Clinical profile and management with immunosuppressants and biologics in Behcet’s uveitis: A cohort of 25 patients from a tertiary eye care center in South India

Purpose: To report the clinical profile of Behcet’s disease and its management with immunosuppressants and biologics in a cohort of 25 patients from a tertiary eye care center in South India. Methods: This was a retrospective, observational study. Records of 45 eyes of 25 patients between January 2016 and December 2021 were retrieved from the hospital database. Complete ophthalmic evaluation and systemic examination by the rheumatologist with appropriate investigations had been done. Results were analyzed using Statistical Package for the Social Sciences (SPSS) software. Results: Males (19, 76%) were found to be more affected than females (6, 24%). Mean age of presentation was 27.68 ± 11.08 years. Twenty patients had bilateral involvement (80%), and unilateral involvement was seen in five patients (20%). Seven eyes of four patients (16%) had isolated anterior uveitis, out of which one patient had unilateral and three patients had bilateral involvement. Twenty?six eyes of 16 patients (64%) had posterior uveitis, out of which six patients had unilateral and 10 had bilateral involvement. Twelve eyes of seven patients (28%) had panuveitis, out of which two patients had unilateral and five had bilateral involvement. Hypopyon was seen in five eyes (11.1%) and posterior synechiae in seven eyes (15.55%). Posterior segment findings included vitritis (24.44%), vasculitis (17.78%), retinitis (17.78%), disc hyperemia (11.11%), and disc pallor (8.89%). Steroids alone were given in five patients (20%) and intravenous methylprednisolone (IVMP) was given in four patients (16%). Immunosuppressive agents along with steroids were given in 20 patients (80%), of which azathioprine alone was given in seven patients (28%), cyclosporin alone was given in two patients (8%), mycophenolate mofetil alone was given in three patients (12%), combination of azathioprine and cyclosporin was given in six patients (24%), and combination of methotrexate and mycophenolate mofetil was given in one patient (4%). Biologics were given in 10 patients (40%) – adalimumab in seven patients (28%) and infliximab in three patients (12%). Conclusion: Behcet’s disease is an uncommon uveitis in India. Addition of immunosuppressants and biologics to conventional steroid therapy gives better visual outcomes.

Coriorretinopatia de Birdshot: relato de caso e perspectivas sobre o tratamento / Birdshot chorioretinopathy: a case report and perspectives on its treatment

RESUMO A coriorretinopatia de Birdshot é uma uveíte posterior bilateral crônica rara que acomete, preferencialmente, mulheres de meia-idade. O quadro clínico é composto de pouco ou nenhum processo inflamatório de segmento anterior, associado a vitreíte e lesões coriorretinianas ovoides branco-amareladas de característica hiperfluorescente na angiofluoresceinografia e hipofluorescente na angiografia com indocianina verde. O tratamento se dá por meio de corticoides e outras drogas imunossupressoras. Todavia, em alguns casos, a doença é refratária a tal terapêutica, sendo necessário lançar mão de outras drogas, como os agentes biológicos. O presente artigo busca relatar um caso de coriorretinopatia de Birdshot em ajuste de terapia imunossupressora que evoluiu com má resposta às drogas iniciais e bom controle após uso de imunobiológico e discutir as opções terapêuticas disponíveis atualmente.

ABSTRACT Birdshot chorioretinopathy is a rare chronic bilateral posterior uveitis that preferentially affects middle-aged women. The clinical picture is composed of little or no anterior segment inflammatory process, associated with vitritis and yellowish-white ovoid chorioretinal lesions with hyperfluorescent characteristics on fluorescein angiography and hypofluorescent characteristics on green indocyanine green angiography. Treatment is with corticosteroids and other immunosuppressive drugs. However, in some cases, the disease is refractory to such therapy, making it necessary to resort to other drugs such as biological agents. The present article seeks to report a case of Birdshot chorioretinopathy in an adjustment of immunosuppressive therapy that evolved with poor response to the initial drugs and good control after the use of immunobiologicals and discuss the currently available therapeutic options.

