahad WH, van der Geld YM, Stegeman CA, Kallenberg CG. Persistent expansion of CD4+ effector memory T cells in Wegener's granulomatosis. Kidney Int 2006;70:938-47.
103. Valenzuela L, Bordignon Draibe J, Fulladosa Oliveras X, Bestard Matamoros O, Cruzado Garrit JM, Torras Ambrós J. T-lymphocyte in ANCA-associated vasculitis: what do we know? A pathophysiological and therapeutic approach. Clin Kidney J 2019;12:503-11.
104. Hirayama K, Ishizu T, Shimohata H, et al. Analysis of T-cell receptor usage in myeloperoxidase - antineutrophil cytoplasmic antibody-associated renal vasculitis. Clin Exp Nephrol 2010;14:36-42.
105. McKinney EF, Lee JC, Jayne DR, Lyons PA, Smith KG. T-cell exhaustion, co-stimulation and clinical outcome in autoimmunity and infection. Nature 2015;523:612-6.
106. Abdulahad WH, Stegeman CA, van der Geld YM, Doornbos-van der Meer B, Limburg PC, Kallenberg CG. Functional defect of circulating regulatory CD4+ T cells in patients with Wegener's granulomatosis in remission. Arthritis Rheum 2007;56:2080-91.
107. Kim S, Boehme L, Nel L, et al. Defective STAT5 activation and aberrant expression of BCL6 in naive CD4 T cells enhances follicular Th cell-like differentiation in patients with granulomatosis with polyangiitis. J Immunol 2022;208:807-18.
108. Goldman FD, Gilman AL, Hollenback C, Kato RM, Premack BA, Rawlings DJ. Hydroxychloroquine inhibits calcium signals in T cells: a new mechanism to explain its immunomodulatory properties. Blood 2000;95:3460-6.
109. van Loosdregt J, Spreafico R, Rossetti M, Prakken BJ, Lotz M, Albani S. Hydroxychloroquine preferentially induces apoptosis of CD45RO+ effector T cells by inhibiting autophagy: a possible mechanism for therapeutic modulation of T cells. J Allergy Clin Immunol 2013;131:1443-6.e1.
110. Kowatsch MM, Lajoie J, Mwangi L, et al. Hydroxychloroquine reduces T cells activation recall antigen responses. PLoS One 2023;18:e0287738.
111. Kim ML, Hardy MY, Edgington-Mitchell LE, et al. Hydroxychloroquine inhibits the mitochondrial antioxidant system in activated T cells. iScience 2021;24:103509.
112. Taverna S, Tonacci A, Ferraro M, et al. High mobility group box 1: biological functions and relevance in oxidative stress related chronic diseases. Cells 2022;11:849.
113. Guan H, Zhong M, Ma K, et al. The comprehensive role of high mobility group box 1 (HMGB1) protein in different tumors: a pan-cancer analysis. J Inflamm Res 2023;16:617-37.
114. Kianian F, Kadkhodaee M, Sadeghipour HR, Karimian SM, Seifi B. An overview of high-mobility group box 1, a potent pro-inflammatory cytokine in asthma. J Basic Clin Physiol Pharmacol 2020:31.
115. Mo J, Hu J, Cheng X. The role of high mobility group box 1 in neuroinflammatory related diseases. Biomed Pharmacother 2023;161:114541.
116. Ge Y, Huang M, Yao YM. The Effect and regulatory mechanism of high mobility group box-1 protein on immune cells in inflammatory diseases. Cells 2021;10:1044.
117. Gou X, Ying J, Yue Y, et al. The roles of high mobility group box 1 in cerebral ischemic injury. Front Cell Neurosci 2020;14:600280.
118. Vijayakumar EC, Bhatt LK, Prabhavalkar KS. High mobility group box-1 (HMGB1): a potential target in therapeutics. Curr Drug Targets 2019;20:1474-85.
119. Bruchfeld A, Wendt M, Bratt J, et al. High-mobility group box-1 protein (HMGB1) is increased in antineutrophilic cytoplasmatic antibody (ANCA)-associated vasculitis with renal manifestations. Mol Med 2011;17:29-35.
120. Wang C, de Souza AW, Westra J, et al. Emerging role of high mobility group box 1 in ANCA-associated vasculitis. Autoimmun Rev 2015;14:1057-65.
121. Wang C, Gou SJ, Chang DY, Yu F, Zhao MH, Chen M. Association of circulating level of high mobility group box 1 with disease activity in antineutrophil cytoplasmic autoantibody-associated vasculitis. Arthritis Care Res 2013;65:1828-34.
122. Wibisono D, Csernok E, Lamprecht P, Holle JU, Gross WL, Moosig F. Serum HMGB1 levels are increased in active Wegener's granulomatosis and differentiate between active forms of ANCA-associated vasculitis. Ann Rheum Dis 2010;69:1888-9.
