Strong indicators of this fact include-
1. AS can occur in individuals who do not carry HLA-B27 gene.
2. Amongst the HLA-B 27 individuals, only about 1-5% individuals develop AS.
3. HLA-B27 positive relatives of AS patients have a risk of developing AS that is 5.6 to 15 times that of HLA-B27 positive individuals in general population. This would mean that there are other non HLA-B27 familial genetic factors involved in causation of AS.

There has been some major work by the Wellcome trust case Control Consortium
& Australo-Anglo-American Spondyloarthritis Consortium to look into the genetics of AS. These (& other) studies have revealed that there are other genes & genetic loci responsible for Ankylosing spondylitis as well—
1. HLA-B60 seen in HLA-B27 positive as well as negative AS patients.
2. HLA-B 39 seen in HLA-B27 negative patients
3. ERAP-1— endoplasmic reticulum aminopeptidase-1
4. Interleukin-23 receptor gene—IL-23R
5. RUNX3
6. KIF21B
7. 2p15
8. IL12B
9. LTBR-TNFRSF1A
10. 21q22
11. ANTXR2
12. PTGER4
13. CARD9
14. TBKBP1

Out of these genes, ERAP-1 & IL-23 R have generated maximum interest. The researchers have found that some variants of ERAP1 protect against the development of Ankylosing spondylitis. For individuals who carry HLA-B27, their risk of developing Ankylosing spondylitis decreases by a factor of four if they carry two copies of the protective variant of ERAP1.

HLA-B27 presents the pathogen antigen to the immune cells. The ERAP-1 gene interacts with HLA-B27 to affect how these peptides are presented to the immune system. The researchers have found that some variants of ERAP1 protect against the development of Ankylosing spondylitis by reducing the amount of peptide available to HLA-B27 within cells. This could prove to be a target for treatment in the future.

Tests for these genetic markers are not available routinely as of now. But, then, if they are found to be clinically useful; tests should be available in the future.

References:
1. Investigating the genetic association between ERAP1 and ankylosing spondylitis. Harvey D & colleagues. Hum Mol Genet. 2009 Nov 1;18(21):4204-12.
2. Progress in the genetics of ankylosing spondylitis. Matthew A brown. Briefings in Functional Genomics (2011) 10 (5): 249-257.
3. Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility. The Australo-Anglo-American Spondyloarthritis Consortium (TASC), the Wellcome Trust Case Control Consortium 2 (WTCCC2), Nature Genetics 43, 761–767 (2011)

This is good as far as awareness is concerned. But, on the flip side, many patients have missed the diagnosis, as they were HLA-B27 negative. This is particularly important, as the average delay in the diagnosis of Ankylosing spondylitis is 8- 11 yrs. The delay for women is even more than that of men. This is quite unacceptable as the first 10 years are the most important for a patient as the treatment can be initiated before permanent limitations of spinal mobility and deformity has set in.

Although HLA-B27 gene is the most important gene predisposing to Ankylosing spondylitis, studies have shown that it contributes only 20-30% of the total genetic risk. No doubt HLA-B27 is a strong risk factor for the development of Ankylosing spondylitis, but that does not mean that it is a must for diagnosis.

So, then how important is HLA-B27 for a diagnosis of Ankylosing spondylitis?
Only about 80-90% of the patients with AS have the HLA-B27 gene. That means that the rest could miss the diagnosis if one would totally depend on HLA-b27 for a diagnosis.
The converse of this is also interesting. Only 1% of people with HLA-B27 develop the disease. So, HLA-B 27 alone cannot be equated with AS in somebody with backache.

Low back pain is a relatively common symptom that may be associated with a variety of conditions other than AS. The single most important feature that raises the suspicion of AS is inflammatory backache. The characteristics of inflammatory backache are –(1) morning stiffness of > 30 minutes, (2) improvement in back pain with exercise but not with rest, (3) awakening because of back pain during the second half of the night only, and (4) alternating buttock pain.

Role of MRI
MRI of the sacroiliac joints is one of the best investigations for a definitive & early diagnosis of AS. HLA-B27 is not diagnostic of AS, but can only guide us towards a diagnosis. MRI of the SI joints can give a definite diagnosis by actually showing the inflamed SI joints. Though, MRI is a costly, time-consuming investigation; its utility in confirming the diagnosis in a particular individual cannot be understated.