Morphological characterization of subretinal hyper-reflective material in posterior uveitis using swept-source optical coherence tomography and optical coherence tomography angiography

Purpose: To analyze the structural features of subretinal hyper-reflective material (SHRM) in posterior uveitis using swept-source optical coherence tomography (SS-OCT) and optical coherence tomography angiography (SS-OCTA). Methods: In this observational study, subjects with quiescent posterior uveitis and the presence of SHRM on SS-OCT were subjected to SS-OCTA to identify the presence of an intrinsic choroidal neovascular (CNV) network. OCT features were compared for SHRM harboring CNV (vascular SHRM) with those without CNV network (avascular SHRM) to identify clinical signs pointing toward the presence of CNVM inside SHRM. Results: Forty-two eyes of 33 subjects (18 males; mean age: 29.52 ± 12.56 years) were evaluated. Two-thirds (28/42) of eyes having SHRM on SS-OCT harbored intrinsic neovascular network (vascular SHRM). Increased reflectivity of SHRM (P < 0.001) and increased transmission of OCT signal underlying SHRM (P = 0.03) were suggestive of the absence of CNVM. The presence of intra/subretinal fluid (P = 0.08) and pitchfork sign (P = 0.017) were important markers of vascular SHRM. Conclusion: SHRM is an important OCT finding in eyes with posterior uveitis. Meticulous assessment of SHRM characteristics on SS-OCT can aid in identifying the underlying intrinsic neovascular network.

Long-term efficacy of dexamethasone intravitreal implant in the treatment of Vogt-Koyanagi-Harada disease relapsing posterior uveitis

Purpose: To investigate the efficacy and safety of dexamethasone intravitreal implant in the treatment of relapsing posterior uveitis in patients with chronic recurrent Vogt–Koyanagi–Harada (VKH) disease. Methods: This was a prospective study of 29 eyes of 16 patients with posterior uveitis in chronic recurrent VKH disease. All patients received previous systemic steroid and immunosuppressive regimens. All patients underwent a comprehensive ophthalmic examination, including best?corrected visual acuity (BCVA), Indocyanine green angiography (ICGA), fundus fluorescein angiography (FFA), and spectral?domain optical coherence tomography (SD?OCT). All patients underwent intravitreal injection with sustained?release dexamethasone 0.7 mg implant (Ozurdex®). Primary outcome measures included mean change in BCVA and central foveal thickness (CFT) at 24 months of follow?up compared to the baseline. Results: At 24 month of follow?up, the mean BCVA improved from 0.82 ± 0.13 to 0.38 ± 0.06 logMAR (P < 0.0001). The mean CFT reduced from 505 ± 29 to 244 ± 23 um (P < 0.0001). The mean intraocular pressure (IOP) changed from 15.1 ± 2.2 to 16.9 ± 3.1 mmHg with no significant value (P?value = 0.0955). Twenty?one eyes (72.4%) received one injection, whereas eight eyes (27.6%) required two injections. The mean number of injections was 1.2 ± 0.60. The mean follow?up time was 24.75 ± 0.9 months. No serious ocular or systemic adverse events were noted during the follow?up period. Ocular hypertension was recorded in three (10.3%) eyes and controlled by IOP lowering medications. Cataract progression occurred in 11 (37.9%) eyes. Conclusion: Our cohort highlights the beneficial effects of the dexamethasone implant of 0.7 mg in the treatment of VKH disease relapsing posterior uveitis improving visual acuity, reducing macular edema, and minimizing the burden of systemic steroids in this sample study

Pattern of uveitis from a tertiary eye care center in Himalayan belt of North India

Purpose: To study the clinical characteristics of uveitis in patients presenting to a tertiary care institute in the northern part of India, predominantly serving the population of Himalayan belt. Methods: In this retrospective descriptive case series, data of 141 eyes of 102 patients diagnosed between January 2019 and January 2021 were analyzed. Patients were diagnosed, named, and meshed as per the Standardization of Uveitis Nomenclature. A panel of investigations (systemic and ocular ancillary investigations) were done, which was individualized according to the clinical picture. Results: The mean age of presentation was 39.1 ± 14.62 years. A male predominance (62.7%) was noted. Unilateral presentation was seen in 61.8% of patients. Specific etiological diagnosis was not reached in 56.7% of cases. The incidence of infectious and noninfectious uveitis was 23.4% and 19.9%, respectively. The frequency of anterior, intermediate, posterior, and panuveitis was 23.4%, 11.3%, 46.8%, and 18.5%, respectively. Posterior uveitis was the most frequent anatomical location (46.8%). Tuberculous uveitis was the most common definitive etiology irrespective of location (18.5%). Anterior, intermediate, and posterior uveitis were more frequently idiopathic in origin. Sympathetic ophthalmitis was the most common cause for panuveitis. Conclusion: Uveitis significantly affected the working age group population. Despite the evolution of diagnostic investigations, etiology remained unknown in many cases of uveitis. Infectious etiology was more common. Posterior uveitis as the most frequent anatomical location in our study may be attributed to the tertiary care referral bias.