123. de Souza AW, Westra J, Limburg PC, Bijl M, Kallenberg CG. HMGB1 in vascular diseases: Its role in vascular inflammation and atherosclerosis. Autoimmun Rev 2012;11:909-17.
124. Niemann B, Puleo A, Stout C, Markel J, Boone BA. Biologic functions of hydroxychloroquine in disease: from COVID-19 to Cancer. Pharmaceutics 2022;14:2551.
125. Yang M, Cao L, Xie M, et al. Chloroquine inhibits HMGB1 inflammatory signaling and protects mice from lethal sepsis. Biochem Pharmacol 2013;86:410-8.
126. Laronha H, Caldeira J. Structure and function of human matrix metalloproteinases. Cells 2020;9:1076.
127. Nagase H, Visse R, Murphy G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res 2006;69:562-73.
128. Cabral-Pacheco GA, Garza-Veloz I, Castruita-De la Rosa C, et al. The roles of matrix metalloproteinases and their inhibitors in human diseases. Int J Mol Sci 2020;21:9739.
129. Zakiyanov O, Chocová Z, Hrušková Z, et al. Matrix metalloproteinases and their tissue inhibitors: an evaluation of novel biomarkers in ANCA-associated vasculitis. Fol Biol 2019;65:227-36.
130. Sanders JS, Huitema MG, Hanemaaijer R, van Goor H, Kallenberg CG, Stegeman CA. Urinary matrix metalloproteinases reflect renal damage in anti-neutrophil cytoplasm autoantibody-associated vasculitis. Am J Physiol Renal Physiol 2007;293:F1927-34.
131. Ishizaki J, Takemori A, Horie K, et al. Research Committee of Intractable Vasculitis Syndrome and the Research Committee of Intractable Renal Disease of the Ministry of Health; Labour and Welfare of Japan. Usefulness of tissue inhibitor of metalloproteinase 1 as a predictor of sustained remission in patients with antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Res Ther 2021;23:91.
132. Rymarz A, Mosakowska M, Niemczyk S. The significance of metalloproteinase 3 (MMP-3), chemokine CXC ligand 13 (CXCL-13) and complement component C5a in different stages of ANCA associated vasculitis. Sci Rep 2021;11:5132.
133. Lesiak A, Narbutt J, Sysa-Jedrzejowska A, Lukamowicz J, McCauliffe DP, Wózniacka A. Effect of chloroquine phosphate treatment on serum MMP-9 and TIMP-1 levels in patients with systemic lupus erythematosus. Lupus 2010;19:683-8.
134. Ertugrul G, Keles D, Oktay G, Aktan S. Matrix metalloproteinase-2 and -9 activity levels increase in cutaneous lupus erythematosus lesions and correlate with disease severity. Arch Dermatol Res 2018;310:173-9.
135. Merkel PA, Lo GH, Holbrook JT, et al. Wegener's Granulomatosis Etanercept Trial Research Group. Brief communication: high incidence of venous thrombotic events among patients with Wegener granulomatosis: the Wegener's clinical occurrence of thrombosis (WeCLOT) study. Ann Intern Med 2005;142:620-6.
136. Liapi M, Jayne D, Merkel PA, Segelmark M, Mohammad AJ. Venous thromboembolism in ANCA-associated vasculitis: a population-based cohort study. Rheumatology 2021;60:4616-23.
137. Hilhorst M, Winckers K, Wilde B, van Oerle R, ten Cate H, Tervaert JW. Patients with antineutrophil cytoplasmic antibodies associated vasculitis in remission are hypercoagulable. J Rheumatol 2013;40:2042-6.
138. Hansrivijit P, Trongtorsak A, Gadhiya KP, et al. Incidence and risk factors of venous thromboembolism in ANCA-associated vasculitis: a metaanalysis and metaregression. Clin Rheumatol 2021;40:2843-53.
139. Isaacs B, Gapud EJ, Antiochos B, Seo P, Geetha D. Venous thrombotic events in ANCA-Associated vasculitis: incidence and risk factors. Kidney360 2020;1:258-62.
140. Carter AE, Eban R, Perrett RD. Prevention of postoperative deep venous thrombosis and pulmonary embolism. Br Med J 1971;1:312-4.
141. Hansen E, Jessing P, Lindewald H, Ostergaard P, Olesen T, Malver E. Hydroxychloroquine sulphate in prevention of deep venous thrombosis following fracture of the hip, pelvis, or thoracolumbar spine. J Bone Joint Surg Am 1976;58:1089-93.