All in all, let us not diagnose AS with HLA-B27 alone. Definitive history of inflammatory backache/ other features & MRI of the sacroiliac joints can be the best guide for the diagnosis.

References:
1. Brown MA, Kennedy LG, MacGregor AJ, et al. Susceptibility to ankylosing spondylitis in twins: the role of genes, HLA, and the environment. Arthritis Rheum 1997; 40: 1823–28.
2. Feldtkeller E, Khan MA, van der Heijde D, van der Linden S, Braun J. Age at disease onset and diagnosis delay in HLA-B27negative vs. positive patients with Ankylosing spondylitis. Rheumatol Int 2003; 23:61–6.
3. Blum U, Buitrago-Tellez C, Mundinger A, et al. Magnetic resonance imaging (MRI) for detection of active sacroiliitis – a prospective study comparing conventional radiography, scintigraphy, and contrast enhanced MRI. J Rheumatol 1996; 23:2107–2115.

However, if we look at the scientific literature & data, there is no consensus on the existence of this association. Nor is there any scientific explanation for this possible association. The scientific community has been trying to explore this association for a long time now.

In 1961, a famous arthritis specialist, J. Hollander M.D., conducted a study in which he built a climate chamber and demonstrated that high humidity combined with low barometric pressure were associated with increased joint pain and stiffness.

Gorin AA & colleagues studied 75 RA patients who recorded their pain for 75 consecutive days. The recordings were then correlated with objective weather indices including temperature, barometric pressure, relative humidity, and percentage of sunlight for those days. Pain levels were highest on cold, overcast days and following days with high barometric pressure & humidity. Some patients were more weather sensitive than the others.

Strusber I & Aikman H studied the effect independently & found that low temperature, high atmospheric pressure, and high humidity did correlate with joint pain & stiffness in RA.

Wiebe R. Patberg studied all the studies published between 1985 to April 2003 & found that temperature and humidity do appear to have clear influences on the symptoms of RA. He concluded that the classic opinion that “Cold and wet is bad, warm and dry is good for RA patients,” seems to be true only as far as humidity is concerned.

How humidity affects the arthritic pain is difficult to understand. The skin is impervious to the moisture & most people remain indoors during the rains. A warm shower does not generally increase the joint pain/ stiffness. The incidence of RA is not different in dry & rainy locations around the globe & not all patients who move to drier areas experience remission.

Theories have been proposed to explain the effect of the drop in air pressure. The drop in barometric pressure that accompanies cold, rainy weather allows tissues in the body to expand to fill up the space. The inflamed synovium is hypothesized to swell & cause more pain. Another explanation is that damp & cold weather causes the muscles to shiver to maintain body temperature thereby producing traction on the joints causing pain.

Other Investigators have not found any significant association between weather & joint pain. They feel the association is ‘all in the head’. Reasons cited include a drop in the pain threshold during the rains. Even amputees have been found to have an increase in the phantom limb pain during the rains. Other factors that may affect the pain include the mood changes with rainy/ cold season & the fact that such weather forces RAers to remain indoors & hence increase the pain & stiffness.

So then, what is the bottom line?
Weather, especially rainy & cold weather does seem to increase the joint pain & stiffness in RAers. This may not be true for every RAer; but does happen in many RAers.

References:
The association between external weather conditions and pain and stiffness in women with rheumatoid arthritis. Drane D, Berry G, Bieri D, McFarlane AC, Brooks P. J Rheumatol. 1997 Jul;24(7):1309-16.

Rheumatoid arthritis patients show weather sensitivity in daily life, but the relationship is not clinically significant. Gorin AA & colleagues. Pain. 1999 May;81(1-2):173-7.

Influence of weather conditions on rheumatic pain. Strusberg I, Mendelberg RC, Serra HA, Strusberg AM. J Rheumatol. 2002 Feb;29(2):335-8.

The association between arthritis and weather. Aikman H Int J Biometeorol. 1997 Jun;40(4):192-9.

Weather Effects in Rheumatoid Arthritis: From Controversy to Consensus. A Review W R. Patberg, J J Rasker J Rheumatol 2004;31:1327-34

However, how early is early enough?