Multiple evanescent white dot syndrome following SARS-CoV-2 infection - A case report

To report a case of MEWDS post-COVID-19 infection with multimodal imaging. A 17-year-old boy reported blurring of vision in both eyes 2 months and 10 days following the SARS-CoV-2 infection. Fundus examination revealed hypopigmented lesions nasal to the optic disc, inferior periphery, and near macula in both eyes. Multimodal imaging was consistent with MEWDS. A complete systemic workup was performed to exclude infectious etiology. Fundus lesions resolved with a course of oral corticosteroids and was confirmed on multimodal imaging.

Vogt-Koyanagi-Harada disease. Case report and review of the literature / Enfermedad de Vogt Koyanagi Harada. Reporte de un caso y revisión de la literatura

ABSTRACT Vogt Koyanagi Harada disease affects several parts of the body, such as eyes, meninges, ears, and skin. The progressive course of the disease can lead to blindness and deafness. The case is presented of a Hispanic woman (mixed-race) with visual alterations, headache, tinnitus, hearing loss, and posterior uveitis with serous detachments of the retina in both eyes, as well as lymphocytic meningitis. The aim of the present study is to review the literature, the diagnostic strategies, and the appropriate treatment, as well as to update the immunogenetic pathogenesis of the disease.

RESUMEN La enfermedad de Vogt Koyanagi Harada compromete múltiples órganos tales como ojos, meninges, oídos y piel. El curso progresivo de la enfermedad puede llevar a ceguera y cofosis. Se describe un caso de esta enfermedad en mujer hispana (mestiza) con alteraciones visuales, cefalalgia, tinnitus e hipoacusia a quien se le encuentra uveítis posterior con desprendimientos serosos de retina en ambos ojos y meningitis linfocitaria. El objetivo del presente estudio es, mediante una revisión de la literatura, actualizar la patogénesis inmunogenética, conocer las estrategias diagnósticas y el tratamiento apropiado.

Active uveitis induces transient refractive error changes / 国际眼科杂志(Guoji Yanke Zazhi)

@#AIM: To evaluate the impact of active uveitis on refractive error changes.<p>METHODS: A prospective cohort study was conducted on 66 patients(88 eyes)with active uveitis. The subjects were classified based on the anatomical location of their disease activity as anterior, intermediate, posterior and pan-uveitis. Cycloplegic refraction was performed in both active and quiescent phases, and the results were compared. <p>RESULTS: Spherical changes in active anterior non-granulomatous uveitis resulted in an average of -0.25(0.77)D(95%<i> CI</i>: -0.5 to 0)shift toward myopia(<i>P</i>=0.039)and in active intermediate uveitis, an average of +0.39(0.8)D(95% <i>CI</i>: 0.09-0.69)shift toward hyperopia(<i>P</i>=0.003). Spherical equivalent changes in active intermediate uveitis resulted in hyperopic shift \〖+0.43(0.94)D, 95% <i>CI</i>: 0.08-0.79, <i>P</i>=0.005\〗. Cylinder had only significant changes in pan-uveitis \〖-0.3(0.39)D, 95% <i>CI</i>: -0.58 to -0.02, <i>P</i>=0.043\〗. In multivariate analysis, we noted that course of disease activity(acute versus recurrent)and anatomical location of disease activity had statistically significant effects on spherical equivalent changes(<i>P</i>=0.003 and <i>P</i>=0.004, respectively).<p>CONCLUSION: Active uveitis has a significant effect on the refractive status of the eye, the changes of which depend on the inflamed anatomical area.