142. Mekinian A, Lazzaroni MG, Kuzenko A, et al. SNFMI and the European Forum on Antiphospholipid Antibodies. The efficacy of hydroxychloroquine for obstetrical outcome in anti-phospholipid syndrome: data from a European multicenter retrospective study. Autoimmun Rev 2015;14:498-502.
143. Belizna C. Hydroxychloroquine as an anti-thrombotic in antiphospholipid syndrome. Autoimmun Rev 2015;14:358-62.
144. Espinola R, Pierangeli S, Ghara A, Harris E. Hydroxychloroquine reverses platelet activation induced by human IgG antiphospholipid antibodies. Thromb Haemost 2002;87:518-22.
145. Belizna CC, Richard V, Thuillez C, Lévesque H, Shoenfeld Y. Insights into atherosclerosis therapy in antiphospholipid syndrome. Autoimmun Rev 2007;7:46-51.
146. Nuri E, Taraborelli M, Andreoli L, et al. Long-term use of hydroxychloroquine reduces antiphospholipid antibodies levels in patients with primary antiphospholipid syndrome. Immunol Res 2017;65:17-24.
147. Erkan D, Yazici Y, Peterson MG, Sammaritano L, Lockshin MD. A cross-sectional study of clinical thrombotic risk factors and preventive treatments in antiphospholipid syndrome. Rheumatology 2002;41:924-9.
148. Rand JH, Wu XX, Quinn AS, et al. Hydroxychloroquine protects the annexin A5 anticoagulant shield from disruption by antiphospholipid antibodies: evidence for a novel effect for an old antimalarial drug. Blood 2010;115:2292-9.
149. Wu XX, Guller S, Rand JH. Hydroxychloroquine reduces binding of antiphospholipid antibodies to syncytiotrophoblasts and restores annexin A5 expression. Am J Obstet Gynecol 2011;205:576.e7-14.
150. Bengtsson C, Andersson SE, Edvinsson L, Edvinsson ML, Sturfelt G, Nived O. Effect of medication on microvascular vasodilatation in patients with systemic lupus erythematosus. Basic Clin Pharmacol Toxicol 2010;107:919-24.
151. Tanay A, Leibovitz E, Frayman A, Zimlichman R, Shargorodsky M, Gavish D. Vascular elasticity of systemic lupus erythematosus patients is associated with steroids and hydroxychloroquine treatment. Ann N Y Acad Sci 2007;1108:24-34.
152. Folci M, Ramponi G, Shiffer D, Zumbo A, Agosti M, Brunetta E. ANCA-Associated vasculitides and hematologic malignancies: lessons from the past and future perspectives. J Immunol Res 2019;2019:1732175.
153. Heijl C, Harper L, Flossmann O, et al. European Vasculitis Study Group (EUVAS). Incidence of malignancy in patients treated for antineutrophil cytoplasm antibody-associated vasculitis: follow-up data from European vasculitis study group clinical trials. Ann Rheum Dis 2011;70:1415-21.
154. Mahr A, Heijl C, Le Guenno G, Faurschou M. ANCA-associated vasculitis and malignancy: current evidence for cause and consequence relationships. Best Pract Res Clin Rheumatol 2013;27:45-56.
155. van Daalen EE, Rizzo R, Kronbichler A, et al. Effect of rituximab on malignancy risk in patients with ANCA-associated vasculitis. Ann Rheum Dis 2017;76:1064-9.
156. Geser A, Brubaker G, Draper CC. Effect of a malaria suppression program on the incidence of African Burkitt's lymphoma. Am J Epidemiol 1989;129:740-52.
157. Gheitasi H, Kostov B, Solans R, et al. SS Study Group; Autoimmune Diseases Study Group (GEAS); Spanish Society of Internal Medicine (SEMI). How are we treating our systemic patients with primary Sjögren syndrome? Analysis of 1120 patients. Int Immunopharmacol 2015;27:194-9.
158. Ko KM, Moon SJ. Prevalence, incidence, and risk factors of malignancy in patients with rheumatoid arthritis: a nationwide cohort study from Korea. Korean J Intern Med 2023;38:113-24.
159. Lee H, Chen SK, Gautam N, et al. Risk of malignant melanoma and non-melanoma skin cancer in rheumatoid arthritis patients initiating methotrexate versus hydroxychloroquine: a cohort study. Clin Exp Rheumatol 2023;41:110-7.
160. Houben E, Penne EL, Voskuyl AE, et al. Cardiovascular events in anti-neutrophil cytoplasmic antibody-associated vasculitis: a meta-analysis of observational studies. Rheumatology 2018;57:555-62.
161. Massicotte-Azarniouch D, Petrcich W, Walsh M, et al. Association of anti-neutrophil cytoplasmic antibody-associated vasculitis and cardiovascular events: a population-based cohort study. Clin Kidney J 2022;15:681-92.