We are very much interested in knowing how early we should be treating RA with DMARDs for the best results. This period is the ‘window of opportunity’. Once missed, the prognosis would change drastically. Initially, this was thought to be 2 years from the onset of symptoms. Later, it was thought that diagnosis & treatment with DMARDs within 6 months from the onset of symptoms should be good enough to take care of the disease.

Michel PM van der Linden studied this ‘window of opportunity’ at the Leiden Early Arthritis Clinic. His group studied 1674 patients with RA over a period of 6 years for the level of improvement with DMARDs & joint destruction. They found that contrary to popular belief, 6 months is too long a period to be considered as the window of opportunity. 12 weeks was found to be the critical period. A delay of more than 12 weeks would mean a lesser chance of achieving a drug free remission & 1.3 times higher risk of joint destruction in the long run. What was very striking was the fact that the effect of the delay could not be nullified by a more potent medication strategy later. Treatment started in this phase had the best chance of inducing remission & reset the disease. The effect was seen for anti CCP positive as well as negative patients.

What this means is that any delay of more than 3 months form the onset of symptoms to the start of DMARDs would mean poor outcome in the long run. Where can this delay occur?
1) Patients taking time to seek help.
2) Time taken at the Family physicians level in diagnosing & referring patients to a Rheumatologists.
3) Time taken at the Rheumatologist level in getting an appointment.

The average delay in UK, Canada & the Netherlands was found to be 23 weeks, 17 weeks & 18.4 weeks respectively. A survey in the UK found that delay at the patient level was the main cause of delay. Hence, an earnest request from my side to anybody suffering from joint pain – please seek a Rheumatologist’s help at the earliest. You can take this quiz to know if you have early arthritis. Please do not underestimate any joint pain or swelling as a part of ageing or as rheumatism that would settle on its own. Seek an expert help & that could mean a whole new life for you in the long run!

References:
1)van der Linden, M. P. M., le Cessie, S., Raza, K., van der Woude, D., Knevel, R., Huizinga, T. W. J. and van der Helm-van Mil, A. H. M. (2010), Long-term impact of delay in assessment of patients with early arthritis. Arthritis & Rheumatism, 62: 3537–3546. doi: 10.1002/art.27692
2)Bykerk, V. and Emery, P. (2010), Delay in receiving rheumatology care leads to long-term harm. Arthritis & Rheumatism, 62: 3519–3521. doi: 10.1002/art.27691
3)Kumar K et al Delay in presentation to Primary care physician is the main reason why patients with Rheumatoid arthritis are seen late by Rheumatologists. Rheumatology (oxford) 2007;46:1438-40
4)Feldman DE et al Rapidity of rheumatology consultation for people in an early inflammatory arthritis cohort. Ann Rheum Dis 2009;68:1790-1.

Mark Bartold, a periodontist and the director of the Colgate Dental Research Centre at the University of Adelaide recently presented his group’s study of mice with preexisting periodontitis & RA at the annual European Congress of Rheumatology. His experiments showed that mice with coexisting periodontitis and RA exhibited more severe joint inflammation than did the mice with just RA. The progress of RA in mice with both conditions followed a more rapid course than it did in mice with just RA or just periodontitis.

What is periodontal disease? The word periodontal literally means ‘around the teeth’. Periodontal disease means infection involving the tissues around the teeth i.e. gums & bone around the teeth. Bacteria in the plaque cause infection of the gums. The bacteria settle down in the space between the tooth & the gum forming a pocket & even destroy the underlying bone.

Recent studies & research has shown that the bacteria involved in the periodontal infection can give rise to anti CCP antibodies & may trigger/ worsen rheumatoid arthritis. Mark Bartold’s work on mice is just one of the studies. Those with gum disease have been found to have a 2.2-fold greater risk of RA than did the general population. Gersuk, V. H. & colleagues studied 6616 subjects from the Olmsted County, MN. They were assessed for periodontal disease, RA & anti CCP antibodies. The study clearly showed that mild to moderate periodontitis is a risk factor developing RA. Periodontitis & smoking were found to be associated with anti CCP antibodies.