A Case of Spontaneous Closure of Macular Hole in Infectious Posterior Uveitis Involving the Fovea

PURPOSE: To report a case of macular hole secondary to presumptive infectious posterior uveitis involving the fovea that spontaneously resolved after medical treatment. CASE SUMMARY: A 33-year-old male visited our clinic for decreased visual acuity in his left eye. He was treated with immunosuppressive therapy including steroid after bone marrow transplantation. Best corrected visual acuity (BCVA) was 0.05 in the left eye. Slit lamp examination showed mild anterior vitritis, and fundus examination showed a macular hole with surrounding whitish infiltration at the fovea. Spectral domain optical coherence tomography (SD-OCT) revealed a full thickness macular hole with surrounding hyper-reflective masses with an infiltration-like appearance involving all retinal layers. Serum anti-toxocara IgG was positive (ELISA), and eosinophil count and immunoglobulin E was elevated. Under diagnosis of presumptive ocular toxocariasis, the patient was treated with albendazole. After medical treatment for toxocariasis, the whitish foveal infiltration became smaller and more discrete. SD-OCT revealed spontaneous closure of the macular hole, and BCVA was improved to 0.4 after a 4-month follow-up. CONCLUSIONS: We report a macular hole complicated by presumptive infectious posterior uveitis that experienced spontaneous closure after medical treatment for underlying infection.

Indocyanine green angiography in posterior uveitis.

Literature review for indocyanine green angiography and evaluate the role of indocyanine green angiogram (ICGA) in patients with posterior uveitis seen at a tertiary referral eye care centre. Detailed review of the literature on ICGA was performed. Retrospective review of medical records of patients with posterior uveitis and dual fundus and ICGA was done after institutional board approval. Eighteen patients (26 eyes) had serpiginous choroiditis out of which 12 patients had active choroiditis and six patients had healed choroiditis, six patients (12 eyes) had ampiginous choroiditis, six patients (12 eyes) had acute multifocal posterior placoid pigment epitheliopathy, eight patients (10 eyes) had multifocal choroiditis, four patients (eight eyes) had presumed ocular histoplasmosis syndrome, four patients (eight eyes) had presumed tuberculous choroiditis, two patients (four eyes) had multiple evanescent white dot syndrome and two patients (four eyes) had Vogt Koyanagi Harada (VKH) syndrome. The most characteristic feature noted on ICGA was the presence of different patterns of hypofluorescent dark spots, which were present at different stages of the angiogram. ICGA provides the clinician with a powerful adjunctive tool in choroidal inflammatory disorders. It is not meant to replace already proven modalities such as the fluorescein angiography, but it can provide additional information that is useful in establishing a more definitive diagnosis in inflammatory chorioretinal diseases associated with multiple spots. It still needs to be determined if ICGA can prove to be a follow up parameter to evaluate disease progression.

Characteristics of fundus autofluorescence and fundus fluorescein angiography in syphilitic posterior uveitis / 中华实验眼科杂志

Background The fundus autofluorescence (FAF)can reflect the function of retinal pigment epithelium(RPE) cell.As an invasive examination,it has been extensive used in retina disease,but there has not any report in syphilitic posterior uveitis.Objective This study was to characterize and contrast the FAF and fundus fluorescein angiography (FFA),indocyanine green angiography (ICGA) findings in patients with syphilitic posterior uveitis.Methods A retrospective series of cases observational study was designed.The clinical data of 27 eyes from 18 patients with syphilitic posterior uveitis were included in Shanghai First People's Hospital from 2010 May to 2012 October,and all the patients were diagnosed by serologic and ophthalmic tests.The patients were assigned to acute stage group(with the course ＜2 months)and chronic stage group(with the course ≥ 2 months).FFA,ICGA and FAF were performed respectively on all the patients,and the examination results were compared and analyzed.Results In the affected eyes with syphilitic posterior uveitis,the FFA image showed a retinal vasculitis sign and mottle-like fluorescence appearance in posterior pole and equator zone,and some affected eyes exhibited edema of optic disc and macula.Hypoautofluorescence zone was seen in the acute stage group and cystoid macular edema was found in the chronic stage group.ICGA presented with a wider damage of RPE,especially in the later phase of ICGA.A confluent of hyperautofluorescence with hypoautofluorescence in the posterior fundus,punctiform hyperautofluorescence as well as hypoautofluorescence in papillitis and macular edema were found on the FAF image.Conclusions The pathological basis of syphilitic posterior uveitis is retinal vasculitis and papillitis.ICGA indicates the damage of choroid membranes and RPE,and FAF reflects a metabolism disorder of RPE in the acute stage and atrophy and loss of RPE in the chronic stage.FAF is helpful for the diagnosis of syphilitic posterior uveitis as an assistant index.