162. Raza K, Thambyrajah J, Townend JN, et al. Suppression of inflammation in primary systemic vasculitis restores vascular endothelial function: lessons for atherosclerotic disease? Circulation 2000;102:1470-2.
163. Booth AD, Jayne DR, Kharbanda RK, et al. Infliximab improves endothelial dysfunction in systemic vasculitis: a model of vascular inflammation. Circulation 2004;109:1718-23.
164. Clifford AH, Cohen Tervaert JW. Cardiovascular events and the role of accelerated atherosclerosis in systemic vasculitis. Atherosclerosis 2021;325:8-15.
165. Tervaert JW. Cardiovascular disease due to accelerated atherosclerosis in systemic vasculitides. Best Pract Res Clin Rheumatol 2013;27:33-44.
166. Penn SK, Kao AH, Schott LL, et al. Hydroxychloroquine and glycemia in women with rheumatoid arthritis and systemic lupus erythematosus. J Rheumatol 2010;37:1136-42.
167. Petri M. Hydroxychloroquine use in the Baltimore Lupus Cohort: effects on lipids, glucose and thrombosis. Lupus 1996;5:16-22.
168. Solomon DH, Garg R, Lu B, et al. Effect of hydroxychloroquine on insulin sensitivity and lipid parameters in rheumatoid arthritis patients without diabetes mellitus: a randomized, blinded crossover trial. Arthritis Care Res 2014;66:1246-51.
169. Petri M, Lakatta C, Magder L, Goldman D. Effect of prednisone and hydroxychloroquine on coronary artery disease risk factors in systemic lupus erythematosus: a longitudinal data analysis. Am J Med 1994;96:254-9.
170. Xu T, Chen Z, Jiang M, et al. Association between different infection profiles and one-year outcomes in ANCA-associated vasculitis: a retrospective study with monthly infection screening. RMD Open 2022;8:e002424.
171. Flossmann O, Berden A, de Groot K, et al. European Vasculitis Study Group. Long-term patient survival in ANCA-associated vasculitis. Ann Rheum Dis 2011;70:488-94.
172. Ruiz-Irastorza G, Olivares N, Ruiz-Arruza I, Martinez-Berriotxoa A, Egurbide MV, Aguirre C. Predictors of major infections in systemic lupus erythematosus. Arthritis Res Ther 2009;11:R109.
173. Smitten AL, Choi HK, Hochberg MC, et al. The risk of hospitalized infection in patients with rheumatoid arthritis. J Rheumatol 2008;35:387-93.
174. Yusuf IH, Foot B, Lotery AJ. The royal college of ophthalmologists recommendations on monitoring for hydroxychloroquine and chloroquine users in the United Kingdom (2020 revision): executive summary. Eye 2021;35:1532-7.
175. Learoyd AE, Arnold L, Reid F, et al. HAVEN study group. The HAVEN study-hydroxychloroquine in ANCA vasculitis evaluation-a multicentre, randomised, double-blind, placebo-controlled trial: study protocol and statistical analysis plan. Trials 2023;24:261.
176. Price EJ, Rauz S, Tappuni AR, et al. British Society for Rheumatology Standards; Guideline and Audit Working Group. The British society for rheumatology guideline for the management of adults with primary Sjögren's syndrome. Rheumatology 2017;56:e24-48.
177. Ramos-Casals M, Brito-Zerón P, Bombardieri S, et al. EULAR-Sjögren Syndrome Task Force Group. EULAR recommendations for the management of Sjögren's syndrome with topical and systemic therapies. Ann Rheum Dis 2020;79:3-18.
178. Fox R, Dixon R, Guarrasi V, Krubel S. Treatment of primary Sjögren's syndrome with hydroxychloroquine: a retrospective, open-label study. Lupus 1996;5:31-6.
179. Cankaya H, Alpöz E, Karabulut G, Güneri P, Boyacioglu H, Kabasakal Y. Effects of hydroxychloroquine on salivary flow rates and oral complaints of Sjögren patients: a prospective sample study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010;110:62-7.
180. Kruize AA, Hené RJ, Kallenberg CG, et al. Hydroxychloroquine treatment for primary Sjögren's syndrome: a two year double blind crossover trial. Ann Rheum Dis 1993;52:360-4.
181. Fox RI, Chan E, Benton L, Fong S, Friedlaender M, Howell FV. Treatment of primary Sjögren's syndrome with hydroxychloroquine. Am J Med 1988;85:62-7.
182. Yoon CH, Lee HJ, Lee EY, et al. Effect of hydroxychloroquine treatment on dry eyes in subjects with primary sjögren's syndrome: a double-blind randomized control study. J Korean Med Sci 2016;31:1127-35.