So then, how would periodontal infection cause anti CCP antibodies or joint inflammation? Porphyromonas gingivalis is a bacterium associated with a dental infection known as periodontitis. This bacterium produces an enzyme called Peptidyl arginine deiminase (PAD). It is hypothesized that this enzyme produced by the bacteria in the oral cavity diffuses into the blood & reaches the joints. It acts on various proteins & citrullinates them. Once in the joints, it may lead to increased citrullination of proteins in the joint. The body recognizes these ‘citrullinated proteins’ as ‘non-self’ & launches an immune attack. Immune cells produce antibodies to these citrullinated proteins i.e. anti-CCP antibody.

Now, would that mean taking care of periodontal infection takes care of RA as well? Yes, indeed. That must have been the reason why Hippocrates & Benjamin Rush stated that taking care of dental infections cures rheumatism. The ameliorating effect of minocycline on RA could be due to its antibacterial effect on the dental bacteria.

Dr. Nabil F. Bissada carried out an elegant study in RA patients on DMARDs & anti TNF biologics. A group of patients was treated for periodontal infection & was compared with the group that was not treated for the same. Non-surgical periodontal therapy was found to have a beneficial effect on the signs and symptoms of RA, regardless of the medications used to treat this condition.

Thus, if you have RA-
Brush your teeth and floss on a regular basis.
See a dental professional twice a year.
If gum disease develops, consult a Periodontist.
If you have a close relative with RA, oral hygiene & dental care is extremely important as dental infection may increase your risk of developing RA in future.

References:
1.Edward C Rosenhow J Dental Res 1919;1;205-265
2.Pre-existing periodontitis exacerbates experimental arthritis in a mouse model. Cantley D M, Haynes d R, marino V, P. Mark Bartold. Journal of Clinical Periodontology Volume 38, Issue 6, pages 532–541, June 2011
3.Molitor et al. Moderate to Severe Adult Periodontitis Increases Risk of Rheumatoid Arthritis in Non-Smokers and Is Associated with Elevated ACPA Titers: The ARIC Study” ACR 2009 abstract #1160
4.Periodontal Therapy Reduces the Severity of Active Rheumatoid Arthritis in Patients Treated With or Without Tumor Necrosis Factor Inhibitors. Bissada NF et al Journal of Periodontology. April 2009, Vol. 80, No. 4, Pages 535-540

I’m sure you would be quite curious to know how fish oils can reduce the joint inflammation in RA. Let us understand the mechanism of inflammation at the cellular level for the same. The cell membrane is made up of polyunsaturated fatty acids (PUFA) containing phospholipids. Inflammatory chemicals are generated from these PUFAs.

There are two major types of PUFAs; omega -6 PUFA & the omega -3 PUFA. The omega-6 PUFA related arachidonic acid is the major substrate for inflammatory chemicals. This arachidonic acid is converted by cox-2 enzyme into the inflammatory chemicals. Cox-2 blocker medicines like celecoxib/ rofecoxib reduce inflammation by blocking this enzyme.

The other PUFA present in the cell membrane is the omega -3 PUFA Eicosapentaenoic Acid (similar to arachidonic acid of omega -6 PUFA). This is again converted by cox-2 enzyme into inflammatory chemicals. However, these are not as potent as the arachidonic acid related chemicals. In fact, some of the chemicals generated have anti-inflammatory effects.

Thus, if one can replace the omega -6 Arachidonic Acid from the cell membrane by the omega -3 Eicosapentaenoic Acid; this may actually help reduce inflammation in the joints. This can be achieved by increasing the omega -3 PUFAs in the diet.

Fish oil is derived form cold water fish like mackerel, salmon, tuna, herring, halibut, cod & contains long chain omega -3 PUFAs. When taken orally, it does replace omega -6 Arachidonic Acid from the cell membrane. Multiple studies in RA patients have shown decreased generation of inflammatory cytokines with oral fish oils. Most of the studies have shown beneficial effects of fish oils on joint inflammation in RA.

Precautions:
1. Fish oils cannot replace DMARDs. They can only be used as a supplement.
2. Look for fish oil brands that do not contain mercury.
3. Fish oils may increase the risk of bleeding when taken with blood thinner medications.
4. Please discuss your prescription with your Rheumatologist before starting fish oils.