Current approach in the diagnosis and management of posterior uveitis.

Posterior uveitic entities are varied entities that are infective or non-infective in etiology. They can affect the adjacent structures such as the retina, vitreous, optic nerve head and retinal blood vessels. Thorough clinical evaluation gives a clue to the diagnosis while ancillary investigations and laboratory tests assist in confirming the diagnosis. Newer evolving techniques in the investigations and management have increased the diagnostic yield. In case of diagnostic dilemma, intraocular fluid evaluation for polymerase chain testing for the genome and antibody testing against the causative agent provide greater diagnostic ability.

Inflammatory choroidal neovascular membrane in posterior uveitis—pathogenesis and treatment.

Choroidal neovascular membrane (CNVM) formation is a well-documented sight-threatening complication of posterior segment intraocular inflammation (PSII). The aim of this article is to review the basic and clinical science literature on the pathogenesis of CNVM formation in PSII and to present results of a case series. We searched the literature using the mesh terms- inflammation, CNVM, age-related macular degeneration, immunosuppression, photodynamic therapy, steroids, vascular endothelial growth factors and posterior uveitis. Additionally, we evaluated the visual outcome of and clinical response to our standard treatment protocol involving a combination treatment for young patients with inflammatory CNVM. The development of CNVM in PSII is promulgated by infiltrating myeloid cells as well as choroidal and retinal myeloid cell activation, subsequent vascular endothelial growth factors, cytokine and chemokine production and complement activation acting in consort to mediate angiogenic responses. No clear standard of care currently exists for the treatment of inflammatory CNVM and various combinations have been tried. Using our combination treatment, visual acuity improved in four, stabilized in one and worsened in four patients. Though significant advances have occurred in the understanding of the pathogenesis and management of this condition, optimizing therapeutic regimens will require further well-constructed prospective cohort series.

Effects of Heme Oxygenase-1 Inducer and Inhibitor on Experimental Autoimmune Uveoretinitis

PURPOSE: Experimental autoimmune uveoretinitis (EAU) is an animal model of posterior uveitis and heme oxygenase-1 (HO-1) is a well-known anti-oxidant factor. However, there is no report a protective role of HO-1 on EAU in vivo. To verify that HO-1 is induced in EAU by interphotoreceptor retinoid-binding protein (IRBP), that an HO-1 inducers ameliorates the associated inflammation, and that an HO-1 inhibitor exacerbates this inflammation. METHODS: Forty four Lewis rats were given either 40 mol/kg hemin or 40 mol/kg SnPP (tin protoporphyrin IX) by intraperitoneal injection and twenty two uveitis control rats were injected with 0.5 mL of saline once daily 5-20 days after IRBP immunization inducing EAU. Three normal control rats were used for Western blotting and ELISA assay of HO-1. The clinical uveitis signs of inflammation were scored in the three groups from 0 to 4 on alternate three days. To confirm the clinical results, histological and immunohistochemical stain of HO-1 were performed on the day of peak inflammation and Western blotting and ELISA assay of HO-1 were performed on 6th, 12th and 18th day after IRBP immunization. RESULTS: Hemin, an inducer of HO-1, ameliorated the clinical signs of EAU. In contrast, SnPP-treated rats show that the severity of the clinical sign were exacerbated at the peak period of the disease. These results are roughly compatible with histological, immunoblotting, and immunohistochemical evaluations and an ELISA assay of HO-1. CONCLUSIONS: We suggest that HO-1 plays an important protective role in EAU.

Clinical Results of Pars Plana Vitrectomy on Posterior Segment Complications in Posterior Uveitis

PURPOSE: This study was undertaken to evaluate the clinical results of pars plana vitrectomy on posterior segment complications in posterior uveitis. METHODS: We reviewed the records of 20 eyes of 19 uveitis patients who were followed up for 6 months or more after vitrectomy. RESULTS: The mean follow-up period was 20 months. Final visual acuity improved in 10 eyes (50%), was maintained in 6 (30%), and decreased in 4 (20%). The mean improvement of vision was 1.6 lines (p=0.019). Detached retina was reattached in 8 (80%) among the 10 eyes with primary surgery. Postoperative complications were cataract (7 eyes), macular degeneration (2 eyes), retinal detachment (2 eyes), and recurrence (1 eye). CONCLUSIONS: These results suggest that pars plana vitrectomy may be a safe and effective treatment for posterior segment complications in posterior uveitis, but that early and complete vitrectomy should be considered for a better visual prognosis.