183. Gottenberg JE, Ravaud P, Puéchal X, et al. Effects of hydroxychloroquine on symptomatic improvement in primary Sjögren syndrome: the JOQUER randomized clinical trial. JAMA 2014;312:249-58.
184. Wang SQ, Zhang LW, Wei P, Hua H. Is hydroxychloroquine effective in treating primary Sjogren's syndrome: a systematic review and meta-analysis. BMC Musculoskelet Disord 2017;18:186.
185. Tektonidou MG, Andreoli L, Limper M, et al. EULAR recommendations for the management of antiphospholipid syndrome in adults. Ann Rheum Dis 2019;78:1296-304.
186. Erkan D, Unlu O, Sciascia S, et al. APS ACTION. Hydroxychloroquine in the primary thrombosis prophylaxis of antiphospholipid antibody positive patients without systemic autoimmune disease. Lupus 2018;27:399-406.
187. Sciascia S, Hunt BJ, Talavera-Garcia E, Lliso G, Khamashta MA, Cuadrado MJ. The impact of hydroxychloroquine treatment on pregnancy outcome in women with antiphospholipid antibodies. Am J Obstet Gynecol 2016;214:273.e1-8.
188. Hooper A, Bacal V, Bedaiwy MA. Does adding hydroxychloroquine to empiric treatment improve the live birth rate in refractory obstetrical antiphospholipid syndrome? A systematic review. Am J Reprod Immunol 2023;90:e13761.
189. Edwards MH, Pierangeli S, Liu X, Barker JH, Anderson G, Harris EN. Hydroxychloroquine reverses thrombogenic properties of antiphospholipid antibodies in mice. Circulation 1997;96:4380-4.
190. Baughman RP, Valeyre D, Korsten P, et al. ERS clinical practice guidelines on treatment of sarcoidosis. Eur Respir J 2021;58:2004079.
191. Thillai M, Atkins CP, Crawshaw A, et al. BTS clinical statement on pulmonary sarcoidosis. Thorax 2021;76:4-20.
192. Smedslund G, Kotar AM, Uhlig T. Sarcoidosis with musculoskeletal manifestations: systematic review of non-pharmacological and pharmacological treatments. Rheumatol Int 2022;42:2109-24.
193. Sharma R, Guleria R, Mohan A. Treatment of pulmonary sarcoidosis with hydroxycholoroquine: result of a pilot study from Indi. Chest 2003;124:109S.
194. Ben Hassine I, Rein C, Comarmond C, et al. Osseous sarcoidosis: A multicenter retrospective case-control study of 48 patients. Joint Bone Spine 2019;86:789-93.
195. Sharma OP. Effectiveness of chloroquine and hydroxychloroquine in treating selected patients with sarcoidosis with neurological involvement. Arch Neurol 1998;55:1248-54.
196. Lee W, Ruijgrok L, Boxma-de Klerk B, et al. Efficacy of hydroxychloroquine in hand osteoarthritis: a randomized, double-blind, placebo-controlled trial. Arthritis Care Res 2018;70:1320-5.
197. Kingsbury SR, Tharmanathan P, Keding A, et al. Hydroxychloroquine effectiveness in reducing symptoms of hand osteoarthritis: a randomized trial. Ann Intern Med 2018;168:385-95.
198. Wright NA, Mazori DR, Patel M, Merola JF, Femia AN, Vleugels RA. Epidemiology and treatment of eosinophilic fasciitis: an analysis of 63 patients from 3 tertiary care centers. JAMA Dermatol 2016;152:97-9.
199. Woo TY, Callen JP, Voorhees JJ, Bickers DR, Hanno R, Hawkins C. Cutaneous lesions of dermatomyositis are improved by hydroxychloroquine. J Am Acad Dermatol 1984;10:592-600.
200. Zhang QC, Liu MY, Chen ZX, Chen YT, Lin CS, Xu Q. Case report: treatment of anti-MDA5-positive amyopathic dermatomyositis accompanied by a rapidly progressive interstitial lung diseases with methylprednisolone pulse therapy combined with cyclosporine A and hydroxychloroquine. Front Med 2020;7:610554.
201. Olson NY, Lindsley CB. Adjunctive use of hydroxychloroquine in childhood dermatomyositis. J Rheumatol 1989;16:1545-7.
202. Lin YC, Huang HH, Nong BR, et al. Pediatric Kikuchi-Fujimoto disease: a clinicopathologic study and the therapeutic effects of hydroxychloroquine. J Microbiol Immunol Infect 2019;52:395-401.
203. Hyun M, So IT, Kim HA, Jung H, Ryu SY. Recurrent Kikuchi's disease treated by hydroxychloroquine. Infect Chemother 2016;48:127-31.