References:
1. Effects of high-dose fish oil on rheumatoid arthritis after stopping nonsteroidal antiinflammatory drugs. Clinical and immune correlates. Arthritis Rheum. 1995 Aug;38(8):1107-14. Kremer JM, Lawrence DA & colleagues
2. Polyunsaturated Fatty Acids and Inflammation: Therapeutic Potential inRheumatoid Arthritis. Philip C. Calder Current Rheumatology Reviews, 2009, 5, 214-225
3. Long-chain polyunsaturated fatty acids and inflammation. Philip C. Calder Scandinavian Journal of Food and Nutrition 2006; 50 (S2): 54 _61

HLA B27 stands for Human Leukocyte Antigen 27. The HLAB 27 gene produces the HLA B27 molecule, which belongs to the family of MHC class I molecules. The function of this family of molecules is to present antigenic peptides to the T cells.

Let us understand this process of antigen presentation further. Whenever a pathogen (bacterium/ virus) enters the body, body’s immunity recognizes these as foreign. The next step is to inform the other immune cells about these pathogens & provide them with sufficient information about the pathogens. With this information, immune cells then launch an attack against these pathogens. This information about the pathogens consists of parts of the pathogen (called antigens) & is presented by the antigen presenting cells to the T cells. These parts are the signatures of these particular virus/ bacteria. The T cells can trace the location of these pathogens based on the signature antigens they have & launch an attack on them.

Now, let us focus on what happens inside these antigen presenting cells. The signature antigens are given final touches in a structure called proteosomes. The final antigens are carried to another structure called the Endoplasmic reticulum where they are mounted onto the MHC class I molecule. The MHC molecule folds & is then taken to the surface of the cell. This complex is presented to the T cells, which then recognize it & mount an attack on the pathogen. The T cells do not recognize the antigens in absence of the HLA molecule.

A few pathogens have antigens that are similar to proteins in our joints. When such pathogens (eg. Yersinia, Chlamydia) enter the body (generally the gut & cause loose motions), their antigens are picked up by the antigen presenting cells. It is hypothesized that HLA-B27 tends to pick up the particular antigens in the pathogen that are similar to the joint proteins & present them to the T cells. T cells recognize these as foreign & attack any structure with these proteins. The pathogen is definitely taken care of; but as I said, T cells also start considering our joints as foreign & attack them as well. This is precisely what happens in reactive arthritis (ankylosing spondylitis & reactive arthritis belong to the same group of arthritis). In reactive arthritis, one has loose motions followed by joint inflammation. This is called the ‘Arthritogenic peptide hypothesis’

There is an alternative hypothesis to explain the cause of joint inflammation. This is called the HLA-B27 folding hypothesis. The difference between HLA-B27 & the other HLA molecules is that B27 has a slower rate of folding & is prone to misfolding. When this happens on a large scale, the endoplasmic reticulum malfunctions & triggers generation of cytokines (TNF-α, IL-1, IL-6). These cytokines attack the joint & cause inflammation. This sequence of events has been shown in cells of the synovial fluid in patients.

This is how the HLA-B27 positivity; in the presence of infections/ environmental factors translates into inflammation of the joints (spine & other joints) & ultimately manifests as ankylosing spondilytis/ reactive arthritis.

References:
Mear JP, Schreiber KL, Munz C, Zhu X, Stevanovic S, Rammensee HG, et al: Misfolding of HLA-B27 as a result of its B pocket suggests a novel mechanism for its role in susceptibility to spondyloarthropathies. J Immunol 163:6665–6670, 1999

Smith JA, Märker-Hermann E, Colbert RA: Pathogenesis of Ankylosing spondylitis: current concepts. Best Pract Res Clin Rheumatol 20:571–591, 2006

Turner MJ, Sowders DP, DeLay ML, Mohapatra R, Bai S, Smith JA, et al: HLA-B27 misfolding in transgenic rats is associated with activation of the unfolded protein response. J Immunol 175: 2438–2448, 2005

Robert A., Monica L., Erin I.: From HLA-B27 to spondyloarthritis: a journey through the ER Immunol Rev. 2010 January ; 233(1): 181–202

Benjamin R, Parham P. Guilt by association: HLA-B27 and ankylosing spondylitis. Immunol Today 1990: 11: 137–42.

However; Ankylosing spondylitis, somehow, has always been a bit ignored as compared to Rheumatoid Arthritis (RA). It is has been that ‘poor cousin’ of RA. If you look at the number of research papers in a year, one would realize that AS attracts much less research than RA (about 2500 research papers on RA as compared to about 500 on AS in the year 2010- source pubmed). The number of DMARDs available for AS is much lesser than RA. We have clear-cut treatment strategies (for eg. Early DMARDs, tight inflammation control) in RA; however, due to relative lack of studies, such strategies are missing in AS.