Prepapillary Vascular Loops Associated with Retinal Diseases

PURPOSE: Prepapillary vascular loops are blood vessels that project from the optic disc into the vitreous cavity and then return to the disc to continue their natural cource. Ninety percent are arterial in origin and usually congenital anomaly. We report four cases of prepapillary vascular loops associated with retinal and choroidal disorders. METHODS: Prepapillary vascular channel which showed twisted or ringlike appearance without leakage on fluorescein angiogram constituted the diagnosis. However, there may be a sector delay in filling of the optic disc or retina supplied by the loop due to the increased distance that blood must travel through the loop. RESULTS: These cases are not associated with vision-threatening diseases. The associated retinal diseases are diabetic retinopathy in one case, retinitis pigmentosa in one case, contralateral posterior uveitis in two cases. They are arterial loops. In two eyes were observed multiple prepapillary vascular loops. The vessels may appear as simple hairpin loops, spiral, or corkscrew configuration. In our cases, the presence of a cilioretinal artery and retinal artery obstruction could not be determined; other complication associated with prepapillary vascular loops were not observed. CONCLUSIONS: We assume that prepapillary vascular loops may occur acquiredly associated with other ocular diseases.

The rapeutic Effects of Low Dose Triple Agents Steroid, Cyclosporine and Azathiprineon Refractory Uveitis

Immunosuppressive agent has been used as a therapeutic agent for Endogeneous posterior uveitis[EPU]. But serious side effect of steriod or cyclosporine and frequent recurrence of ocular inflammation warrant the addition of other immunosuppressive agents. In this study, we evaluated the therapeutic effectiveness of low dose triple therapy using steroid, cyclosporine and azathioprine when combination therapy with steroid and cyclosporine had failed. We reviewed the records of 10 Behcet's patients[18 eyes]and 2 sympathetic ophthalmia patients[2 eyes]who had been resistant to steroid and cyclosporine combination therapy. The median follow up duration of triple therapy was 16.3 months. Recurrence, severity of inflammation, systemic manifestations associated with Behcet's disease, and side effect of therapeutic agents were evaluated. There was a significantly decrease in the frequency[0.37/month during pretriple therapy and 0.14/month after triple therapy]and severity of ocular inflammation[p<0.01]. The frequency and severity of systemic manifestations also decreased. Visual acuity remained stable in 7 eyes[35%]and improved in 13 eyes[65%]. No serious side effects or newly developed side effect were developed during triple therapy except reversible mild anemia in 1 patient. The results of our study suggest that triple agent immunosuppressive therapy is well tolerated and appears to be effective for the severe uveitis which is refraction to steroid and cyclosporine combination therapy.

Analysis of Typing in Patients with Uveitis in Korean Population

In order to evaluate association of particular HLA typing with certain uveitis in Korean population, HLA antigens were analyzed in 114 uneitis patients(acute anterior uveitis: 32 cases, Behcet`s disease: 25 cases, intermediate uveitis: 19 cases, Vogt-Koyanagi-Harada (V-K-H) syndrome: 10 cases, retinal vasculitis: 12 cases, Eale`s disease: 3 cases, posterior uveitis: 9 cases, pan.uveitis: 4 cases). The stronger association between acute anterior uveitis and HLA-B27 was statistically significant, and this result was similar to reports in other ethnic groups. Also, the association between V-K-H syndrome and HLA-DR4 showed same results. But the high frequency of HLA-DR7 in the patients with V-K-H syndrome was unque in patients of Korean popjlation and statistically significant. The association between HLA-A2 and posterior uveitis was high in patients of Korean population and statistically significant. Behcet`s disease was stronger association with HLA-B51 but not statistically significant and much weaker association than reports in Japanese group. Although many similarities of associations between particular uveitis and HLA typing were detected as compared with other ethnic groups, distinctive HLA associations were demonstrated in Korean population. Additional cases and long-term follow-up are required to confirm the association with HLA typing and the relationship with prognosis including clinical and laboratory variabilities.