204. Sun L, Gong YR, Chen Q, et al. Application and safety of hydroxychloroquine in chronic disease among children. Zhonghua Er Ke Za Zhi 2021;59:107-12.
205. Nogueira IA, Cordeiro RA, Henn GAL, Oliveira JL. Hydroxychloroquine for the management of chronic chikungunya arthritis. Rev Inst Med Trop Sao Paulo 2023;65:e26.
206. Mohammadpour F, Kargar M, Hadjibabaie M. The role of hydroxychloroquine as a steroid-sparing agent in the treatment of immune thrombocytopenia: a review of the literature. J Res Pharm Pract 2018;7:4-12.
207. Bockow B, Kaplan TB. Refractory immune thrombocytopenia successfully treated with high-dose vitamin D supplementation and hydroxychloroquine: two case reports. J Med Case Rep 2013;7:91.
208. Zhang J, Lu X, Feng J, Li H, Wang S. Effects of hydroxychloroquine on proteinuria in IgA nephropathy: a systematic review and meta-analysis. Biomed Res Int 2021;2021:9171715.
209. Liu LJ, Yang YZ, Shi SF, et al. Effects of hydroxychloroquine on proteinuria in IgA nephropathy: a randomized controlled trial. Am J Kidney Dis 2019;74:15-22.
210. Si FL, Tang C, Lv JC, et al. Comparison between hydroxychloroquine and systemic corticosteroids in IgA nephropathy: a two-year follow-up study. BMC Nephrol 2023;24:175.
211. WHO guidelines for malaria. Available from https://www.who.int/publications/i/item/guidelines-for-malaria [Last accessed on 27 Feb 2024].
212. Horby P, Mafham M, Linsell L, et al. RECOVERY Collaborative Group. Effect of hydroxychloroquine in hospitalized patients with Covid-19. N Engl J Med 2020;383:2030-40.
213. Arabi YM, Gordon AC, Derde LPG, et al. REMAP-CAP Investigators. Lopinavir-ritonavir and hydroxychloroquine for critically ill patients with COVID-19: REMAP-CAP randomized controlled trial. Intensive Care Med 2021;47:867-86.
214. Sivapalan P, Ulrik CS, Lapperre TS, et al. ProPAC-COVID writing group on behalf of the ProPAC-COVID Study Group. Azithromycin and hydroxychloroquine in hospitalised patients with confirmed COVID-19: a randomised double-blinded placebo-controlled trial. Eur Respir J 2022;59:2100752.
215. Pan H, Peto R, Henao-Restrepo AM, et al. WHO Solidarity Trial Consortium. Repurposed antiviral drugs for Covid-19 - interim WHO solidarity trial results. N Engl J Med 2021;384:497-511.
216. Pradelle A, Mainbourg S, Provencher S, Massy E, Grenet G, Lega JC. Deaths induced by compassionate use of hydroxychloroquine during the first COVID-19 wave: an estimate. Biomed Pharmacother 2024;171:116055.
217. Diagnosis and management of Q fever - United States, 2013: recommendations from CDC and the Q fever working group. Available from: https:// www.cdc.gov/mmwr/preview/mmwrhtml/rr6203a1.htm [Last accessed on 27 Feb 2024].
218. Coxiella burnetii infection. BMJ Best Practice Available from: https://bestpractice.bmj.com/topics/en-gb/1139 [Last accessed on 27 Feb 2024].
219. Whipple’s disease. BMJ Best Practice Available from: https://bestpractice.bmj.com/topics/en-gb/467 [Last accessed on 27 Feb 2024].
220. Wang X, Long X, Jia S, et al. In vitro and in vivo synergistic effects of hydroxychloroquine and itraconazole on Cryptococcus neoformans. Folia Microbiol 2023;68:595-605.
221. Luo W, Che D, Lu H, Jiang Y. New perspectives from misdiagnosis: a case of primary cutaneous cryptococcosis treated with hydroxychloroquine sulfate successfully. Mycopathologia 2020;185:595-6.
222. Rolain JM, Colson P, Raoult D. Recycling of chloroquine and its hydroxyl analogue to face bacterial, fungal and viral infections in the 21st century. Int J Antimicrob Agents 2007;30:297-308.
223. Dias-Melicio LA, Moreira AP, Calvi SA, Soares AM. Chloroquine inhibits paracoccidioides brasiliensis survival within human monocytes by limiting the availability of intracellular iron. Microbiol Immunol 2006;50:307-14.
224. Naghipour S, Ghodousi M, Rahsepar S, Elyasi S. Repurposing of well-known medications as antivirals: hydroxychloroquine and chloroquine - from HIV-1 infection to COVID-19. Expert Rev Anti Infect Ther 2020;18:1119-33.