Even on the patient/ health care social media (hcsm) front, there are very few AS blogs as compared to RA blogs.

This is a humble effort from my side to bridge this gap & empower the Ankies (Those with Ankylosing spondylitis; just like RAers!) to take care of themselves.

We are in the age of organ transplant. Kidney transplant has become an established therapy for those with kidney failure. How about immunity transplant since RA is an immune dysfunction. This is precisely what led the scientists to try out stem cell therapy for RA.

Unlike kidney, the immune system is not a solid organ that can be removed; hence chemotherapy is used to ablate the marrow (organ where the immune cells are generated). This is followed by infusion of stem cells. The stem cells give rise to a whole new immune system that does not attack the joints.

Geoff McColl first reported a successful stem cell therapy in a man with resistant RA in the October 1999 issue of Annals of Internal Medicine. A 39-year-old man with RA who had failed standard RA therapy was treated with stem cells from his identical twin brother. The results were dramatic & the patient could swim, ride a bicycle & was free of RA symptoms even after 2 years of the therapy.

Richard K. Burt also reported about a successful stem cell therapy in a lady with resistant RA in the August 2004 issue of Arthritis & Rheumatism. A 52-year-old lady with treatment resistant RA was treated with stem cells from her sister. She remained in remission even after 1 year of stem cell therapy. Her rheumatoid factor disappeared & so did the rheumatoid nodules. The joint inflammation & the morning stiffness settled & the ESR normalized.

However, this is easier said than done. These stories sound fabulous. Studies were taken up to study this therapy further. A study from Netherlands included 14 RA patients. Of the 12 who completed the study, 8 patients improved significantly within one year of therapy. 4 patients failed to respond & those who had responded relapsed & required reinstitution of DMARDs within 2 years of therapy. Snowden J & colleagues analysed the registry data of 76 patients who received the therapy in different studies. In most patients, disease-modifying anti-rheumatic drugs had to be reinstituted within 6 months for persistent or recurrent disease activity.

Zhang-Huo li and a team of researchers from Peking university People’s Hospital have come with a new approach recently. They studied the umbilical cord mesenchymal stem cells. They found that these cells can suppress the inflammatory effects of RA related fibroblast-like synoviocytes and T cells in cultures. They also showed promising results in animal models of inflammatory arthritis.

All in all, stem cell therapy for RA is in a developing phase. We will have to wait for further studies with different medications/ designs for a definitive take on this approach.

References:
High-Dose Chemotherapy and Syngeneic Hemopoietic Stem-Cell Transplantation for Severe, Seronegative Rheumatoid Arthritis Geoff McColl et al October 5, 1999 131(7) 507-509

Verburg RJ, Kruize AA, van den Hoogen FH, et al. High-dose chemotherapy and autologous hematopoietic stem cell transplantation in patients with rheumatoid arthritis: results of an open study to assess feasibility, safety, and efficacy. Arthritis Rheum. 2001;44:754-760.

Snowden J, Moore J, Passweg JR, et al. Autologous stem cell transplantation in rheumatoid arthritis. Blood. 2001;98:860a.

Therapeutic potential of human umbilical cord mesenchymal stem cells in the treatment of rheumatoid arthritis. Liu Y et al Arthritis Res Ther. 2010;12(6):R210

Attention was first drawn to Methotrexate related liver side effects in the late 1960s, when isolated cases of Methotrexate induced liver toxicity in psoriasis patients were reported. Studies conducted to look into this matter showed that psoriasis patients on Methotrexate indeed have varying degrees of liver fibrosis.

The next logical step from the scientific community was to confirm whether Methotrexate was responsible for the liver fibrosis. Liver fibrosis can be only be confirmed by a liver biopsy. Hence, studies were conducted with a liver biopsy before & after starting Methotrexate to confirm the cause & effect relationship. A few facts emerged from these studies – 1) many psoriasis patients (as many as 50%) had liver fibrosis even before starting Methotrexate; alcohol being the main causative factor. 2) methotrexate was given on a daily basis in those days & this was found to increase the chances of liver toxicity four fold as compared to weekly doses. 3) Risk factors contributing to liver toxicity were identified as alcohol consumption, diabetes, obesity & preexisting liver disease. 4) No consensus was reached regarding Methotrexate as the cause of liver fibrosis since different studies came up with contrasting results.