225. Shiryaev SA, Mesci P, Pinto A, et al. Repurposing of the anti-malaria drug chloroquine for Zika virus treatment and prophylaxis. Sci Rep 2017;7:15771.
226. Hamilton BK. Updates in chronic graft-versus-host disease. Hematol Am Soc Hematol Educ Program 2021;2021:648-54.
227. Gilman AL, Chan KW, Mogul A, et al. Hydroxychloroquine for the treatment of chronic graft-versus-host disease. Biol Blood Marrow Transplant 2000;6:327-34.
228. Khoury H, Trinkaus K, Zhang MJ, et al. Hydroxychloroquine for the prevention of acute graft-versus-host disease after unrelated donor transplantation. Biol Blood Marrow Transplant 2003;9:714-21.
229. Fong T, Trinkaus K, Adkins D, et al. A randomized double-blind trial of hydroxychloroquine for the prevention of chronic graft-versus-host disease after allogeneic peripheral blood stem cell transplantation. Biol Blood Marrow Transplant 2007;13:1201-6.
230. Gilman AL, Schultz KR, Goldman FD, et al. Randomized trial of hydroxychloroquine for newly diagnosed chronic graft-versus-host disease in children: a children's oncology group study. Biol Blood Marrow Transplant 2012;18:84-91.
231. Lagneaux L, Delforge A, Dejeneffe M, Massy M, Bernier M, Bron D. Hydroxychloroquine-induced apoptosis of chronic lymphocytic leukemia involves activation of caspase-3 and modulation of Bcl-2/bax/ratio. Leuk Lymphoma 2002;43:1087-95.
232. Mansilla E, Marin GH, Nuñez L, et al. The lysosomotropic agent, hydroxychloroquine, delivered in a biodegradable nanoparticle system, overcomes drug resistance of B-chronic lymphocytic leukemia cells in vitro. Cancer Biother Radiopharm 2010;25:97-103.
233. Jiang PD, Zhao YL, Shi W, et al. Cell growth inhibition, G2/M cell cycle arrest, and apoptosis induced by chloroquine in human breast cancer cell line Bcap-37. Cell Physiol Biochem 2008;22:431-40.
234. Rahim R, Strobl JS. Hydroxychloroquine, chloroquine, and all-trans retinoic acid regulate growth, survival, and histone acetylation in breast cancer cells. Anticancer Drugs 2009;20:736-45.
236. Cainelli T, Di Padova C, Marchesi L, et al. Hydroxychloroquine versus phlebotomy in the treatment of porphyria cutanea tarda. Br J Dermatol 1983;108:593-600.
237. Marchesi L, Di Padova C, Cainelli T, et al. A comparative trial of desferrioxamine and hydroxychloroquine for treatment of porphyria cutanea tarda in alcoholic patients. Photodermatology 1984;1:286-92.
238. Singal AK, Kormos-Hallberg C, Lee C, et al. Low-dose hydroxychloroquine is as effective as phlebotomy in treatment of patients with porphyria cutanea tarda. Clin Gastroenterol Hepatol 2012;10:1402-9.
239. Pareek A, Khopkar U, Sacchidanand S, Chandurkar N, Naik GS. Comparative study of efficacy and safety of hydroxychloroquine and chloroquine in polymorphic light eruption: a randomized, double-blind, multicentric study. Indian J Dermatol Venereol Leprol 2008;74:18-22.
240. Hrin ML, Feldman SR, Huang WW. Hydroxychloroquine for generalized granuloma annulare: 35% response rate in a retrospective case series of 26 patients. J Am Acad Dermatol 2022;87:144-7.
241. Eisen D. Hydroxychloroquine sulfate (Plaquenil) improves oral lichen planus: an open trial. J Am Acad Dermatol 1993;28:609-12.
242. Husein-ElAhmed H, Gieler U, Steinhoff M. Lichen planus: a comprehensive evidence-based analysis of medical treatment. J Eur Acad Dermatol Venereol 2019;33:1847-62.
243. Stoopler ET, Kulkarni R, Alawi F, Sollecito TP. Novel combination therapy of hydroxychloroquine and topical tacrolimus for chronic ulcerative stomatitis. Int J Dermatol 2021;60:e162-3.
244. Brant EG, Akilov O. Hydroxychloroquine for the treatment of hidradenitis suppurativa. JAAD Case Rep 2023;37:64-7.
245. Khan N, Epstein TG, DuBuske I, Strobel M, Bernstein DI. Effectiveness of hydroxychloroquine and omalizumab in chronic spontaneous urticaria: a real-world study. J Allergy Clin Immunol Pract 2022;10:3300-5.
246. Reeves GE, Boyle MJ, Bonfield J, Dobson P, Loewenthal M. Impact of hydroxychloroquine therapy on chronic urticaria: chronic autoimmune urticaria study and evaluation. Intern Med J 2004;34:182-6.