Similar studies were conducted in Rheumatoid arthritis (RA) patients. These studies revealed that- 1) Liver fibrosis (baseline biopsies) is much less common in RA patients as compared to those with psoriasis. 2) Liver toxicity with Methotrexate is much less common in RA as compared to psoriasis. 3) Folate & hydroxychloroquine reduce the risk of Methotrexate induced liver side effects. 4) A few studies showed that Methotrexate induced liver fibrosis/ cirrhosis occurred only in the presence of other risk factors mentioned above. Alcohol was the main risk factor.

Thus, these studies added three main safety features to Methotrexate therapy: Weekly doses (in contrast to daily Methotrexate in the past), folate supplementation & avoiding alcohol. They also cleared the air about severe liver toxicity with Methotrexate.

Pincus & colleagues studied 248 RA patients treated with Methotrexate over 13 years. This amounted to 1007 person years (Person years is the product of the number of years times the number of members. 1007 would mean approximately 100 patients taking methotrextae for 10 years.) of Methotrexate exposure. The incidence of severe liver enzyme abnormalities was only 0.9 per 100 years. A similar study by Kramer & colleagues showed that severe ALT elevation was found in 6% & did not require withdrawal of Methotrexate. Paget & colleagues found a rate of 3.4% abnormal liver function tests in 182 patients. Salliot C & colleagues studied 88 available studies of Methotrexate in RA & concluded that transient elevation of liver enzymes with Methotrexate is seen in about 20.2% patients. This number definitely looks bigger but it is worthwhile to note that folate was not given to patients in many of the included studies.

Walker A M & colleagues also studied methotrexate liver toxicity & found that severe liver toxicity is rare. The study concluded that on an average, one case of serious liver disease is seen per 1000 patients treated for 5 years.

The incidence of liver enzyme abnormalities observed with methotrexate are much lower than that listed for Rofecoxib, celecoxib & other NSAIDs. Pincus & colleagues thus concluded that low dose weekly Methotrexate with folate supplementation is safe (probably even safer than the NSAIDs). In fact, the side effects of untreated RA are substantially greater than the observed side effects of Methotrexate.

Thus, Methotrexate does have the potential to affect the liver; however, with weekly doses, folate supplementation the risk is substantially reduced. Regular clinical monitoring, & that of liver enzyme make it a safe drug to use. Side effects of untreated RA are many times bigger that the liver toxicity risk associated with Methotrexate.

References:
· Y Yazici, T Sokka, H Kautiainen, C Swearingen, I Kulman, T Pincus Long term safety of methotrexate in routine clinical Care : discontinuation is unusual and rarely the result of laboratory abnormalities. Annals of Rheumatic Disease 2005;64:207-211

· Yazici Y, Erkan D, Paget SA. Monitoring methotrexate hepatic toxicity in rheumatoid arthritis: is it time to update the guidelines? Journal of Rheumatol 2002;29:1586–9.

· Bridges SL, Alarcon GS, Koopman WJ. Methotrexate-induced liver abnormalities in rheumatoid arthritis. Journal of Rheumatol 1989;16:1180–3.

· Shergy WJ, Polisson RP, Caldwell DS, Rice JR, Pisetsky DS, Allen NB. Methotrexate-associated hepatotoxicity: retrospective analysis of 210 patients with rheumatoid arthritis. American Journal of Medicine 1988;85:771–4.

· Cartwright VW, Michaud K, Choi HK, Wolfe F. Methotrexate, laboratory testing and risk of serious illness: analyses in 20 000 patients. Arthritis Rheumatism 2003;48:S428.

· C Salliot, D Van der Heijde Long-term safety of methotrexate monotherapy in patients with rheumatoid arthritis: a systematic literature research Annals Rheumatic Diseases 2009;68:1100-1104

· Walker Am, Funch D, Dreyer NA et al. Determinants of serious liver disease among patients receiving low-dose methotrexate for Rheumatoid Arthritis. Arthritis Rheumatism 1987; 36:186-95.