247. Koch MW, Kaur S, Sage K, et al. Hydroxychloroquine for primary progressive multiple sclerosis. Ann Neurol 2021;90:940-8.
248. Sun L, Kuang XY, Zhang J, Huang WY. Hydroxychloroquine ameliorates hematuria in children with X-linked alport syndrome: retrospective case series study. Pharmgenomics Pers Med 2023;16:145-51.
249. Plantone D, Koudriavtseva T. Current and future use of chloroquine and hydroxychloroquine in infectious, immune, neoplastic, and neurological diseases: a mini-review. Clin Drug Investig 2018;38:653-71.
250. Guennec P, Dromer C, Sixou L, Marc V, Coustals P, Fournié B. Treatment of horton disease. value of synthetic antimalarials. apropos of a retrospective study of 36 patients. Rev Rhum Ed Fr 1994;61:485-90.
251. Hydroxychloroquine in giant cell arteritis. Available from: https://classic.clinicaltrials.gov/ct2/show/record/NCT00430807 [Last accessed on 27 Feb 2024].
252. Rongyi C, Zongfei J, Jiang L, et al. Effect of hydroxychloroquine on angiographic progression in routine treatment of takayasu arteritis. Mod Rheumatol 2021;31:1135-41.
253. Casian A, Sangle S, D'cruz D. AB0531 the role of hydroxychloroquine in ANCA positive and negative vasculitis. Ann Rheum Dis 2016;75:1086-7.
254. Papachristodoulou E, Kakoullis L, Tiniakou E, Parperis K. Therapeutic options for cutaneous polyarteritis nodosa: a systematic review. Rheumatology 2021;60:4039-47.
255. Panda PK, Sharawat IK, Natarajan V, Bhakat R, Panda P, Dawman L. COVID-19 treatment in children: a systematic review and meta-analysis. J Family Med Prim Care 2021;10:3292-302.
256. Kolkhir P, Grakhova M, Bonnekoh H, Krause K, Maurer M. Treatment of urticarial vasculitis: a systematic review. J Allergy Clin Immunol 2019;143:458-66.
257. Bostan E, Akdogan N, Gokoz O, Dogan S. Rapid response to combination of hydroxychloroquine and prednisolone in a patient with refractory hypocomplementemic urticarial vasculitis. Dermatol Ther 2020;33:e14531.
258. Lopez LR, Davis KC, Kohler PF, Schocket AL. The hypocomplementemic urticarial-vasculitis syndrome: therapeutic response to hydroxychloroquine. J Allergy Clin Immunol 1984;73:600-3.
259. Batioğlu F, Taner P, Aydintuğ OT, Heper AO, Ozmert E. Recurrent optic disc and retinal vasculitis in a patient with drug-induced urticarial vasculitis. Cutan Ocul Toxicol 2006;25:281-5.
260. Farkas H, Szongoth M, Bély M, et al. Angiooedema due to acquired deficiency of C1-esterase inhibitor associated with leucocytoclastic vasculitis. Acta Derm Venereol 2001;81:298-300.
261. Jachiet M, Flageul B, Deroux A, et al. French Vasculitis Study Group. The clinical spectrum and therapeutic management of hypocomplementemic urticarial vasculitis: data from a French nationwide study of fifty-seven patients. Arthritis Rheumatol 2015;67:527-34.
262. Basnet A, Cholankeril MR. Hemophagocytic lymphohistiocytosis in a patient with goodpasture's syndrome: a rare clinical association. Am J Case Rep 2014;15:431-6.
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Jain S, Sangle SR, Kim S, John S, D’Cruz D. Hydroxychloroquine as a potential therapy for ANCA-associated vasculitis. Vessel Plus 2024;8:8. http://dx.doi.org/10.20517/2574-1209.2023.142
AMA Style
Jain S, Sangle SR, Kim S, John S, D’Cruz D. Hydroxychloroquine as a potential therapy for ANCA-associated vasculitis. Vessel Plus. 2024; 8: 8. http://dx.doi.org/10.20517/2574-1209.2023.142
Chicago/Turabian Style
Jain, Sahil, Shirish R. Sangle, Sangmi Kim, Susan John, David D’Cruz. 2024. "Hydroxychloroquine as a potential therapy for ANCA-associated vasculitis" Vessel Plus. 8: 8. http://dx.doi.org/10.20517/2574-1209.2023.142
ACS Style
Jain, S.; Sangle SR.; Kim S.; John S.; D’Cruz D. Hydroxychloroquine as a potential therapy for ANCA-associated vasculitis. Vessel Plus. 2024, 8, 8. http://dx.doi.org/10.20517/2574-1209.2023.142
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